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Mellors PW, Lange AN, Casino Remondo B, Shestov M, Planer JD, Peterson AR, Ying Y, Zhou S, Christie JD, Diamond JM, Cantu E, Basil MC, Gill S. Shared roles of immune and stromal cells in the pathogenesis of human bronchiolitis obliterans syndrome. JCI Insight 2025; 10:e176596. [PMID: 40232854 DOI: 10.1172/jci.insight.176596] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 04/11/2025] [Indexed: 04/17/2025] Open
Abstract
Bronchiolitis obliterans syndrome (BOS) is a progressive, fatal obstructive lung disease that occurs following lung transplant, where it is termed chronic lung allograft dysfunction BOS (CLAD-BOS), or as the primary manifestation of pulmonary chronic graft versus host disease (cGVHD-BOS) following allogeneic hematopoietic stem cell transplant. Disease pathogenesis is poorly understood; however, chronic alloreactivity is common to both conditions, suggesting a shared pathophysiology. We performed single-cell RNA-Seq (scRNA-Seq) on explanted human lungs from 4 patients with CLAD-BOS, 3 patients with cGVHD-BOS, and 3 deceased controls to identify cell types, genes, and pathways enriched in BOS to better understand disease mechanisms. In both forms of BOS, we found an expanded population of CD8+ tissue resident memory T cells (TRM), which was distinct to BOS compared with other chronic lung diseases. In addition, BOS samples expressed genes and pathways associated with macrophage chemotaxis and proliferation, including in nonimmune cell populations. We also identified dysfunctional stromal cells in BOS, characterized by pro- and antifibrotic gene programs. These data suggest substantial cellular and molecular overlap between CLAD- and cGVHD-BOS and, therefore, common pathways for possible therapeutic intervention.
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Affiliation(s)
- Patrick W Mellors
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania (Penn), Philadelphia, Pennsylvania, USA
- Center for Cellular Immunotherapies and
| | - Ana N Lange
- Department of Medicine, Perelman School of Medicine, Penn, Philadelphia, Pennsylvania, USA
- Penn-CHOP Lung Biology Institute and
- Penn Cardiovascular Institute, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | | | | | - Joseph D Planer
- Department of Medicine, Perelman School of Medicine, Penn, Philadelphia, Pennsylvania, USA
- Penn-CHOP Lung Biology Institute and
- Penn Cardiovascular Institute, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Andrew R Peterson
- Department of Medicine, Perelman School of Medicine, Penn, Philadelphia, Pennsylvania, USA
- Penn-CHOP Lung Biology Institute and
- Penn Cardiovascular Institute, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Yun Ying
- Department of Medicine, Perelman School of Medicine, Penn, Philadelphia, Pennsylvania, USA
- Penn-CHOP Lung Biology Institute and
- Penn Cardiovascular Institute, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Su Zhou
- Department of Medicine, Perelman School of Medicine, Penn, Philadelphia, Pennsylvania, USA
- Penn-CHOP Lung Biology Institute and
- Penn Cardiovascular Institute, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Jason D Christie
- Department of Medicine, Perelman School of Medicine, Penn, Philadelphia, Pennsylvania, USA
- Penn-CHOP Lung Biology Institute and
| | - Joshua M Diamond
- Department of Medicine, Perelman School of Medicine, Penn, Philadelphia, Pennsylvania, USA
- Penn-CHOP Lung Biology Institute and
| | - Edward Cantu
- Penn-CHOP Lung Biology Institute and
- Department of Surgery, Perelman School of Medicine, Penn, Philadelphia, Pennsylvania, USA
| | - Maria C Basil
- Department of Medicine, Perelman School of Medicine, Penn, Philadelphia, Pennsylvania, USA
- Penn-CHOP Lung Biology Institute and
- Penn Cardiovascular Institute, Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Saar Gill
- Division of Hematology/Oncology, Department of Medicine, University of Pennsylvania (Penn), Philadelphia, Pennsylvania, USA
- Center for Cellular Immunotherapies and
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Tan Y, Yang YG, Zhang X, Zhao L, Wang X, Liu W. Tumor cell-derived osteopontin promotes tumor fibrosis indirectly via tumor-associated macrophages. J Transl Med 2025; 23:432. [PMID: 40217301 PMCID: PMC11992893 DOI: 10.1186/s12967-025-06444-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Accepted: 03/28/2025] [Indexed: 04/14/2025] Open
Abstract
BACKGROUND High fibrosis of the tumor microenvironment (TME) not only impedes the effective infiltration of T cells but also serves as a physical barrier to inhibit the penetration of chemotherapy drugs. Triple-negative breast cancer (TNBC) is characterized by significant infiltration of tumor-associated macrophages (TAMs) and high fibrosis. However, the mechanism of high fibrosis in such tumors is still under debate. METHODS We first investigated the correlation between tumor-derived osteopontin (OPN) and tumor fibrosis as well as TAM enrichment using a tumor model characterized by OPN genetic inactivation or overexpression. We further compared the effects of macrophage depletion on tumor fibrosis in mice bearing TNBC tumors (4T1WT or 4T1Spp1 - KO). To elucidate the mechanism by which TAMs promote tumor fibrosis, we evaluated their potential to recruit cancer-associated fibroblasts (CAFs) through in vitro migration assays and compared the production of transforming growth factor-beta 1 (TGFβ1) among different TAM subpopulations. RESULTS Our study revealed that OPN secretion by tumor cells correlates positively with both tumor fibrosis and TAM enrichment. Specifically, within the enriched TAM population, Ly6C+CD206- TAMs recruit CAFs via CCL5 secretion, while Ly6C-CD206high TAMs secrete TGFβ1 to activate CAFs. Blocking the tumor cell-derived OPN can effectively prevent tumor fibrosis. CONCLUSIONS This study shows that tumor-derived OPN primarily drives TAM enrichment in mouse cancer model, indirectly promoting tumor fibrosis through Ly6C+CD206-/low and Ly6C-CD206high TAMs. Our findings have potential application in preventing tumors from excessive fibrosis and enhancing the efficacy of immunotherapy and chemotherapy.
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Affiliation(s)
- Yuying Tan
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
- Echocardiography Department, The First Hospital of Jilin University, Changchun, China
| | - Yong-Guang Yang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
- International Center of Future Science, Jilin University, Changchun, China
| | - Xiaoying Zhang
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Lei Zhao
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China
- National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China
| | - Xiaocong Wang
- Echocardiography Department, The First Hospital of Jilin University, Changchun, China.
| | - Wentao Liu
- Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin University, Changchun, China.
- National-local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, Changchun, China.
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Zhong Z, Gao Y, He C, Li W, Sang L, Huang Y, Chen X, Xie M, Zhang C, Yu Y, Zhu T, Sun J. Nintedanib improves bleomycin-induced pulmonary fibrosis by inhibiting the Clec7a/SPP1 pathway in interstitial macrophages. Cell Signal 2025; 128:111635. [PMID: 39892726 DOI: 10.1016/j.cellsig.2025.111635] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 01/17/2025] [Accepted: 01/29/2025] [Indexed: 02/04/2025]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a terminal lung disease with high mortality rate. Although Nintedanib (Nin) is an effective treatment for IPF, its precise mechanism of action remains unclear. In this study, we performed an integrated analysis of single-cell sequencing and RNA-seq data from lung tissues of both fibrotic and Nin-treated fibrotic mice to uncover new therapeutic mechanisms of Nin in IPF. Our results revealed an increase in interstitial macrophages following bleomycin (BLM) treatment. We used Monocle2, Cellchat, and in vivo experiments to demonstrate that Nin can inhibit Clec7a in interstitial macrophages, thereby suppressing the SPP1-mediated profibrotic pathway. Additionally, we utilized Scenic to predict transcription factors and identified NFκB as a major transcription factor in interstitial macrophages. In the in vitro experiments, we found that inhibiting Clec7a improved the secretion of SPP1 by M2 macrophages through the NFκB pathway. In subsequent in vivo experiments, we found that inhibiting of Clec7a improves pulmonary fibrosis through the NFκB/SPP1 pathway, and Nin alleviated BLM-induced pulmonary fibrosis by inhibiting Clec7a in interstitial macrophages. In summary, our study indicates that interstitial macrophages are upregulated in pulmonary fibrosis, and Nin reduces fibrosis by inhibiting Clec7a in interstitial macrophages, which in turn diminishes the NFκB /SPP1 pathway. These findings provided a new perspective on the mechanism of action of Nin in treating pulmonary fibrosis.
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Affiliation(s)
- Zuoquan Zhong
- Department of Pulmonary and Critical Care Medicine, Shaoxing People's Hospital, Shaoxing, China
| | - Yefei Gao
- Shaoxing People's Hospital, Shaoxing, China
| | - Chunxiao He
- Department of Pulmonary and Critical Care Medicine, Shaoxing People's Hospital, Shaoxing, China
| | - Weijie Li
- Department of Pulmonary and Critical Care Medicine, Shaoxing People's Hospital, Shaoxing, China
| | - Le Sang
- Department of Pulmonary and Critical Care Medicine, Shaoxing People's Hospital, Shaoxing, China
| | - Yunlei Huang
- Department of Pulmonary and Critical Care Medicine, Shaoxing People's Hospital, Shaoxing, China
| | - Xing Chen
- Department of Pulmonary and Critical Care Medicine, Shaoxing People's Hospital, Shaoxing, China
| | - Mengyao Xie
- Department of Pulmonary and Critical Care Medicine, Shaoxing People's Hospital, Shaoxing, China
| | - Chu Zhang
- Department of Thoracic Surgery, Shaoxing People's Hospital, Shaoxing, China
| | - Yuefang Yu
- Department of Pulmonary and Critical Care Medicine, Shaoxing People's Hospital, Shaoxing, China
| | - Ting Zhu
- Department of Thoracic Surgery, Shaoxing People's Hospital, Shaoxing, China.
| | - Jian Sun
- Department of Pulmonary and Critical Care Medicine, Shaoxing People's Hospital, Shaoxing, China.
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4
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Luo P, Gu Q, Wang J, Meng X, Zhao M. Developing an IPF Prognostic Model and Screening for Key Genes Based on Cold Exposure-Related Genes Using Bioinformatics Approaches. Biomedicines 2025; 13:690. [PMID: 40149666 PMCID: PMC11940207 DOI: 10.3390/biomedicines13030690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2025] [Revised: 03/05/2025] [Accepted: 03/08/2025] [Indexed: 03/29/2025] Open
Abstract
Background: Cold exposure has an impact on various respiratory diseases. However, its relationship with idiopathic pulmonary fibrosis (IPF) remains to be elucidated. In this study, bioinformatics methods were utilized to explore the potential link between cold exposure and IPF. Methods: Cold exposure-related genes (CERGs) were identified using RNA-Seq data from mice exposed to cold versus room temperature conditions, along with cross-species orthologous gene conversion. Consensus clustering analysis was performed based on the CERGs. A prognostic model was established using univariate and multivariate risk analyses, as well as Lasso-Cox analysis. Differential analysis, WGCNA, and Lasso-Cox methods were employed to screen for signature genes. Results: This study identified 151 CERGs. Clustering analysis based on these CERGs revealed that IPF patients could be divided into two subgroups with differing severity levels. Significant differences were observed between these two subgroups in terms of hypoxia score, EMT score, GAP score, immune infiltration patterns, and mortality rates. A nine-gene prognostic model for IPF was established based on the CERG (AUC: 1 year: 0.81, 3 years: 0.79, 5 years: 0.91), which outperformed the GAP score (AUC: 1 year: 0.66, 3 years: 0.75, 5 years: 0.72) in prognostic accuracy. IPF patients were classified into high-risk and low-risk groups based on the RiskScore from the prognostic model, with significant differences observed between these groups in hypoxia score, EMT score, GAP score, immune infiltration patterns, and mortality rates. Ultimately, six high-risk signature genes associated with cold exposure in IPF were identified: GASK1B, HRK1, HTRA1, KCNN4, MMP9, and SPP1. Conclusions: This study suggests that cold exposure may be a potential environmental factor contributing to the progression of IPF. The prognostic model built upon cold exposure-related genes provides an effective tool for assessing the severity of IPF patients. Meanwhile, GASK1B, HRK1, HTRA1, KCNN4, MMP9, and SPP1 hold promise as potential biomarkers and therapeutic targets for IPF.
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Affiliation(s)
- Peiyao Luo
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
- Heilongjiang Provincial Key Laboratory of Critical Care Medicine, No. 2075, Qunli Seventh Avenue, Daoli District, Harbin 150001, China
| | - Quankuan Gu
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
- Heilongjiang Provincial Key Laboratory of Critical Care Medicine, No. 2075, Qunli Seventh Avenue, Daoli District, Harbin 150001, China
| | - Jianpeng Wang
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
- Heilongjiang Provincial Key Laboratory of Critical Care Medicine, No. 2075, Qunli Seventh Avenue, Daoli District, Harbin 150001, China
| | - Xianglin Meng
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
- Heilongjiang Provincial Key Laboratory of Critical Care Medicine, No. 2075, Qunli Seventh Avenue, Daoli District, Harbin 150001, China
| | - Mingyan Zhao
- Department of Critical Care Medicine, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, China
- Heilongjiang Provincial Key Laboratory of Critical Care Medicine, No. 2075, Qunli Seventh Avenue, Daoli District, Harbin 150001, China
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Zhang B, Geng H, Zhao K, Omorou M, Liu S, Ye Z, Zhang F, Luan H, Zhang X. FSTL1 aggravates high glucose-induced oxidative stress and transdifferentiation in HK-2 cells. Sci Rep 2025; 15:434. [PMID: 39748077 PMCID: PMC11696259 DOI: 10.1038/s41598-024-84462-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 12/23/2024] [Indexed: 01/04/2025] Open
Abstract
Chronic hyperglycemia, a hallmark of diabetes, can trigger inflammatory responses in the kidney, leading to diabetic nephropathy (DN). Follistatin-like protein 1 (FSTL1) has emerged as a potential therapeutic target in various kidney diseases. This study investigated the effect of high glucose on FSTL1 expression and its role in oxidative stress and cellular transdifferentiation injury in HK-2 human proximal tubule epithelial cells, a model of DN. We investigated FSTL1's level in HK-2 cells exposed to high glucose using Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). FSTL1 was manipulated using recombinant human FSTL1 (rhFSTL1) or lentiviral shFSTL1. We then analyzed proliferation, oxidative stress, transdifferentiation, cell migration, and the nuclear factor kappa-B (NF-κB) signaling pathway potentially involved in FSTL1 effects. Finally, we blocked the NF-κB pathway to see its influence on these cellular processes. High glucose exposure significantly increased FSTL1 in HK-2 cells, with longer/higher glucose further amplifying this effect. Silencing of FSTL1 ameliorates cellular damage by promoting proliferation, enhancing superoxide dismutase (SOD) and glutathione (GSH) activity, and reducing malondialdehyde (MDA) production, inhibiting cell migration. Furthermore, it prevented the harmful conversion of HK-2 cells from epithelial to myofibroblast-like phenotypes, evidenced by decreased fibronectin (FN) and α-smooth muscle actin (α-SMA) and preserved E-cadherin. Notably, silencing FSTL1 also inhibited the NF-κB signaling pathway. Conversely, rhFSTL1 exhibited opposite effects. Importantly, blocking NF-κB reversed the detrimental effects of FSTL1. These findings suggest that FSTL1 contributes to high glucose-induced kidney injury by promoting oxidative stress and cellular transdifferentiation potentially via the NF-κB pathway. Targeting FSTL1 may represent a novel therapeutic strategy for preventing or mitigating DN progression.
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Affiliation(s)
- Baoyuan Zhang
- Department of Histology and Embryology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
| | - Hang Geng
- Medical Imaging Center, First Affiliated Hospital, Jiamusi University, Jiamusi, Heilongjiang, China
| | - Kai Zhao
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
- Department of Physiology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
| | - Moussa Omorou
- Laboratory of Medical Biochemistry, First Affiliated Hospital, University of Lomé, Lomé, Togo
| | - Shuang Liu
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
- Department of Biology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
| | - Zhihui Ye
- Department of Orthodontics, Second Affiliated Hospital, Jiamusi University, Jiamusi, Heilongjiang, China
| | - Fanting Zhang
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
- Department of Physiology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China
| | - Haiyan Luan
- Key Laboratory of Microecology-Immune Regulatory Network and Related Diseases, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China.
- Department of Physiology, School of Basic Medicine, Jiamusi University, Jiamusi, Heilongjiang, China.
| | - Xuesong Zhang
- Medical Imaging Center, First Affiliated Hospital, Jiamusi University, Jiamusi, Heilongjiang, China.
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6
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Pavan C, Leinardi R, Benhida A, Ibouraadaten S, Yakoub Y, Brule SVD, Lison D, Turci F, Huaux F. Short- and long-term pathologic responses to quartz are induced by nearly free silanols formed during crystal fracturing. Part Fibre Toxicol 2024; 21:52. [PMID: 39633374 PMCID: PMC11619699 DOI: 10.1186/s12989-024-00611-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2024] [Accepted: 11/21/2024] [Indexed: 12/07/2024] Open
Abstract
BACKGROUND Inhalation of respirable crystalline silica particles, including quartz, is associated with an increased risk of developing pathologies, including persistent lung inflammation, fibrosis, cancer, and systemic autoimmunity. We demonstrated that the nearly free silanols (NFS) generated upon quartz fracturing trigger the early molecular events determining quartz toxicity. Here, we address the involvement of NFS in driving short- and long-term pathogenic responses, including lung inflammation, fibrosis, cancer, and autoimmunity in multiple mouse models. RESULTS In vivo pulmonary responses to as-grown NFS-poor quartz (gQ) and fractured NFS-rich quartz (gQ-f) of synthetic origin were compared to two NFS-rich reference quartz dusts (Min-U-Sil 5, mQ-f). Acute and persistent inflammation, as well as fibrosis, were assessed 3 and 60 days, respectively, after administering one dose of particles (2 mg) via oropharyngeal aspiration (o.p.a.) to C57BL/6 mice. The carcinogenic potential was assessed in a co-carcinogenicity study using A/J mice, which were pre-treated with 3-methylcholanthrene (3-MC) and administered four doses of quartz particles (4 × 1 mg, o.p.a.), then sacrificed after 10 months. Autoimmunity was evaluated in autoimmune-prone 129/Sv mice 4 months after particle administration (2 × 1.25 mg, o.p.a). Mice exposed to NFS-rich quartz exhibited a strong acute lung inflammatory response, characterized by pro-inflammatory cytokine release and leukocyte accumulation, which persisted for up to 60 days. No inflammatory effect was observed in mice treated with NFS-poor gQ. Fibrosis onset (i.e., increased levels of pro-fibrotic factors, hydroxyproline, and collagen) was prominent in mice exposed to NFS-rich but not to NFS-poor quartz. Additionally, lung cancer development (tumour numbers) and autoimmune responses (elevated IgG and anti-dsDNA autoantibody levels) were only observed after exposure to NFS-rich quartz. CONCLUSIONS Collectively, the results indicate that NFS, which occur upon fracturing of quartz particles, play a crucial role in the short- and long-term local and systemic responses to quartz. The assessment of NFS on amorphous or crystalline silica particles may help create a predictive model of silica pathogenicity.
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Affiliation(s)
- Cristina Pavan
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institute of Experimental and Clinical Research (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium.
- Department of Chemistry, University of Turin, Turin, Italy.
- "G. Scansetti" Interdepartmental Centre for Studies on Asbestos and Other Toxic Particulates, University of Turin, Turin, Italy.
| | - Riccardo Leinardi
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institute of Experimental and Clinical Research (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Anissa Benhida
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institute of Experimental and Clinical Research (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Saloua Ibouraadaten
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institute of Experimental and Clinical Research (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Yousof Yakoub
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institute of Experimental and Clinical Research (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Sybille van den Brule
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institute of Experimental and Clinical Research (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Dominique Lison
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institute of Experimental and Clinical Research (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
| | - Francesco Turci
- Department of Chemistry, University of Turin, Turin, Italy
- "G. Scansetti" Interdepartmental Centre for Studies on Asbestos and Other Toxic Particulates, University of Turin, Turin, Italy
| | - François Huaux
- Louvain Centre for Toxicology and Applied Pharmacology (LTAP), Institute of Experimental and Clinical Research (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium.
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Sullivan DI, Ascherman DP. Rheumatoid Arthritis-Associated Interstitial Lung Disease (RA-ILD): Update on Prevalence, Risk Factors, Pathogenesis, and Therapy. Curr Rheumatol Rep 2024; 26:431-449. [PMID: 39320427 DOI: 10.1007/s11926-024-01155-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2024] [Indexed: 09/26/2024]
Abstract
PURPOSE OF REVIEW Rheumatoid arthritis is frequently complicated by interstitial lung disease (RA-ILD), an underappreciated contributor to excess morbidity and mortality. The true prevalence of RA-ILD is difficult to define given the variability in diagnostic criteria used. The lack of standardized screening methods, an incomplete understanding of disease pathogenesis, and dearth of validated biomarkers have limited the development of controlled clinical trials for this disease. RECENT FINDINGS Numerous studies have focused on clinical, radiographic, genetic, molecular, and/or serologic markers of disease severity as well as risk of disease progression. In addition to defining valuable clinical biomarkers, these studies have provided insights regarding the pathogenesis of RA-ILD and potential therapeutic targets. Additional studies involving immunomodulatory and/or anti-fibrotic agents have assessed new therapeutic options for different stages of RA-ILD. RA-ILD continues to be a major contributor to the increased morbidity and mortality associated with RA. Advancements in our understanding of disease pathogenesis at a molecular level are necessary to drive the development of more targeted therapy.
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Affiliation(s)
- Daniel I Sullivan
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, University of Pittsburgh, UPMC Montefiore Hospital, 3459 Fifth Ave, NW 628, Pittsburgh, PA, 15213, USA.
| | - Dana P Ascherman
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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8
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Chen X, Zhou Z, Yazgan Z, Xie L, Rossi F, Liu Y, Zhang B, Polanco PM, Zeh HJ, Kim AC, Huang H. Single-cell resolution spatial analysis of antigen-presenting cancer-associated fibroblast niches. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.15.623232. [PMID: 39605724 PMCID: PMC11601292 DOI: 10.1101/2024.11.15.623232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Recent studies have identified a unique subtype of cancer-associated fibroblasts (CAFs) termed antigen-presenting CAFs (apCAFs), which remain the least understood CAF subtype. To gain a comprehensive understanding of the origin and function apCAFs, we construct a fibroblast molecular atlas across 14 types of solid tumors. Our integration study unexpectedly reveals two distinct apCAF lineages present in most cancer types: one associated with mesothelial-like cells and the other with fibrocytes. Using a high-resolution single-cell spatial imaging platform, we characterize the spatial niches of these apCAF lineages. We find that mesothelial-like apCAFs are located near cancer cells, while fibrocyte-like apCAFs are associated with tertiary lymphoid structures. Additionally, we discover that both apCAF lineages can up-regulate the secreted protein SPP1, which facilitates primary tumor formation and peritoneal metastasis. Taken together, this study offers an unprecedented resolution in analyzing apCAF lineages and their spatial niches.
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Kim SJ, Cecchini MJ, Woo E, Jayawardena N, Passos DT, Dick FA, Mura M. Spatially resolved gene expression profiles of fibrosing interstitial lung diseases. Sci Rep 2024; 14:26470. [PMID: 39488596 PMCID: PMC11531500 DOI: 10.1038/s41598-024-77469-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 10/22/2024] [Indexed: 11/04/2024] Open
Abstract
Fibrosing interstitial lung diseases (ILDs) encompass a diverse range of scarring disorders that lead to progressive lung failure. Previous gene expression profiling studies focused on idiopathic pulmonary fibrosis (IPF) and bulk tissue samples. We employed digital spatial profiling to gain new insights into the spatial resolution of gene expression across distinct lung microenvironments (LMEs) in IPF, chronic hypersensitivity pneumonitis (CHP) and non-specific interstitial pneumonia (NSIP). We identified differentially expressed genes between LMEs within each condition, and across histologically similar regions between conditions. Uninvolved regions in IPF and CHP were distinct from normal controls, and displayed potential therapeutic targets. Hallmark LMEs of each condition retained distinct gene signatures, but these could not be reproduced in matched lung tissue samples. Based on these profiles and unsupervised clustering, we grouped previously unclassified ILD cases into NSIP or CHP. Overall, our work uniquely dissects gene expression profiles between LMEs within and across different types of fibrosing ILDs.
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Affiliation(s)
- Seung J Kim
- Interstitial Lung Disease Research Laboratory, Lawson Health Research Institute, London, ON, Canada.
- London Health Sciences Research Institute, London, ON, Canada.
| | - Matthew J Cecchini
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Elissa Woo
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
| | - Nathashi Jayawardena
- Interstitial Lung Disease Research Laboratory, Lawson Health Research Institute, London, ON, Canada
- London Health Sciences Research Institute, London, ON, Canada
| | - Daniel T Passos
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- London Health Sciences Research Institute, London, ON, Canada
- Verspeeten Family Cancer Centre, London, ON, Canada
| | - Frederick A Dick
- Department of Pathology and Laboratory Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
- London Health Sciences Research Institute, London, ON, Canada
- Verspeeten Family Cancer Centre, London, ON, Canada
| | - Marco Mura
- Interstitial Lung Disease Research Laboratory, Lawson Health Research Institute, London, ON, Canada
- Division of Respirology, Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada
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10
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Kumar A, Mark ZF, Carbajal MP, DeLima DS, Chamberlain N, Walzer J, Ruban M, Chandrasekaran R, Daphtary N, Aliyeva M, Poynter ME, Janssen-Heininger YMW, Bates JH, Alcorn JF, Britto CJ, Dela Cruz CS, Jegga AG, Anathy V. The protein disulfide isomerase A3 and osteopontin axis promotes influenza-induced lung remodelling. Br J Pharmacol 2024; 181:4610-4627. [PMID: 39118388 DOI: 10.1111/bph.16511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 06/07/2024] [Accepted: 06/24/2024] [Indexed: 08/10/2024] Open
Abstract
BACKGROUND AND PURPOSE Fibrotic lung remodelling after a respiratory viral infection represents a debilitating clinical sequela. Studying or managing viral-fibrotic sequela remains challenging, due to limited therapeutic options and lack of understanding of mechanisms. This study determined whether protein disulfide isomerase A3 (PDIA3) and secreted phosphoprotein 1 (SPP1), which are associated with pulmonary fibrosis, can promote influenza-induced lung fibrotic remodelling and whether inhibition of PDIA3 or SPP1 can resolve viral-mediated fibrotic remodelling. EXPERIMENTAL APPROACH A retrospective analysis of TriNetX data sets was conducted. Serum from healthy controls and influenza A virus (IAV)-infected patients was analysed. An inhibitor of PDIA3, punicalagin, and a neutralizing antibody for SPP1 were administered in mice. Macrophage cells treated with macrophage colony-stimulating factor (M-CSF) were used as a cell culture model. KEY RESULTS The TriNetX data set showed an increase in lung fibrosis and decline in lung function in flu-infected acute respiratory distress syndrome (ARDS) patients compared with non-ARDS patients. Serum samples revealed a significant increase in SPP1 and PDIA3 in influenza-infected patients. Lung PDIA3 and SPP1 expression increased following viral infection in mouse models. Punicalagin administration 2 weeks after IAV infection in mice caused a significant decrease in lung fibrosis and improved oxygen saturation. Administration of neutralizing SPP1 antibody decreased lung fibrosis. Inhibition of PDIA3 decreased SPP1secretion from macrophages, in association with diminished disulfide bonds in SPP1. CONCLUSION AND IMPLICATIONS The PDIA3-SPP1 axis promotes post-influenza lung fibrosis in mice and that pharmacological inhibition of PDIA3 or SPP1 can treat virus-induced lung fibrotic sequela.
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Affiliation(s)
- Amit Kumar
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Zoe F Mark
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Morgan P Carbajal
- Division of Pulmonary Disease and Critical Care Medicine, Department of Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Dhemerson Souza DeLima
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Nicolas Chamberlain
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Joseph Walzer
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Mona Ruban
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Ravishankar Chandrasekaran
- Division of Pulmonary Disease and Critical Care Medicine, Department of Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Nirav Daphtary
- Division of Pulmonary Disease and Critical Care Medicine, Department of Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Minara Aliyeva
- Division of Pulmonary Disease and Critical Care Medicine, Department of Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Matthew E Poynter
- Division of Pulmonary Disease and Critical Care Medicine, Department of Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Yvonne M W Janssen-Heininger
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - Jason H Bates
- Division of Pulmonary Disease and Critical Care Medicine, Department of Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
| | - John F Alcorn
- Division of Pulmonary Medicine, Allergy, and Immunology, Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Clemente J Britto
- Department of Pulmonary, Critical Care and Sleep Medicine, Yale University, New Haven, Connecticut, USA
| | - Charles S Dela Cruz
- Department of Pulmonary, Critical Care and Sleep Medicine, Yale University, New Haven, Connecticut, USA
| | - Anil G Jegga
- Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
- Department of Computer Science, University of Cincinnati College of Engineering and Applied Science, Cincinnati, Ohio, USA
| | - Vikas Anathy
- Department of Pathology and Laboratory Medicine, Larner College of Medicine, The University of Vermont, Burlington, Vermont, USA
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11
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Künzel SR, Klapproth E, Zimmermann N, Kämmerer S, Schubert M, Künzel K, Hoffmann M, Drukewitz S, Vehlow A, Eitler J, Arriens M, Thiel J, Kronstein-Wiedemann R, Tietze M, Beissert S, Renner B, El-Armouche A, Günther C. Radiation-induced morphea of the breast - characterization and treatment of fibroblast dysfunction with repurposed mesalazine. Sci Rep 2024; 14:26132. [PMID: 39477958 PMCID: PMC11525966 DOI: 10.1038/s41598-024-74206-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 09/24/2024] [Indexed: 11/02/2024] Open
Abstract
Radiation-induced morphea (RIM) is a rare complication of radiotherapy presenting as inflammatory fibrosis, most commonly reported in breast cancer patients. As underlying disease mechanisms are not well understood, targeted therapies are lacking. Since fibroblasts are the key mediators of all fibroproliferative diseases, this study aimed to characterize patient-derived fibroblasts to identify therapeutic targets. We studied primary human control and RIM-fibroblasts on a functional and molecular basis, analyzed peripheral blood and tissue samples and conducted, based on our findings, a treatment attempt in one patient. In RIM, we identified a distinct myofibroblast phenotype reflected by increased alpha-smooth-muscle-actin (αSMA) expression, reduced proliferation and migration rates, and overexpression of osteopontin (OPN). Our RNA sequencing identified aberrant Myc activation as a potential disease driver in RIM fibroblasts, similar to previous findings in systemic sclerosis. Treatment with the anti-inflammatory drug mesalazine reversed the myofibroblast phenotype by targeting Myc. Based on these findings, a patient with RIM was successfully treated with mesalazine, resulting in reduced inflammation and pain and tissue softening, while serum OPN was halved. The present study provides a comprehensive characterization of RIM fibroblasts, suggests a disease-driving role for Myc, demonstrates promising antifibrotic effects of mesalazine and proposes OPN as a biomarker for RIM.
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Affiliation(s)
- Stephan R Künzel
- Institute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
- Institute for Clinical Pharmacology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, Dresden, Germany.
- Institute for Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden and DRK Blutspendedienst Nord-Ost gGmbH, Dresden, Germany.
| | - Erik Klapproth
- Institute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Nick Zimmermann
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, Dresden, Germany
| | - Susanne Kämmerer
- Institute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Mario Schubert
- Institute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Karolina Künzel
- Institute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Maximilian Hoffmann
- Institute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Stephan Drukewitz
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
- Core Unit for Molecular Tumor Diagnostics, NCT Dresden and DKFZ, Dresden, Germany
| | - Anne Vehlow
- OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jiri Eitler
- Institute for Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden and DRK Blutspendedienst Nord-Ost gGmbH, Dresden, Germany
| | - Marieke Arriens
- Institute for Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden and DRK Blutspendedienst Nord-Ost gGmbH, Dresden, Germany
| | - Jessica Thiel
- Institute for Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden and DRK Blutspendedienst Nord-Ost gGmbH, Dresden, Germany
| | - Romy Kronstein-Wiedemann
- Institute for Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden and DRK Blutspendedienst Nord-Ost gGmbH, Dresden, Germany
| | - Maximiliane Tietze
- Institute for Transfusion Medicine, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden and DRK Blutspendedienst Nord-Ost gGmbH, Dresden, Germany
| | - Stefan Beissert
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, Dresden, Germany
| | - Bertold Renner
- Institute for Clinical Pharmacology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Ali El-Armouche
- Institute for Pharmacology and Toxicology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Institute for Clinical Pharmacology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Claudia Günther
- Department of Dermatology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, Dresden, Dresden, Germany.
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12
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Zhang H, Hua H, Liu J, Wang C, Zhu C, Xia Q, Jiang W, Cheng X, Hu X, Zhang Y. Integrative analysis of the efficacy and pharmacological mechanism of Xuefu Zhuyu decoction in idiopathic pulmonary fibrosis via evidence-based medicine, bioinformatics, and experimental verification. Heliyon 2024; 10:e38122. [PMID: 39416822 PMCID: PMC11481653 DOI: 10.1016/j.heliyon.2024.e38122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2024] [Revised: 09/16/2024] [Accepted: 09/18/2024] [Indexed: 10/19/2024] Open
Abstract
Objective We used evidence-based medicine, bioinformatics and experimental verification to comprehensively analyze the efficacy and pharmacological mechanism of Xuefu Zhuyu decoction (XFZYD) in the treatment of idiopathic pulmonary fibrosis (IPF). Methods Major databases were retrieved for randomized controlled trials (RCTs) of XFZYD treating IPF to perform meta-analysis. Active ingredients and target genes of XFZYD were identified from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). IPF-related differentially expressed genes (DEGs) were identified from the Gene Expression Omnibus (GEO) database. The RGUI software was utilized for Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The ingredient-target and protein-protein interaction (PPI) networks were achieved through Cytoscape software and the STRING database to identify the key compounds and target proteins. Molecular docking was performed using AutoDockTool and AutoDock Vina software. The effect between key compounds and target proteins was verified in animal experiments. Results Six RCTs were included for meta-analysis, which uncovered that the total effective rate of clinical efficacy was higher in the experimental group than control group. Then, 156 active ingredients and 254 target genes of XFZYD, and 1,566 IPF-related DEGs were identified. The intersection analysis identified 48 target genes correlating with 130 active ingredients of XFZYD treating IPF. GO functional enrichment, KEGG pathway enrichment, ingredient-target network and PPI network were achieved. Following the identification of key compounds and target proteins, we performed molecular docking. Ultimately, our research focused on the key compound quercetin for experimental validation to assess its interactions with two key target proteins, JUN and PTGS2. Conclusion The effectiveness of XFZYD on IPF has been substantiated through evidence-based medicine. The pharmacological mechanism of XFZYD for IPF treatment involves a complex interplay of various compounds and targets, with quercetin exerting pronounced impacts on JUN and PTGS2 proteins.
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Affiliation(s)
- Huizhe Zhang
- Department of Respiratory Medicine, Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Yancheng TCM Hospital, Yancheng, Jiangsu, 224005, China
| | - Haibing Hua
- Department of Gastroenterology, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangyin, Jiangsu, 214400, China
| | - Jian Liu
- Department of Respiratory Medicine, Xuejia People's Hospital of Xinbei District, Changzhou, Jiangsu, 213003, China
| | - Cong Wang
- Department of Pulmonary and Critical Care Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangyin, Jiangsu, 214400, China
- Research Institute of Respiratory Diseases, Jiangsu Province Clinical Academy of Traditional Chinese Medicine (Jiangyin Branch), Jiangyin, Jiangsu, 214400, China
| | - Chenjing Zhu
- Department of Pulmonary and Critical Care Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangyin, Jiangsu, 214400, China
- Research Institute of Respiratory Diseases, Jiangsu Province Clinical Academy of Traditional Chinese Medicine (Jiangyin Branch), Jiangyin, Jiangsu, 214400, China
| | - Qingqing Xia
- Department of Pulmonary and Critical Care Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangyin, Jiangsu, 214400, China
- Research Institute of Respiratory Diseases, Jiangsu Province Clinical Academy of Traditional Chinese Medicine (Jiangyin Branch), Jiangyin, Jiangsu, 214400, China
| | - Weilong Jiang
- Department of Pulmonary and Critical Care Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangyin, Jiangsu, 214400, China
- Research Institute of Respiratory Diseases, Jiangsu Province Clinical Academy of Traditional Chinese Medicine (Jiangyin Branch), Jiangyin, Jiangsu, 214400, China
| | - Xiangjin Cheng
- Department of Critical Care Medicine, Yancheng TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Yancheng TCM Hospital, Yancheng, Jiangsu, 224005, China
| | - Xiaodong Hu
- Department of Pulmonary and Critical Care Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangyin, Jiangsu, 214400, China
- Research Institute of Respiratory Diseases, Jiangsu Province Clinical Academy of Traditional Chinese Medicine (Jiangyin Branch), Jiangyin, Jiangsu, 214400, China
| | - Yufeng Zhang
- Department of Pulmonary and Critical Care Medicine, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangyin, Jiangsu, 214400, China
- Research Institute of Respiratory Diseases, Jiangsu Province Clinical Academy of Traditional Chinese Medicine (Jiangyin Branch), Jiangyin, Jiangsu, 214400, China
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13
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Okabe Y, Toda E, Urushiyama H, Terashima Y, Kunugi S, Kajimoto Y, Terasaki M, Matsushima K, Saito A, Yamauchi Y, Nagase T, Shimizu A, Terasaki Y. Antifibrotic effect of disulfiram on bleomycin-induced lung fibrosis in mice and its impact on macrophage infiltration. Sci Rep 2024; 14:23653. [PMID: 39384840 PMCID: PMC11464646 DOI: 10.1038/s41598-024-71770-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 08/30/2024] [Indexed: 10/11/2024] Open
Abstract
The accumulation of monocyte-derived macrophages in the lung tissue during inflammation is important for the pathogenesis of fibrotic lung disease. Deficiencies in chemokine receptors CCR2 and CCR5 and their ligands, which mediate monocyte/macrophage migration, ameliorate bleomycin (BLM)-induced lung fibrosis. Disulfiram (DSF), which is used to treat alcoholism because of its aldehyde dehydrogenase (ALDH)-inhibiting effect, inhibits monocyte/macrophage migration by inhibiting FROUNT, an intracellular regulator of CCR2/CCR5 signalling. Here, we investigated the antifibrotic effect of oral DSF administration in a mouse model of BLM-induced lung fibrosis, focusing on macrophage response and fibrosis progression. The direct inhibitory activity of DSF on monocyte migration was measured using the Boyden chamber assay and compared with that of DSF-related inhibitors with different FROUNT-inhibition activities. Quantitative PCR was used to determine the expression of fibrosis-promoting genes in the lung tissue. DSF significantly suppressed macrophage infiltration into lung tissues and attenuated BLM-induced lung fibrosis. DSF and its metabolites, diethyldithiocarbamate (DDC) and copper diethyldithiocarbamate (Cu(DDC)2), inhibited monocyte migration toward the culture supernatant of primary mouse lung cells mainly comprising CCL2, whereas cyanamide, another ALDH inhibitor, did not. DSF, with higher inhibitory activity against FROUNT than DDC and Cu(DDC)2, inhibited monocyte migration most strongly. In BLM-induced fibrotic lung tissues, profibrotic factors were highly expressed but were reduced by DSF treatment. These results suggest DSF inhibits macrophage infiltration, which might be attributed to its inhibitory effect on FROUNT, and attenuates BLM-induced lung fibrosis. In addition, multiplex immunofluorescence imaging revealed reduced infiltration of S100A4+ macrophages into the lungs in DSF-treated mice and high expression of FROUNT in S100A4+ macrophages in idiopathic pulmonary fibrosis (IPF). These findings underscore the potential of macrophage-targeted therapy with DSF as a promising drug repositioning approach for treating fibrotic lung diseases, including IPF.
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Affiliation(s)
- Yugo Okabe
- Department of Analytic Human Pathology, Nippon Medical School, 1-25-16 Nezu, Bunkyo-ku, Tokyo, 113-0031, Japan
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Etsuko Toda
- Department of Analytic Human Pathology, Nippon Medical School, 1-25-16 Nezu, Bunkyo-ku, Tokyo, 113-0031, Japan
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, 278-8510, Japan
- Laboratory for Morphological and Biomolecular Imaging, Nippon Medical School, Tokyo, 113‑0031, Japan
| | - Hirokazu Urushiyama
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Yuya Terashima
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, 278-8510, Japan
| | - Shinobu Kunugi
- Department of Analytic Human Pathology, Nippon Medical School, 1-25-16 Nezu, Bunkyo-ku, Tokyo, 113-0031, Japan
| | - Yusuke Kajimoto
- Department of Analytic Human Pathology, Nippon Medical School, 1-25-16 Nezu, Bunkyo-ku, Tokyo, 113-0031, Japan
| | - Mika Terasaki
- Department of Analytic Human Pathology, Nippon Medical School, 1-25-16 Nezu, Bunkyo-ku, Tokyo, 113-0031, Japan
| | - Kouji Matsushima
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, 278-8510, Japan
| | - Akira Saito
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Yasuhiro Yamauchi
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
- Health Care Center, Tokyo University of Foreign Studies, Tokyo, 183‑8534, Japan
| | - Takahide Nagase
- Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan
| | - Akira Shimizu
- Department of Analytic Human Pathology, Nippon Medical School, 1-25-16 Nezu, Bunkyo-ku, Tokyo, 113-0031, Japan
| | - Yasuhiro Terasaki
- Department of Analytic Human Pathology, Nippon Medical School, 1-25-16 Nezu, Bunkyo-ku, Tokyo, 113-0031, Japan.
- Division of Pathology, Nippon Medical School Hospital, Tokyo, 113‑8603, Japan.
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14
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Chen Y, Cao S, Shao S, Tong Z. Identifying prothrombin and bone sialoprotein as potential drug targets for idiopathic pulmonary fibrosis. BMC Pulm Med 2024; 24:488. [PMID: 39375737 PMCID: PMC11459707 DOI: 10.1186/s12890-024-03289-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 09/18/2024] [Indexed: 10/09/2024] Open
Abstract
BACKGROUND Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease with scarce therapeutic alternatives, which imposes a significant economic burden on society. The identification of novel drug targets is thus critically essential. Plasma proteins with discernible causal evidence hold promise as viable drug targets for this condition. METHODS We performed a proteome-wide Mendelian randomization (MR) analysis to assess the causal effects of 4,907 circulating proteins from the deCODE study on the risk of IPF from the Finngen Database (2,018 cases vs. 373,064 controls). We further replicated the MR analysis in 1426 proteins from the ARIC study and IPF from the UK Biobank (1,369 cases vs. 435,866 controls). Then a series of analyses including Bayesian colocalization, Steiger filtering, and phenotype scanning were conducted to validate the credibility of the MR results. Subsequently, protein-protein interaction (PPI) analysis, pathway enrichment analysis, and druggability assessment were executed to elucidate the underlying mechanisms. Finally, the findings were corroborated using a bleomycin-induced pulmonary fibrosis mouse model. RESULTS The MR analysis bolstered by robust evidence of colocalization, indicated a significant positive association between Prothrombin and increased IPF risk (OR = 3.26,95%CI 1.75-6.07). Conversely, Bone Sialoprotein (IBSP) demonstrated an inverse association with IPF susceptibility (OR = 0.27,95%CI 0.14-0.55). CONCLUSIONS The integrative analysis suggests that Prothrombin and IBSP are promising candidates as potential drug targets for IPF. Additional clinical investigations are warranted to substantiate these findings.
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Affiliation(s)
- Yusha Chen
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongren Tiyuchang South Road, Chaoyang District, Beijing, 100020, China
- Beijing Research Center for Respiratory Infectious Diseases, Beijing, China
| | - Siyu Cao
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongren Tiyuchang South Road, Chaoyang District, Beijing, 100020, China
- Beijing Research Center for Respiratory Infectious Diseases, Beijing, China
| | - Shuai Shao
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongren Tiyuchang South Road, Chaoyang District, Beijing, 100020, China
- Beijing Research Center for Respiratory Infectious Diseases, Beijing, China
| | - Zhaohui Tong
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, No.8 Gongren Tiyuchang South Road, Chaoyang District, Beijing, 100020, China.
- Beijing Research Center for Respiratory Infectious Diseases, Beijing, China.
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15
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Estepa M, Niehues MH, Vakhrusheva O, Haritonow N, Ladilov Y, Barcena ML, Regitz-Zagrosek V. Sex Differences in Expression of Pro-Inflammatory Markers and miRNAs in a Mouse Model of CVB3 Myocarditis. Int J Mol Sci 2024; 25:9666. [PMID: 39273613 PMCID: PMC11395254 DOI: 10.3390/ijms25179666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 08/26/2024] [Accepted: 08/30/2024] [Indexed: 09/15/2024] Open
Abstract
Myocarditis is an inflammatory disease that may lead to dilated cardiomyopathy. Viral infection of the myocardium triggers immune responses, which involve, among others, macrophage infiltration, oxidative stress, expression of pro-inflammatory cytokines, and microRNAs (miRNAs). The cardioprotective role of estrogen in myocarditis is well documented; however, sex differences in the miRNA expression in chronic myocarditis are still poorly understood, and studying them further was the aim of the present study. Male and female ABY/SnJ mice were infected with CVB3. Twenty-eight days later, cardiac tissue from both infected and control mice was used for real-time PCR and Western blot analysis. NFκB, IL-6, iNOS, TNF-α, IL-1β, MCP-1, c-fos, and osteopontin (OPN) were used to examine the inflammatory state in the heart. Furthermore, the expression of several inflammation- and remodeling-related miRNAs was analyzed. NFκB, IL-6, TNF-α, IL-1β, iNOS, and MCP-1 were significantly upregulated in male mice with CVB3-induced chronic myocarditis, whereas OPN mRNA expression was increased only in females. Further analysis revealed downregulation of some anti-inflammatory miRNA in male hearts (let7a), with upregulation in female hearts (let7b). In addition, dysregulation of remodeling-related miRNAs (miR27b and mir199a) in a sex-dependent manner was observed. Taken together, the results of the present study suggest a sex-specific expression of pro-inflammatory markers as well as inflammation- and remodeling-related miRNAs, with a higher pro-inflammatory response in male CVB3 myocarditis mice.
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Affiliation(s)
- Misael Estepa
- Department of Internal Medicine and Cardiology, Deutsches Herzzentrum der Charité, 13353 Berlin, Germany
| | - Maximilian H Niehues
- Institute for Gender in Medicine, Center for Cardiovascular Research, Charité University Hospital, 10115 Berlin, Germany
| | - Olesya Vakhrusheva
- Department of Urology, University Hospital Tübingen, 72076 Tübingen, Germany
| | - Natalie Haritonow
- Department of Geriatrics and Medical Gerontology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
| | - Yury Ladilov
- Heart Center Brandenburg, Department of Cardiovascular Surgery, Brandenburg Medical School, 16321 Bernau bei Berlin, Germany
| | - Maria Luisa Barcena
- Department of Urology, University Hospital Tübingen, 72076 Tübingen, Germany
| | - Vera Regitz-Zagrosek
- Institute for Gender in Medicine, Center for Cardiovascular Research, Charité University Hospital, 10115 Berlin, Germany
- Department of Cardiology, University Hospital Zürich, University of Zürich, 8091 Zürich, Switzerland
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16
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Adegunsoye A, Kropski JA, Behr J, Blackwell TS, Corte TJ, Cottin V, Glanville AR, Glassberg MK, Griese M, Hunninghake GM, Johannson KA, Keane MP, Kim JS, Kolb M, Maher TM, Oldham JM, Podolanczuk AJ, Rosas IO, Martinez FJ, Noth I, Schwartz DA. Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine. Am J Respir Crit Care Med 2024; 210:401-423. [PMID: 38573068 PMCID: PMC11351799 DOI: 10.1164/rccm.202401-0238so] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 04/04/2024] [Indexed: 04/05/2024] Open
Abstract
Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common SNPs. The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis and clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. In addition, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multiomic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.
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Affiliation(s)
- Ayodeji Adegunsoye
- Pulmonary/Critical Care, and
- Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, Illinois
| | - Jonathan A. Kropski
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Juergen Behr
- Department of Medicine V, University Hospital, Ludwig Maximilian University of Munich, Munich, Germany
- Comprehensive Pneumology Center Munich, member of the German Center for Lung Research (DZL), Munich, Germany
| | - Timothy S. Blackwell
- Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee
- Department of Veterans Affairs Medical Center, Nashville, Tennessee
| | - Tamera J. Corte
- Centre of Research Excellence in Pulmonary Fibrosis, Camperdown, New South Wales, Australia
- Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
- University of Sydney, Sydney, New South Wales, Australia
| | - Vincent Cottin
- National Reference Center for Rare Pulmonary Diseases (OrphaLung), Louis Pradel Hospital, Hospices Civils de Lyon, ERN-LUNG (European Reference Network on Rare Respiratory Diseases), Lyon, France
- Claude Bernard University Lyon, Lyon, France
| | - Allan R. Glanville
- Lung Transplant Unit, St. Vincent’s Hospital Sydney, Sydney, New South Wales, Australia
| | - Marilyn K. Glassberg
- Department of Medicine, Loyola Chicago Stritch School of Medicine, Chicago, Illinois
| | - Matthias Griese
- Department of Pediatric Pneumology, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University, German Center for Lung Research, Munich, Germany
| | - Gary M. Hunninghake
- Harvard Medical School, Boston, Massachusetts
- Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
| | | | - Michael P. Keane
- Department of Respiratory Medicine, St. Vincent’s University Hospital and School of Medicine, University College Dublin, Dublin, Ireland
| | - John S. Kim
- Department of Medicine, School of Medicine, and
| | - Martin Kolb
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Toby M. Maher
- Department of Medicine, Keck School of Medicine of University of Southern California, Los Angeles, California
- National Heart and Lung Institute, Imperial College, London, United Kingdom
| | - Justin M. Oldham
- Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan
| | | | | | - Fernando J. Martinez
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Weill Cornell Medicine, New York, New York; and
| | - Imre Noth
- Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia
| | - David A. Schwartz
- Department of Medicine, School of Medicine, University of Colorado, Aurora, Colorado
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17
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Ran Z, Mu BR, Zhu T, Zhang Y, Luo JX, Yang X, Li B, Wang DM, Lu MH. Predicting biomarkers related to idiopathic pulmonary fibrosis: Robust ranking aggregation analysis and animal experiment verification. Int Immunopharmacol 2024; 139:112766. [PMID: 39067403 DOI: 10.1016/j.intimp.2024.112766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 06/22/2024] [Accepted: 07/22/2024] [Indexed: 07/30/2024]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable lung disease characterized by unknown etiology. This study employs robust ranking aggregation to identify consistent differential genes across multiple datasets, aiming to enhance prognostic evaluation and facilitate the development of more effective immunotherapy strategies for IPF. Using the GSE10667, GSE110147, and GSE24206 datasets, the analysis identifies 92 robust differentially expressed genes (DEGs), including SPP1, IGF1, ASPN, and KLHL13, highlighted as potential biomarkers through machine learning and experimental validation. Additionally, significant differences in immune cell types between IPF samples and controls, such as Plasma cells, Macrophages M0, Mast cells resting, T cells CD8, and NK cells resting, inform the construction of diagnostic and survival prediction models, demonstrating good applicability. These findings provide insights into IPF pathophysiology and suggest potential therapeutic targets.
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Affiliation(s)
- Zhao Ran
- Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ben-Rong Mu
- Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tao Zhu
- Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yu Zhang
- Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jia-Xin Luo
- Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiong Yang
- Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Bin Li
- Department of Respiratory Medicine, Guangyuan Hospital of Traditional Chinese Medicine, No.133 Jianshe Road, Lizhou District, Guangyuan 628099, Sichuan, China
| | - Dong-Mei Wang
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Mei-Hong Lu
- Chongqing Key Laboratory of Sichuan-Chongqing Co-construction for Diagnosis and Treatment of Infectious Diseases Integrated Traditional Chinese and Western Medicine, College of Medical Technology, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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18
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Zhang Y, Zhang Z, Mo Y, Zhang Y, Yuan J, Zhang Q. MMP-3 mediates copper oxide nanoparticle-induced pulmonary inflammation and fibrosis. J Nanobiotechnology 2024; 22:428. [PMID: 39030581 PMCID: PMC11264740 DOI: 10.1186/s12951-024-02707-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Accepted: 07/05/2024] [Indexed: 07/21/2024] Open
Abstract
BACKGROUND The increasing production and usage of copper oxide nanoparticles (Nano-CuO) raise human health concerns. Previous studies have demonstrated that exposure to Nano-CuO could induce lung inflammation, injury, and fibrosis. However, the potential underlying mechanisms are still unclear. Here, we proposed that matrix metalloproteinase-3 (MMP-3) might play an important role in Nano-CuO-induced lung inflammation, injury, and fibrosis. RESULTS Exposure of mice to Nano-CuO caused acute lung inflammation and injury in a dose-dependent manner, which was reflected by increased total cell number, neutrophil count, macrophage count, lactate dehydrogenase (LDH) activity, and CXCL1/KC level in bronchoalveolar lavage fluid (BALF) obtained on day 3 post-exposure. The time-response study showed that Nano-CuO-induced acute lung inflammation and injury appeared as early as day 1 after exposure, peaked on day 3, and ameliorated over time. However, even on day 42 post-exposure, the LDH activity and macrophage count were still higher than those in the control group, suggesting that Nano-CuO caused chronic lung inflammation. The Nano-CuO-induced pulmonary inflammation was further confirmed by H&E staining of lung sections. Trichrome staining showed that Nano-CuO exposure caused pulmonary fibrosis from day 14 to day 42 post-exposure with an increasing tendency over time. Increased hydroxyproline content and expression levels of fibrosis-associated proteins in mouse lungs were also observed. In addition, Nano-CuO exposure induced MMP-3 overexpression and increased MMP-3 secretion in mouse lungs. Knocking down MMP-3 in mouse lungs significantly attenuated Nano-CuO-induced acute and chronic lung inflammation and fibrosis. Moreover, Nano-CuO exposure caused sustained production of cleaved osteopontin (OPN) in mouse lungs, which was also significantly decreased by knocking down MMP-3. CONCLUSIONS Our results demonstrated that short-term Nano-CuO exposure caused acute lung inflammation and injury, while long-term exposure induced chronic pulmonary inflammation and fibrosis. Knocking down MMP-3 significantly ameliorated Nano-CuO-induced pulmonary inflammation, injury, and fibrosis, and also attenuated Nano-CuO-induced cleaved OPN level. Our study suggests that MMP-3 may play important roles in Nano-CuO-induced pulmonary inflammation and fibrosis via cleavage of OPN and may provide a further understanding of the mechanisms underlying Nano-CuO-induced pulmonary toxicity.
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Affiliation(s)
- Yuanbao Zhang
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY, 40202, USA
- Beijing Key Laboratory of Occupational Safety and Health, Institute of Urban Safety and Environmental Science, Beijing Academy of Science and Technology, Beijing, 100054, China
| | - Zhenyu Zhang
- Department of Emergency, Xiang'An Hospital of Xiamen University, Xiamen, 361104, Fujian, China
| | - Yiqun Mo
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY, 40202, USA
| | - Yue Zhang
- Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Jiali Yuan
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY, 40202, USA
| | - Qunwei Zhang
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY, 40202, USA.
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19
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Renaud L, Wilson CL, Lafyatis R, Schnapp LM, Feghali-Bostwick CA. Transcriptomic characterization of lung pericytes in systemic sclerosis-associated pulmonary fibrosis. iScience 2024; 27:110010. [PMID: 38868196 PMCID: PMC11167435 DOI: 10.1016/j.isci.2024.110010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 02/09/2024] [Accepted: 05/14/2024] [Indexed: 06/14/2024] Open
Abstract
Systemic sclerosis (SSc) is a chronic disease characterized by fibrosis and vascular abnormalities in the skin and internal organs, including the lung. SSc-associated pulmonary fibrosis (SSc-PF) is the leading cause of death in SSc patients. Pericytes are key regulators of vascular integrity and endothelial function. The role that pericytes play in SSc-PF remains unclear. We compared the transcriptome of pericytes from SSc-PF lungs (SScL) to pericytes from normal lungs (NORML). We identified 1,179 differentially expressed genes in SScL pericytes. Pathways enriched in SScL pericytes included prostaglandin, PI3K-AKT, calcium, and vascular remodeling signaling. Decreased cyclic AMP production and altered phosphorylation of AKT in response to prostaglandin E2 in SScL pericytes demonstrate the functional consequence of changes in the prostaglandin pathway that may contribute to fibrosis. The transcriptomic signature of SSc lung pericytes suggests that they promote vascular dysfunction and contribute to the loss of protection against lung inflammation and fibrosis.
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Affiliation(s)
- Ludivine Renaud
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Carole L. Wilson
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Medicine, University of Wisconsin, Madison, WI 53705, USA
| | - Robert Lafyatis
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
| | - Lynn M. Schnapp
- Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA
- Department of Medicine, University of Wisconsin, Madison, WI 53705, USA
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20
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Iturbe-Fernández D, Pulito-Cueto V, Mora-Cuesta VM, Remuzgo-Martínez S, Ferrer-Pargada DJ, Genre F, Alonso-Lecue P, López-Mejías R, Atienza-Mateo B, González-Gay MA, Cifrián-Martínez JM. Osteopontin as a Biomarker in Interstitial Lung Diseases. Biomedicines 2024; 12:1108. [PMID: 38791069 PMCID: PMC11118604 DOI: 10.3390/biomedicines12051108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Revised: 05/09/2024] [Accepted: 05/13/2024] [Indexed: 05/26/2024] Open
Abstract
Osteopontin (OPN) is a glycoprotein involved in Th1 and Th17 differentiation, and inflammation and tissue remodeling. OPN is a biomarker of disease activity in patients with autoimmune inflammatory conditions. This study aimed to assess the diagnostic and prognostic value of OPN in interstitial lung diseases (ILDs). Between May 2016 and October 2019, 344 patients with ILD were recruited at the Hospital Universitario Marqués de Valdecilla (Spain) and were prospectively followed-up. This study involved the determination of OPN serum levels by ELISA and OPN RNA expression quantified using qPCR. Six genetic polymorphisms in OPN (rs28357094, rs2853749, rs2853750, rs11728697, rs7695531, and rs1126616) were genotyped using TaqMan assays. OPN serum levels were also assessed in 140 healthy controls. OPN serum levels (median [interquartile range]) were significantly higher in ILD patients than in controls (1.05 [0.75-1.51] ng/mL versus 0.81 [0.65-0.98] ng/mL in healthy controls; p < 0.01). OPN serum levels were inversely correlated with the forced vital capacity. OPN serum levels were also higher in ILD patients who died or underwent lung transplantation when compared with the remaining ILD patients (1.15 [0.80-1.72] ng/mL versus 0.99 [0.66-1.32] ng/mL; p = 0.05). Survival worsened in ILD patients with OPN > 1.03 ng/mL at 1, 3, and 5 years. No statistically significant differences in the genetic frequencies of OPN polymorphisms or the RNA expression were found among the different ILD groups. Elevated levels of OPN in the serum may be a useful indicator in identifying patients with ILD who are more likely to experience poor outcomes.
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Affiliation(s)
- David Iturbe-Fernández
- Pneumology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain; (V.M.M.-C.); (D.J.F.-P.)
| | - Verónica Pulito-Cueto
- Valdecilla Research Institute (IDIVAL), 39008 Santander, Spain; (V.P.-C.); (S.R.-M.); (F.G.); (P.A.-L.); (R.L.-M.); (B.A.-M.)
| | - Víctor M. Mora-Cuesta
- Pneumology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain; (V.M.M.-C.); (D.J.F.-P.)
| | - Sara Remuzgo-Martínez
- Valdecilla Research Institute (IDIVAL), 39008 Santander, Spain; (V.P.-C.); (S.R.-M.); (F.G.); (P.A.-L.); (R.L.-M.); (B.A.-M.)
| | - Diego J. Ferrer-Pargada
- Pneumology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain; (V.M.M.-C.); (D.J.F.-P.)
| | - Fernanda Genre
- Valdecilla Research Institute (IDIVAL), 39008 Santander, Spain; (V.P.-C.); (S.R.-M.); (F.G.); (P.A.-L.); (R.L.-M.); (B.A.-M.)
| | - Pilar Alonso-Lecue
- Valdecilla Research Institute (IDIVAL), 39008 Santander, Spain; (V.P.-C.); (S.R.-M.); (F.G.); (P.A.-L.); (R.L.-M.); (B.A.-M.)
| | - Raquel López-Mejías
- Valdecilla Research Institute (IDIVAL), 39008 Santander, Spain; (V.P.-C.); (S.R.-M.); (F.G.); (P.A.-L.); (R.L.-M.); (B.A.-M.)
| | - Belén Atienza-Mateo
- Valdecilla Research Institute (IDIVAL), 39008 Santander, Spain; (V.P.-C.); (S.R.-M.); (F.G.); (P.A.-L.); (R.L.-M.); (B.A.-M.)
- Division of Rheumatology, Marqués de Valdecilla University Hospital, 39008 Santander, Spain
| | - Miguel A. González-Gay
- Medicine and Psychiatry Department, University of Cantabria, 39005 Santander, Spain;
- Division of Rheumatology, IIS-Fundación Jiménez Díaz, 28040 Madrid, Spain
| | - José M. Cifrián-Martínez
- Pneumology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain; (V.M.M.-C.); (D.J.F.-P.)
- Valdecilla Research Institute (IDIVAL), 39008 Santander, Spain; (V.P.-C.); (S.R.-M.); (F.G.); (P.A.-L.); (R.L.-M.); (B.A.-M.)
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21
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Saviano A, Roehlen N, Baumert TF. Tight Junction Proteins as Therapeutic Targets to Treat Liver Fibrosis and Hepatocellular Carcinoma. Semin Liver Dis 2024; 44:180-190. [PMID: 38648796 DOI: 10.1055/s-0044-1785646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/25/2024]
Abstract
In the last decade tight junction proteins exposed at the surface of liver or cancer cells have been uncovered as mediators of liver disease biology: Claudin-1 and Occludin are host factors for hepatitis C virus entry and Claudin-1 has been identified as a driver for liver fibrosis and hepatocellular carcinoma (HCC). Moreover, Claudins have emerged as therapeutic targets for liver disease and HCC. CLDN1 expression is upregulated in liver fibrosis and HCC. Monoclonal antibodies (mAbs) targeting Claudin-1 have completed preclinical proof-of-concept studies for treatment of liver fibrosis and HCC and are currently in clinical development for advanced liver fibrosis. Claudin-6 overexpression is associated with an HCC aggressive phenotype and treatment resistance. Claudin-6 mAbs or chimeric antigen receptor-T cells therapies are currently being clinically investigated for Claudin-6 overexpressing tumors. In conclusion, targeting Claudin proteins offers a novel clinical opportunity for the treatment of patients with advanced liver fibrosis and HCC.
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Affiliation(s)
- Antonio Saviano
- Inserm, U1110, Institute of Translational Medicine and Liver Disease, Strasbourg, France
- University of Strasbourg, Strasbourg, France
- Service d'hépato-gastroentérologie, Pôle Hépato-digestif, Institut-Hospitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Natascha Roehlen
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology and Infectious Diseases, Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Berta-Ottenstein-Programme, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Thomas F Baumert
- Inserm, U1110, Institute of Translational Medicine and Liver Disease, Strasbourg, France
- University of Strasbourg, Strasbourg, France
- Service d'hépato-gastroentérologie, Pôle Hépato-digestif, Institut-Hospitalo-Universitaire, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- Institut Universitaire de France, Paris, France
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22
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Zhu X, Ji J, Han X. Osteopontin: an essential regulatory protein in idiopathic pulmonary fibrosis. J Mol Histol 2024; 55:1-13. [PMID: 37878112 DOI: 10.1007/s10735-023-10169-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Accepted: 10/12/2023] [Indexed: 10/26/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic lung disease characterized by abnormal proliferation and activation of fibroblasts, excessive accumulation of extracellular matrix (ECM), inflammatory damage, and disrupted alveolar structure. Despite its increasing morbidity and mortality rates, effective clinical treatments for IPF remain elusive. Osteopontin (OPN), a multifunctional ECM protein found in various tissues, has been implicated in numerous biological processes such as bone remodeling, innate immunity, acute and chronic inflammation, and cancer. Recent studies have highlighted the pivotal role of OPN in the pathogenesis of IPF. This review aims to delve into the involvement of OPN in the inflammatory response, ECM deposition, and epithelial-mesenchymal transition (EMT) during IPF, and intends to lay a solid theoretical groundwork for the development of therapeutic strategies for IPF.
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Affiliation(s)
- Xiaoyu Zhu
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China
| | - Jie Ji
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China
| | - Xiaodong Han
- Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Hankou Road 22, Nanjing, 210093, China.
- Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China.
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23
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Jia Q, Ouyang Y, Yang Y, Yao S, Chen X, Hu Z. Osteopontin: A Novel Therapeutic Target for Respiratory Diseases. Lung 2024; 202:25-39. [PMID: 38060060 DOI: 10.1007/s00408-023-00665-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 11/22/2023] [Indexed: 12/08/2023]
Abstract
Osteopontin (OPN) is a multifunctional phosphorylated protein that is involved in physiological and pathological events. Emerging evidence suggests that OPN also plays a critical role in the pathogenesis of respiratory diseases. OPN can be produced and secreted by various cell types in lungs and overexpression of OPN has been found in acute lung injury/acute respiratory distress syndrome (ALI/ARDS), pulmonary hypertension (PH), pulmonary fibrosis diseases, lung cancer, lung infection, chronic obstructive pulmonary disease (COPD), and asthma. OPN exerts diverse effects on the inflammatory response, immune cell activation, fibrosis and tissue remodeling, and tumorigenesis of these respiratory diseases, and genetic and pharmacological moudulation of OPN exerts therapeutic effects in the treatment of respiratory diseases. In this review, we summarize the recent evidence of multifaceted roles and underlying mechanisms of OPN in these respiratory diseases, and targeting OPN appears to be a potential therapeutic intervention for these diseases.
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Affiliation(s)
- Qi Jia
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan, 430022, China
| | - Yeling Ouyang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan, 430022, China
| | - Yiyi Yang
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan, 430022, China
| | - Shanglong Yao
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan, 430022, China
| | - Xiangdong Chen
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan, 430022, China
| | - Zhiqiang Hu
- Department of Anesthesiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Institute of Anesthesia and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan, 430022, China.
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24
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Yang MM, Lee S, Neely J, Hinchcliff M, Wolters PJ, Sirota M. Gene expression meta-analysis reveals aging and cellular senescence signatures in scleroderma-associated interstitial lung disease. Front Immunol 2024; 15:1326922. [PMID: 38348044 PMCID: PMC10859856 DOI: 10.3389/fimmu.2024.1326922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 01/05/2024] [Indexed: 02/15/2024] Open
Abstract
Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma-associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging- and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissues from 38 SSc-ILD and 18 healthy controls and found that markers (GDF15, COMP, and CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found that epithelial and fibroblast senescence signatures had a 3.6- and 3.7-fold enrichment, respectively, in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, and NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in the lung tissue and found that, independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.
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Affiliation(s)
- Monica M. Yang
- Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Seoyeon Lee
- Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Jessica Neely
- Division of Pediatric Rheumatology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, United States
| | - Monique Hinchcliff
- Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States
| | - Paul J. Wolters
- Division of Pulmonary, Critical Care, Allergy and Sleep Medicine, Department of Medicine, University of California, San Francisco, San Francisco, CA, United States
| | - Marina Sirota
- Department of Pediatrics, University of California, San Francisco, San Francisco, CA, United States
- Bakar Computational Health Sciences Institute, University of California, San Francisco, San Francisco, CA, United States
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Zhu W, Liu C, Tan C, Zhang J. Predictive biomarkers of disease progression in idiopathic pulmonary fibrosis. Heliyon 2024; 10:e23543. [PMID: 38173501 PMCID: PMC10761784 DOI: 10.1016/j.heliyon.2023.e23543] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 12/04/2023] [Accepted: 12/06/2023] [Indexed: 01/05/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial disease that cannot be cured, and treatment options for IPF are very limited. Early diagnosis, close monitoring of disease progression, and timely treatment are therefore the best options for patients due to the irreversibility of IPF. Effective markers help doctors judge the development and prognosis of disease. Recent research on traditional biomarkers (KL-6, SP-D, MMP-7, TIMPs, CCL18) has provided novel ideas for predicting disease progression and prognosis. Some emerging biomarkers (HE4, GDF15, PRDX4, inflammatory cells, G-CSF) also provide more possibilities for disease prediction. In addition to markers in serum and bronchoalveolar lavage fluid (BALF), some improvements related to the GAP model and chest HRCT also show good predictive ability for disease prognosis.
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Affiliation(s)
- Weiwei Zhu
- Department of Pulmonary and Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University, China
| | - Chunquan Liu
- Department of Thoracic Surgery, Beijing Friendship Hospital, Capital Medical University, China
| | - Chunting Tan
- Department of Pulmonary and Critical Care Medicine, Beijing Friendship Hospital, Capital Medical University, China
| | - Jie Zhang
- Department of Pulmonary and Critical Care Medicine, Beijing Tiantan Hospital, Capital Medical University, China
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26
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Pappas AG, Eleftheriou K, Vlahakos V, Magkouta SF, Riba T, Dede K, Siampani R, Kompogiorgas S, Polydora E, Papalampidou A, Loutsidi NE, Mantas N, Tavernaraki E, Exarchos D, Kalomenidis I. High Plasma Osteopontin Levels Are Associated with Serious Post-Acute-COVID-19-Related Dyspnea. J Clin Med 2024; 13:392. [PMID: 38256526 PMCID: PMC10816040 DOI: 10.3390/jcm13020392] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 12/30/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
COVID-19 survivors commonly report persistent symptoms. In this observational study, we investigated the link between osteopontin (OPN) and post-acute COVID-19 symptoms and lung functional/imaging abnormalities. We recorded symptoms and lung imaging/functional data from previously hospitalized COVID-19 patients, who were followed for 4-84 weeks (122 patients/181 visits) post-symptom onset at our outpatient clinic. Circulating OPN was determined using ELISA. Plasma OPN levels were higher in symptomatic patients (compared with the asymptomatic ones); those with dyspnea (compared with those without dyspnea);those with a combination of serious symptoms, i.e., the presence of at least one of the following: dyspnea, fatigue and muscular weakness (compared with those with none of these symptoms); and those with dyspnea and m-MRC > 1 (compared with those with m-MRC = 0-1). Plasma OPN levels were inversely correlated with EQ-VAS (visual analog scale of the EQ-5D-5L health-related quality-of-life questionnaire) values. High-resolution CT or diffusion lung capacity (DLCO) findings were not related to circulating OPN. In the multiple logistic regression, the presence of symptoms, dyspnea, or the combination of serious symptoms were linked to female gender, increased BMI and pre-existing dyspnea (before the acute disease), while increased plasma OPN levels, female gender and pre-existing dyspnea with m-MRC > 1 were independently associated with severe post-COVID-19 dyspnea (m-MRC > 1). Using a correlation matrix to investigate multiple correlations between EQ-VAS, OPN and epidemiological data, we observed an inverse correlation between the OPN and EQ-VAS values. Increased circulating OPN was linked to the persistence of severe exertional dyspnea and impaired quality of life in previously hospitalized COVID-19 patients.
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Affiliation(s)
- Apostolos G. Pappas
- First Department of Critical Care and Pulmonary Medicine, “Evangelismos” General Hospital, School of Medicine, National and Kapodistrian University of Athens, 10676 Athens, Greece (T.R.); (K.D.); (A.P.); (I.K.)
| | - Konstantinos Eleftheriou
- First Department of Critical Care and Pulmonary Medicine, “Evangelismos” General Hospital, School of Medicine, National and Kapodistrian University of Athens, 10676 Athens, Greece (T.R.); (K.D.); (A.P.); (I.K.)
| | - Vassilios Vlahakos
- First Department of Critical Care and Pulmonary Medicine, “Evangelismos” General Hospital, School of Medicine, National and Kapodistrian University of Athens, 10676 Athens, Greece (T.R.); (K.D.); (A.P.); (I.K.)
| | - Sophia F. Magkouta
- “Marianthi Simou Laboratory”, First Department of Critical Care and Pulmonary Medicine, “Evangelismos” General Hospital, School of Medicine, National and Kapodistrian University of Athens, 10676 Athens, Greece
| | - Theofani Riba
- First Department of Critical Care and Pulmonary Medicine, “Evangelismos” General Hospital, School of Medicine, National and Kapodistrian University of Athens, 10676 Athens, Greece (T.R.); (K.D.); (A.P.); (I.K.)
| | - Konstantina Dede
- First Department of Critical Care and Pulmonary Medicine, “Evangelismos” General Hospital, School of Medicine, National and Kapodistrian University of Athens, 10676 Athens, Greece (T.R.); (K.D.); (A.P.); (I.K.)
| | - Rafaela Siampani
- First Department of Critical Care and Pulmonary Medicine, “Evangelismos” General Hospital, School of Medicine, National and Kapodistrian University of Athens, 10676 Athens, Greece (T.R.); (K.D.); (A.P.); (I.K.)
| | - Steven Kompogiorgas
- Department of Pulmonary Medicine, “Evangelismos” General Hospital, 10676 Athens, Greece
| | - Eftychia Polydora
- First Department of Critical Care and Pulmonary Medicine, “Evangelismos” General Hospital, School of Medicine, National and Kapodistrian University of Athens, 10676 Athens, Greece (T.R.); (K.D.); (A.P.); (I.K.)
| | - Athanasia Papalampidou
- First Department of Critical Care and Pulmonary Medicine, “Evangelismos” General Hospital, School of Medicine, National and Kapodistrian University of Athens, 10676 Athens, Greece (T.R.); (K.D.); (A.P.); (I.K.)
| | - Natasa-Eleni Loutsidi
- Hematology—Lymphomas Department and Bone Marrow Transplant Unit, “Evangelismos” General Hospital, 10676 Athens, Greece;
| | - Nikolaos Mantas
- Department of CT-MRI, “Evangelismos” General Hospital, 10676 Athens, Greece (D.E.)
| | | | - Demetrios Exarchos
- Department of CT-MRI, “Evangelismos” General Hospital, 10676 Athens, Greece (D.E.)
| | - Ioannis Kalomenidis
- First Department of Critical Care and Pulmonary Medicine, “Evangelismos” General Hospital, School of Medicine, National and Kapodistrian University of Athens, 10676 Athens, Greece (T.R.); (K.D.); (A.P.); (I.K.)
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27
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Alarcon-Dionet A, Ruiz A, Chavez-Galan L, Buendia-Roldan I, Selman M. GDF15 as a potential biomarker to distinguish fibrotic from non-fibrotic hypersensitivity pneumonitis. Sci Rep 2024; 14:859. [PMID: 38195721 PMCID: PMC10776671 DOI: 10.1038/s41598-023-49459-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Accepted: 12/08/2023] [Indexed: 01/11/2024] Open
Abstract
Hypersensitivity Pneumonitis (HP) is an immune-mediated interstitial lung disease (ILD) characterized by fibrotic HP (fHP) or non-fibrotic HP (non-fHP). Fibrosis is associated with poor prognosis, emphasizing the need for biomarkers to distinguish fHP from non-fHP. This study aimed to determine the plasma levels of GDF15 in HP patients and assess its association with lung function and phenotype classification. GDF15 levels were quantified by ELISA in HP (n = 64), idiopathic pulmonary fibrosis (n = 54), and healthy control (n = 128) groups. Clinical, demographic, and functional data were obtained from medical records. High-resolution chest CT scans were used to classify HP patients into fHP and non-fHP groups. In addition, receiver operating characteristic analysis was performed to determine the cut-off point, sensitivity, and specificity. Our results revealed significantly elevated GDF15 levels in fHP compared to non-fHP (2539 ± 821 pg/ml versus 1783 ± 801 pg/ml; p = 0.009). The estimated cut-off point for plasma GDF15 levels to distinguish fHP from non-fHP was 2193.4 pg/ml (AUC 0.75). These findings suggest that GDF15 may serve as a valuable biomarker for differentiating between fHP and non-fHP, potentially indicating its involvement in lung fibrosis development in HP.
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Affiliation(s)
- A Alarcon-Dionet
- Translational Research Laboratory on Aging and Pulmonary Fibrosis, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, 14080, Mexico City, Mexico
| | - A Ruiz
- Laboratory of Integrative Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, 14080, Mexico City, Mexico
| | - L Chavez-Galan
- Laboratory of Integrative Immunology, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, 14080, Mexico City, Mexico
| | - I Buendia-Roldan
- Translational Research Laboratory on Aging and Pulmonary Fibrosis, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, 14080, Mexico City, Mexico.
| | - M Selman
- Translational Research Laboratory on Aging and Pulmonary Fibrosis, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas, 14080, Mexico City, Mexico
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Al Hamwi G, Namasivayam V, Büschbell B, Gedschold R, Golz S, Müller CE. Proinflammatory chemokine CXCL14 activates MAS-related G protein-coupled receptor MRGPRX2 and its putative mouse ortholog MRGPRB2. Commun Biol 2024; 7:52. [PMID: 38184723 PMCID: PMC10771525 DOI: 10.1038/s42003-023-05739-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Accepted: 12/21/2023] [Indexed: 01/08/2024] Open
Abstract
Patients with idiopathic pulmonary fibrosis show a strongly upregulated expression of chemokine CXCL14, whose target is still unknown. Screening of CXCL14 in a panel of human G protein-coupled receptors (GPCRs) revealed its potent and selective activation of the orphan MAS-related GPCR X2 (MRGPRX2). This receptor is expressed on mast cells and - like CXCL14 - upregulated in bronchial inflammation. CXCL14 induces robust activation of MRGPRX2 and its putative mouse ortholog MRGPRB2 in G protein-dependent and β-arrestin recruitment assays that is blocked by a selective MRGPRX2/B2 antagonist. Truncation combined with mutagenesis and computational studies identified the pharmacophoric sequence of CXCL14 and its presumed interaction with the receptor. Intriguingly, C-terminal domain sequences of CXCL14 consisting of 4 to 11 amino acids display similar or increased potency and efficacy compared to the full CXCL14 sequence (77 amino acids). These results provide a rational basis for the future development of potential idiopathic pulmonary fibrosis therapies.
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Affiliation(s)
- Ghazl Al Hamwi
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany
| | - Vigneshwaran Namasivayam
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany
| | - Beatriz Büschbell
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany
| | - Robin Gedschold
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany
| | - Stefan Golz
- Lead Identification & Characterization, Pharma Research and Development Center, Bayer AG, Wuppertal, Germany
| | - Christa E Müller
- PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
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Tang Z, Xia Z, Wang X, Liu Y. The critical role of osteopontin (OPN) in fibrotic diseases. Cytokine Growth Factor Rev 2023; 74:86-99. [PMID: 37648616 DOI: 10.1016/j.cytogfr.2023.08.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 08/22/2023] [Accepted: 08/22/2023] [Indexed: 09/01/2023]
Abstract
Fibrosis is a pathological condition characterized by the excessive deposition of extracellular matrix components in tissues and organs, leading to progressive architectural remodelling and contributing to the development of various diseases. Osteopontin (OPN), a highly phosphorylated glycoprotein, has been increasingly recognized for its involvement in the progression of tissue fibrosis. This review provides a comprehensive overview of the genetic and protein structure of OPN and focuses on our current understanding of the role of OPN in the development of fibrosis in the lungs and other tissues. Additionally, special attention is given to the potential of OPN as a biomarker and a novel therapeutic target in the treatment of fibrosis.
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Affiliation(s)
- Ziyi Tang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Rare Diseases Center, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zijing Xia
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Rare Diseases Center, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiangpeng Wang
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Department of Rheumatology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100000, China
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Laboratory of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu 610041, China; Rare Diseases Center, Institute of Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
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30
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Yang MM, Lee S, Neely J, Hinchcliff M, Wolters PJ, Sirota M. Gene Expression Meta-Analysis Reveals Aging and Cellular Senescence Signatures in Scleroderma-associated Interstitial Lung Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.06.565810. [PMID: 37986995 PMCID: PMC10659335 DOI: 10.1101/2023.11.06.565810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissue from 38 SSc-ILD and 18 healthy controls and found markers (GDF15, COMP, CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found epithelial and fibroblast senescence signatures had a 3.6-fold and 3.7-fold enrichment respectively in the lung tissue of SSc-ILD and that lung aging genes ( CDKN2A, FRZB, PDE1A, NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in lung tissue and found independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.
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31
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Fastrès A, Roels E, Tutunaru AC, Bolen G, Merveille A, Day MJ, Garigliany M, Antoine N, Clercx C. Osteopontin and fibronectin in lung tissue, serum, and bronchoalveolar lavage fluid of dogs with idiopathic pulmonary fibrosis and control dogs. J Vet Intern Med 2023; 37:2468-2477. [PMID: 37853926 PMCID: PMC10658509 DOI: 10.1111/jvim.16870] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 09/08/2023] [Indexed: 10/20/2023] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) affects West Highland white terriers (WHWTs). Osteopontin (SPP1) and fibronectin (FN1) are associated with human IPF and are overexpressed by bronchoalveolar lavage fluid (BALF) macrophages in dogs with IPF. OBJECTIVE To investigate the value of these proteins as biomarkers of IPF. ANIMALS West Highland white terriers (WHWTs) with IPF, control WHWTs, and terriers. METHODS Cross-sectional observational study. Immunohistochemistry was used to localize SPP1 and FN1 in lung tissue. Serum and BALF SPP1 and FN1 concentrations were measured using canine ELISA kits and compared between groups. RESULTS Osteopontin stained ciliated epithelial cells, smooth muscular cells, and macrophages of all included dogs, and type-II pneumocytes and extracellular matrix of all 12 diseased WHWTs, 4/6 control WHWTs, and none of the 3 terriers. Osteopontin serum concentration was higher in diseased WHWTs (n = 22; 2.15 ng/mL [0.74-5.30]) compared with control WHWTs (n = 13; 0.63 ng/mL [0.41-1.63]; P = .005) and terriers (n = 15; 0.31 ng/mL [0.19-0.51]; P < .0001), and in control WHWTs compared with terriers (P = .005). Osteopontin BALF concentrations were higher in diseased (0.27 ng/mL [0.14-0.43]) and control WHWTs (0.25 ng/mL [0.14-0.40]), compared with terriers (0.02 ng/mL [0.01-0.08]; P < .0001 and P = .003, respectively). Fibronectin (FN1) serum concentrations were lower in diseased dogs (1.03 ng/mL [0.35-1.48]) and control WHWTs (0.61 ng/mL [0.24-0.65]) compared with terriers (2.72 ng/mL [0.15-5.21]; P < .0001 and P = .0001, respectively). There was no difference in FN1 immunostaining and FN1 BALF concentrations between groups. CONCLUSIONS Results suggest that SPP1 is involved in pathogenesis of IPF and could predispose that breed to the disease. Osteopontin serum concentration could serve as a diagnostic biomarker of IPF.
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Affiliation(s)
- Aline Fastrès
- Department of Clinical Sciences, FARAH, Faculty of Veterinary MedicineUniversity of LiègeLiègeBelgium
| | - Elodie Roels
- Department of Clinical Sciences, FARAH, Faculty of Veterinary MedicineUniversity of LiègeLiègeBelgium
| | - Alexandru C. Tutunaru
- Department of Clinical Sciences, FARAH, Faculty of Veterinary MedicineUniversity of LiègeLiègeBelgium
| | - Géraldine Bolen
- Department of Clinical Sciences, FARAH, Faculty of Veterinary MedicineUniversity of LiègeLiègeBelgium
| | - Anne‐Christine Merveille
- Department of Clinical Sciences, FARAH, Faculty of Veterinary MedicineUniversity of LiègeLiègeBelgium
| | - Michael J. Day
- School of Veterinary SciencesUniversity of BristolLangfordUnited Kingdom
| | - Mutien‐Marie Garigliany
- Department of Morphology and Pathology, FARAH, Faculty of Veterinary MedicineUniversity of LiègeLiègeBelgium
| | - Nadine Antoine
- Department of Morphology and Pathology, FARAH, Faculty of Veterinary MedicineUniversity of LiègeLiègeBelgium
| | - Cécile Clercx
- Department of Clinical Sciences, FARAH, Faculty of Veterinary MedicineUniversity of LiègeLiègeBelgium
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Morlacchi LC, Zanini U, Gramegna A, Faverio P, Blasi F, Luppi F. Idiopathic interstitial pneumonia in a patient with von Hippel-Lindau syndrome: a first case. ERJ Open Res 2023; 9:00504-2023. [PMID: 38020566 PMCID: PMC10680027 DOI: 10.1183/23120541.00504-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Although the mechanisms are not known, this is a case of progressive interstitial lung involvement, with a NSIP radiological pattern, evolving in pulmonary fibrosis in a patient with von Hippel-Lindau syndrome, without extrapulmonary fibrosis. https://bit.ly/3QlNStu.
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Affiliation(s)
- Letizia Corinna Morlacchi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
- Internal Medicine Department, Respiratory Unit and Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
- These authors contributed equally
| | - Umberto Zanini
- UOC Pneumologia, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
- These authors contributed equally
| | - Andrea Gramegna
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
- Internal Medicine Department, Respiratory Unit and Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Paola Faverio
- UOC Pneumologia, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
| | - Francesco Blasi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
- Internal Medicine Department, Respiratory Unit and Cystic Fibrosis Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Fabrizio Luppi
- UOC Pneumologia, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
- School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
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Silver SV, Popovics P. The Multifaceted Role of Osteopontin in Prostate Pathologies. Biomedicines 2023; 11:2895. [PMID: 38001899 PMCID: PMC10669591 DOI: 10.3390/biomedicines11112895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 10/22/2023] [Accepted: 10/23/2023] [Indexed: 11/26/2023] Open
Abstract
The prostate gland, located beneath the bladder and surrounding the proximal urethra in men, plays a vital role in reproductive physiology and sexual health. Despite its importance, the prostate is vulnerable to various pathologies, including prostatitis, benign prostatic hyperplasia (BPH) and prostate cancer (PCa). Osteopontin (OPN), a versatile protein involved in wound healing, inflammatory responses, and fibrotic diseases, has been implicated in all three prostate conditions. The role of OPN in prostatic pathophysiology, affecting both benign and malignant prostate conditions, is significant. Current evidence strongly suggests that OPN is expressed at a higher level in prostate cancer and promotes tumor progression and aggressiveness. Conversely, OPN is primarily secreted by macrophages and foam cells in benign prostate conditions and provokes inflammation and fibrosis. This review discusses the accumulating evidence on the role of OPN in prostatic diseases, cellular sources, and potential roles while also highlighting areas for future investigations.
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Affiliation(s)
- Samara V. Silver
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23507, USA;
- Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23507, USA
| | - Petra Popovics
- Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23507, USA;
- Leroy T. Canoles Jr. Cancer Research Center, Eastern Virginia Medical School, Norfolk, VA 23507, USA
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Tomos I, Roussis I, Matthaiou AM, Dimakou K. Molecular and Genetic Biomarkers in Idiopathic Pulmonary Fibrosis: Where Are We Now? Biomedicines 2023; 11:2796. [PMID: 37893169 PMCID: PMC10604739 DOI: 10.3390/biomedicines11102796] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/05/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) represents a chronic progressive fibrotic interstitial lung disease of unknown cause with an ominous prognosis. It remains an unprecedent clinical challenge due to its delayed diagnosis and unpredictable clinical course. The need for accurate diagnostic, prognostic and predisposition biomarkers in everyday clinical practice becomes more necessary than ever to ensure prompt diagnoses and early treatment. The identification of such blood biomarkers may also unravel novel drug targets against IPF development and progression. So far, the role of diverse blood biomarkers, implicated in various pathogenetic pathways, such as in fibrogenesis (S100A4), extracellular matrix remodelling (YKL-40, MMP-7, ICAM-1, LOXL2, periostin), chemotaxis (CCL-18, IL-8), epithelial cell injury (KL-6, SP-A, SP-D), autophagy and unfolded protein response has been investigated in IPF with various results. Moreover, the recent progress in genetics in IPF allows for a better understanding of the underlying disease mechanisms. So far, the causative mutations in pulmonary fibrosis include mutations in telomere-related genes and in surfactant-related genes, markers that could act as predisposition biomarkers in IPF. The aim of this review is to provide a comprehensive overview from the bench to bedside of current knowledge and recent insights on biomarkers in IPF, and to suggest future directions for research. Large-scale studies are still needed to confirm the exact role of these biomarkers.
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Affiliation(s)
- Ioannis Tomos
- 5th Department of Respiratory Medicine, ‘SOTIRIA’ Chest Diseases Hospital of Athens, 11527 Athens, Greece; (I.R.); (A.M.M.); (K.D.)
| | - Ioannis Roussis
- 5th Department of Respiratory Medicine, ‘SOTIRIA’ Chest Diseases Hospital of Athens, 11527 Athens, Greece; (I.R.); (A.M.M.); (K.D.)
| | - Andreas M. Matthaiou
- 5th Department of Respiratory Medicine, ‘SOTIRIA’ Chest Diseases Hospital of Athens, 11527 Athens, Greece; (I.R.); (A.M.M.); (K.D.)
- Laboratory of Molecular and Cellular Pneumonology, Medical School, University of Crete, 714 09 Heraklion, Greece
- Respiratory Physiology Laboratory, Medical School, University of Cyprus, Nicosia 2029, Cyprus
| | - Katerina Dimakou
- 5th Department of Respiratory Medicine, ‘SOTIRIA’ Chest Diseases Hospital of Athens, 11527 Athens, Greece; (I.R.); (A.M.M.); (K.D.)
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Velázquez-Enríquez JM, Reyes-Avendaño I, Santos-Álvarez JC, Reyes-Jiménez E, Vásquez-Garzón VR, Baltiérrez-Hoyos R. Identification of Hub Genes in Idiopathic Pulmonary Fibrosis and Their Association with Lung Cancer by Bioinformatics Analysis. Adv Respir Med 2023; 91:407-431. [PMID: 37887075 PMCID: PMC10604190 DOI: 10.3390/arm91050032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 10/06/2023] [Accepted: 10/10/2023] [Indexed: 10/28/2023]
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible disease with a high mortality rate worldwide. However, the etiology and pathogenesis of IPF have not yet been fully described. Moreover, lung cancer is a significant complication of IPF and is associated with increased mortality. Nevertheless, identifying common genes involved in developing IPF and its progression to lung cancer remains an unmet need. The present study aimed to identify hub genes related to the development of IPF by meta-analysis. In addition, we analyzed their expression and their relationship with patients' progression in lung cancer. METHOD Microarray datasets GSE24206, GSE21369, GSE110147, GSE72073, and GSE32539 were downloaded from Gene Expression Omnibus (GEO). Next, we conducted a series of bioinformatics analysis to explore possible hub genes in IPF and evaluated the expression of hub genes in lung cancer and their relationship with the progression of different stages of cancer. RESULTS A total of 1888 differentially expressed genes (DEGs) were identified, including 1105 upregulated and 783 downregulated genes. The 10 hub genes that exhibited a high degree of connectivity from the PPI network were identified. Analysis of the KEGG pathways showed that hub genes correlate with pathways such as the ECM-receptor interaction. Finally, we found that these hub genes are expressed in lung cancer and are associated with the progression of different stages of lung cancer. CONCLUSIONS Based on the integration of GEO microarray datasets, the present study identified DEGs and hub genes that could play an essential role in the pathogenesis of IPF and its association with the development of lung cancer in these patients, which could be considered potential diagnostic biomarkers or therapeutic targets for the disease.
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Affiliation(s)
- Juan Manuel Velázquez-Enríquez
- Laboratorio de Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua, Oaxaca 68020, Mexico; (J.M.V.-E.); (I.R.-A.); (J.C.S.-Á.); (E.R.-J.); (V.R.V.-G.)
| | - Itayetzi Reyes-Avendaño
- Laboratorio de Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua, Oaxaca 68020, Mexico; (J.M.V.-E.); (I.R.-A.); (J.C.S.-Á.); (E.R.-J.); (V.R.V.-G.)
| | - Jovito Cesar Santos-Álvarez
- Laboratorio de Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua, Oaxaca 68020, Mexico; (J.M.V.-E.); (I.R.-A.); (J.C.S.-Á.); (E.R.-J.); (V.R.V.-G.)
| | - Edilburga Reyes-Jiménez
- Laboratorio de Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua, Oaxaca 68020, Mexico; (J.M.V.-E.); (I.R.-A.); (J.C.S.-Á.); (E.R.-J.); (V.R.V.-G.)
| | - Verónica Rocío Vásquez-Garzón
- Laboratorio de Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua, Oaxaca 68020, Mexico; (J.M.V.-E.); (I.R.-A.); (J.C.S.-Á.); (E.R.-J.); (V.R.V.-G.)
- CONAHCYT-Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua, Oaxaca 68020, Mexico
| | - Rafael Baltiérrez-Hoyos
- Laboratorio de Fibrosis y Cáncer, Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua, Oaxaca 68020, Mexico; (J.M.V.-E.); (I.R.-A.); (J.C.S.-Á.); (E.R.-J.); (V.R.V.-G.)
- CONAHCYT-Facultad de Medicina y Cirugía, Universidad Autónoma Benito Juárez de Oaxaca, Ex Hacienda de Aguilera S/N, Sur, San Felipe del Agua, Oaxaca 68020, Mexico
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Zhang Z, Guan Q, Tian Y, Shao X, Zhao P, Huang L, Li J. Integrated bioinformatics analysis for the identification of idiopathic pulmonary fibrosis-related genes and potential therapeutic drugs. BMC Pulm Med 2023; 23:373. [PMID: 37794454 PMCID: PMC10552267 DOI: 10.1186/s12890-023-02678-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 09/26/2023] [Indexed: 10/06/2023] Open
Abstract
OBJECTIVE The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear. We sought to identify IPF-related genes that may participate in the pathogenesis and predict potential targeted traditional Chinese medicines (TCMs). METHODS Using IPF gene-expression data, Wilcoxon rank-sum tests were performed to identify differentially expressed genes (DEGs). Protein-protein interaction (PPI) networks, hub genes, and competitive endogenous RNA (ceRNA) networks were constructed or identified by Cytoscape. Quantitative polymerase chain reaction (qPCR) experiments in TGF-β1-induced human fetal lung (HFL) fibroblast cells and a pulmonary fibrosis mouse model verified gene reliability. The SymMap database predicted potential TCMs targeting IPF. The reliability of TCMs was verified in TGF-β1-induced MRC-5 cells. MATERIALS Multiple gene-expression profile data of normal lung and IPF tissues were downloaded from the Gene Expression Omnibus database. HFL fibroblast cells and MRC-5 cells were purchased from Wuhan Procell Life Science and Technology Co., Ltd. (Wuhan, China). C57BL/12 mice were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd. (Beijing, China). RESULTS In datasets GSE134692 and GSE15197, DEGs were identified using Wilcoxon rank-sum tests (both p < 0.05). Among them, 1885 DEGs were commonly identified, and 87% (1640 genes) had identical dysregulation directions (binomial test, p < 1.00E-16). A PPI network with 1623 nodes and 8159 edges was constructed, and 18 hub genes were identified using the Analyze Network plugin in Cytoscape. Of 18 genes, CAV1, PECAM1, BMP4, VEGFA, FYN, SPP1, and COL1A1 were further validated in the GeneCards database and independent dataset GSE24206. ceRNA networks of VEGFA, SPP1, and COL1A1 were constructed. The genes were verified by qPCR in samples of TGF-β1-induced HFL fibroblast cells and pulmonary fibrosis mice. Finally, Sea Buckthorn and Gnaphalium Affine were predicted as potential TCMs for IPF. The TCMs were verified by qPCR in TGF-β1-induced MRC-5 cells. CONCLUSION This analysis strategy may be useful for elucidating novel mechanisms underlying IPF at the transcriptome level. The identified hub genes may play key roles in IPF pathogenesis and therapy.
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Affiliation(s)
- Zhenzhen Zhang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-Constructed By Henan Province and Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Qingzhou Guan
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-Constructed By Henan Province and Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, 450046, China.
| | - Yange Tian
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-Constructed By Henan Province and Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Xuejie Shao
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-Constructed By Henan Province and Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Peng Zhao
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-Constructed By Henan Province and Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Lidong Huang
- Academy of Chinese Medical Sciences, Henan University of Chinese Medicine, Zhengzhou, 450046, China
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-Constructed By Henan Province and Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, 450046, China
| | - Jiansheng Li
- Henan Key Laboratory of Chinese Medicine for Respiratory Disease, Collaborative Innovation Center for Chinese Medicine and Respiratory Diseases Co-Constructed By Henan Province and Education Ministry of P.R. China, Henan University of Chinese Medicine, Zhengzhou, 450046, China
- Department of Respiratory Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, 450000, China
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Salati NA, Sharma M, Rao NN, Shetty SS, Radhakrishnan RA. Role of osteopontin in oral epithelial dysplasia, oral submucous fibrosis and oral squamous cell carcinoma. J Oral Maxillofac Pathol 2023; 27:706-714. [PMID: 38304518 PMCID: PMC10829450 DOI: 10.4103/jomfp.jomfp_492_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/27/2022] [Accepted: 03/06/2023] [Indexed: 02/03/2024] Open
Abstract
Background Inflammatory cells and cytokines in the chronically injured mucosa promote fibrosis in the oral submucous fibrosis (OSF) fibrotic milieu. Osteopontin (OPN) is a wound-healing mediator that upregulates the inflammatory response and is involved in the malignancy and fibrosis of multiple organ systems. Objectives We investigated the expression of OPN in oral potentially malignant disorders (OPMDs) and oral squamous cell carcinomas (OSCCs) to determine its role in the malignant transformation and fibrosis of oral tissues. The expression of OPN in OPMDs and OSCCs was compared and correlated, and the role of OPN as a fibrotic mediator in OSF was explained. Study Design A total of 30 cases of normal mucosa and OPMDs (mild dysplasia, severe dysplasia, OSF and OSCCs) were studied by purposive sampling. In these groups, OPN immunoreactivity was examined and correlated with clinical findings. Results In mild dysplasia, OPN expression was restricted to the basal cell layer with moderate staining intensity. In severe dysplasia, it was extremely intense and extended throughout the epithelium. In the OSF, OPN expression was moderate in the perinuclear areas of the basal cell layer. The expression of OPN was very strong in OSCC. A flow diagram explaining the profibrotic role of OPN in OSF has been provided. Conclusion A positive role of OPN in both pathogenesis and malignant transformation of OPMDs and OSCC has been demonstrated.
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Affiliation(s)
- Nasir A. Salati
- Department of Oral and Maxillofacial Pathology, Dr. Ziauddin Ahmad Dental College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India
| | - Mohit Sharma
- Department of Oral Pathology, SGT Dental College Hospital and Research Institute, Gurugram, Haryana, India
| | - Nirmala N. Rao
- Former Dean, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Smitha S. Shetty
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Raghu A. Radhakrishnan
- Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, India
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Ouyang JF, Mishra K, Xie Y, Park H, Huang KY, Petretto E, Behmoaras J. Systems level identification of a matrisome-associated macrophage polarisation state in multi-organ fibrosis. eLife 2023; 12:e85530. [PMID: 37706477 PMCID: PMC10547479 DOI: 10.7554/elife.85530] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 09/13/2023] [Indexed: 09/15/2023] Open
Abstract
Tissue fibrosis affects multiple organs and involves a master-regulatory role of macrophages which respond to an initial inflammatory insult common in all forms of fibrosis. The recently unravelled multi-organ heterogeneity of macrophages in healthy and fibrotic human disease suggests that macrophages expressing osteopontin (SPP1) associate with lung and liver fibrosis. However, the conservation of this SPP1+ macrophage population across different tissues and its specificity to fibrotic diseases with different etiologies remain unclear. Integrating 15 single-cell RNA-sequencing datasets to profile 235,930 tissue macrophages from healthy and fibrotic heart, lung, liver, kidney, skin, and endometrium, we extended the association of SPP1+ macrophages with fibrosis to all these tissues. We also identified a subpopulation expressing matrisome-associated genes (e.g., matrix metalloproteinases and their tissue inhibitors), functionally enriched for ECM remodelling and cell metabolism, representative of a matrisome-associated macrophage (MAM) polarisation state within SPP1+ macrophages. Importantly, the MAM polarisation state follows a differentiation trajectory from SPP1+ macrophages and is associated with a core set of regulon activity. SPP1+ macrophages without the MAM polarisation state (SPP1+MAM-) show a positive association with ageing lung in mice and humans. These results suggest an advanced and conserved polarisation state of SPP1+ macrophages in fibrotic tissues resulting from prolonged inflammatory cues within each tissue microenvironment.
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Affiliation(s)
- John F Ouyang
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
| | - Kunal Mishra
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
| | - Yi Xie
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
| | - Harry Park
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
| | - Kevin Y Huang
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
| | - Enrico Petretto
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
- Institute for Big Data and Artificial Intelligence in Medicine, School of Science, China Pharmaceutical University (CPU)NanjingChina
| | - Jacques Behmoaras
- Centre for Computational Biology, Duke-NUS Medical SchoolSingaporeSingapore
- Programme in Cardiovascular and Metabolic Disorders, Duke-NUS Medical SchoolSingaporeSingapore
- Department of Immunology and Inflammation, Centre for Inflammatory Disease, Imperial College LondonLondonUnited Kingdom
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Cao Y, Zhang H, Tang XH, Tu GL, Tian Y, Luo GH, Wang YD, Wang Z, An LY, Luo MX, Tang L. Alterations in the balance of sex hormones may affect rat prostatic inflammation and fibrosis, and osteopontin might be involved in this process. Int Urol Nephrol 2023; 55:2355-2365. [PMID: 36890408 DOI: 10.1007/s11255-023-03544-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 02/28/2023] [Indexed: 03/10/2023]
Abstract
OBJECTIVE This study aimed to investigate the effects of sex hormone imbalance on rat prostatic inflammation and fibrosis and identify the key molecules involved. METHODS Castrated Sprague-Dawley (SD) rats were treated with a constant dose of oestradiol (E2) and different doses of dihydrotestosterone (DHT) to achieve different oestrogen/androgen ratios. After 8 weeks, serum E2 and DHT concentrations, relative seminal vesicle weights, histopathological changes and inflammation were measured, collagen fiber content and oestrogen receptor (ER) and androgen receptor (AR) expression were detected, mRNA sequencing and bioinformatics analysis were performed to identify differentially expressed genes (DEGs). RESULTS The severity of inflammation in the rat dorsolateral prostate (DLP) was higher, collagen fibre content and ER expression in the rat DLP and prostatic urethra were increased and AR expression in the rat DLP was decreased in the 1:1 E2/DHT-treated group than that in the 1:10 E2/DHT-treated group. RNA-seq analysis identified 487 DEGs, and striking increases in the expression of mRNAs encoding collagen, collagen synthesis and degradation enzymes, growth factors and binding proteins, cytokines and chemokines, and cell-surface molecules were confirmed in the 1:1 E2/DHT-treated group compared to the 1:10 E2/DHT-treated group. mRNA expression of secreted phosphoprotein 1 (Spp1) and protein expression of osteopontin (OPN, encoded by Spp1) were increased in the 1:1 E2/DHT-treated group compared to the 1:10 E2/DHT-treated group, and Spp1 expression correlated positively with Mmp7, Cxcl6 and Igfn1 expression. CONCLUSIONS The imbalance in the oestrogen/androgen ratio may affect rat prostatic inflammation and fibrosis, and OPN might be involved in this process.
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Affiliation(s)
- Ying Cao
- Guizhou University Medical College, Guiyang, 550025, China.
| | - Heng Zhang
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Xiao-Hu Tang
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Gui-Lan Tu
- Department of Pathology, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Ye Tian
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Guang-Heng Luo
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Yan-Dong Wang
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Zhen Wang
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Lin-Yue An
- Department of Urology, Guizhou Provincial People's Hospital, Guiyang, 550002, China
| | - Mu-Xia Luo
- Guizhou University Medical College, Guiyang, 550025, China
| | - Lei Tang
- Guizhou University Medical College, Guiyang, 550025, China
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Wei J, Zhan J, Ji H, Xu Y, Xu Q, Zhu X, Liu Y. Fibroblast Upregulation of Vitamin D Receptor Represents a Self-Protective Response to Limit Fibroblast Proliferation and Activation during Pulmonary Fibrosis. Antioxidants (Basel) 2023; 12:1634. [PMID: 37627629 PMCID: PMC10451996 DOI: 10.3390/antiox12081634] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 08/10/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
Dysregulation of vitamin D receptor (VDR) is implicated in chronic obstructive pulmonary disease. However, whether VDR dysregulation contributes to the development of pulmonary fibrosis remains largely unknown. Analysis of bulk and single-cell RNA profiling datasets revealed VDR upregulation in lung fibroblasts from patients with pulmonary fibrosis or fibrotic mice, which was validated in lung fibroblasts from bleomycin-exposed mice and bleomycin-treated fibroblasts. Stable VDR knockdown promoted, whereas the VDR agonist paricalcitol suppressed lung fibroblast proliferation and activation. Gene set enrichment analysis (GSEA) showed that the JAK/STAT pathway and unfolded protein response (UPR), a process related to endoplasmic reticulum (ER) stress, were enriched in lung fibroblasts of fibrotic lungs. Stable VDR knockdown stimulated, but paricalcitol suppressed ER stress and JAK1/STAT3 activation in lung fibroblasts. The STAT3 inhibitor blocked bleomycin- or stable VDR knockdown-induced ER stress. Paricalcitol inhibited the bleomycin-induced enrichment of STAT3 to the ATF6 promoter, thereby suppressing ATF6 expression in fibroblasts. Paricalcitol or intrapulmonary VDR overexpression inactivated JAK1/STAT3 and suppressed ER stress in bleomycin-treated mice, thus resulting in the inhibition of fibroblast proliferation and activation. Collectively, this study suggests that fibroblast VDR upregulation may be a self-protective response to limit fibroblast proliferation and activation during pulmonary fibrosis by suppressing the JAK1/STAT3/ER stress pathway.
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Affiliation(s)
- Juan Wei
- School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; (J.W.); (J.Z.); (H.J.); (Y.X.); (Q.X.)
- School of Sports and Health, Nanjing Sport Institute, Nanjing 210014, China
| | - Junhui Zhan
- School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; (J.W.); (J.Z.); (H.J.); (Y.X.); (Q.X.)
| | - Hui Ji
- School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; (J.W.); (J.Z.); (H.J.); (Y.X.); (Q.X.)
| | - Yitong Xu
- School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; (J.W.); (J.Z.); (H.J.); (Y.X.); (Q.X.)
| | - Qingfeng Xu
- School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; (J.W.); (J.Z.); (H.J.); (Y.X.); (Q.X.)
| | - Xiaoyan Zhu
- Department of Physiology, Navy Medical University, Shanghai 200433, China
| | - Yujian Liu
- School of Kinesiology, The Key Laboratory of Exercise and Health Sciences of Ministry of Education, Shanghai University of Sport, Shanghai 200438, China; (J.W.); (J.Z.); (H.J.); (Y.X.); (Q.X.)
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Drakopanagiotakis F, Markart P, Steiropoulos P. Acute Exacerbations of Interstitial Lung Diseases: Focus on Biomarkers. Int J Mol Sci 2023; 24:10196. [PMID: 37373339 DOI: 10.3390/ijms241210196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 06/07/2023] [Accepted: 06/13/2023] [Indexed: 06/29/2023] Open
Abstract
Interstitial lung diseases (ILDs) are a large group of pulmonary disorders characterized histologically by the cardinal involvement of the pulmonary interstitium. The prototype of ILDs is idiopathic pulmonary fibrosis (IPF), an incurable disease characterized by progressive distortion and loss of normal lung architecture through unchecked collagen deposition. Acute exacerbations are dramatic events during the clinical course of ILDs, associated with high morbidity and mortality. Infections, microaspiration, and advanced lung disease might be involved in the pathogenesis of acute exacerbations. Despite clinical scores, the prediction of the onset and outcome of acute exacerbations is still inaccurate. Biomarkers are necessary to characterize acute exacerbations better. We review the evidence for alveolar epithelial cell, fibropoliferation, and immunity molecules as potential biomarkers for acute exacerbations of interstitial lung disease.
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Affiliation(s)
- Fotios Drakopanagiotakis
- Department of Respiratory Medicine, Medical School, Democritus University, 68100 Alexandroupolis, Greece
| | - Philipp Markart
- Department of Respiratory Medicine, Klinikum Fulda and University Medicine Campus Fulda, Pacelliallee 4, 36043 Fulda, Germany
| | - Paschalis Steiropoulos
- Department of Respiratory Medicine, Medical School, Democritus University, 68100 Alexandroupolis, Greece
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Wang Q, Xie Z, Wan N, Yang L, Jin Z, Jin F, Huang Z, Chen M, Wang H, Feng J. Potential biomarkers for diagnosis and disease evaluation of idiopathic pulmonary fibrosis. Chin Med J (Engl) 2023; 136:1278-1290. [PMID: 37130223 PMCID: PMC10309524 DOI: 10.1097/cm9.0000000000002171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Indexed: 05/04/2023] Open
Abstract
ABSTRACT Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease characterized by progressive lung fibrogenesis and histological features of usual interstitial pneumonia. IPF has a poor prognosis and presents a spectrum of disease courses ranging from slow evolving disease to rapid deterioration; thus, a differential diagnosis remains challenging. Several biomarkers have been identified to achieve a differential diagnosis; however, comprehensive reviews are lacking. This review summarizes over 100 biomarkers which can be divided into six categories according to their functions: differentially expressed biomarkers in the IPF compared to healthy controls; biomarkers distinguishing IPF from other types of interstitial lung disease; biomarkers differentiating acute exacerbation of IPF from stable disease; biomarkers predicting disease progression; biomarkers related to disease severity; and biomarkers related to treatment. Specimen used for the diagnosis of IPF included serum, bronchoalveolar lavage fluid, lung tissue, and sputum. IPF-specific biomarkers are of great clinical value for the differential diagnosis of IPF. Currently, the physiological measurements used to evaluate the occurrence of acute exacerbation, disease progression, and disease severity have limitations. Combining physiological measurements with biomarkers may increase the accuracy and sensitivity of diagnosis and disease evaluation of IPF. Most biomarkers described in this review are not routinely used in clinical practice. Future large-scale multicenter studies are required to design and validate suitable biomarker panels that have diagnostic utility for IPF.
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Affiliation(s)
- Qing Wang
- Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China
- Department of Respiratory and Critical Care Medicine of Kunming Municipal First People's Hospital, Kunming, Yunnan 650000, China
| | - Zhaoliang Xie
- Respiratory Department of Sanming Yong’an General Hospital, Sanming, Fujian 366000, China
| | - Nansheng Wan
- Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Lei Yang
- Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Zhixian Jin
- Department of Respiratory and Critical Care Medicine of Kunming Municipal First People's Hospital, Kunming, Yunnan 650000, China
| | - Fang Jin
- Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Zhaoming Huang
- Department of Respiratory and Critical Care Medicine of Kunming Municipal First People's Hospital, Kunming, Yunnan 650000, China
| | - Min Chen
- Department of Respiratory and Critical Care Medicine of Kunming Municipal First People's Hospital, Kunming, Yunnan 650000, China
| | - Huiming Wang
- Department of Respiratory and Critical Care Medicine of Kunming Municipal First People's Hospital, Kunming, Yunnan 650000, China
| | - Jing Feng
- Department of Respiratory and Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China
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Arif M, Basu A, Wolf KM, Park JK, Pommerolle L, Behee M, Gochuico BR, Cinar R. An Integrative Multiomics Framework for Identification of Therapeutic Targets in Pulmonary Fibrosis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2207454. [PMID: 37038090 PMCID: PMC10238219 DOI: 10.1002/advs.202207454] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 02/26/2023] [Indexed: 06/04/2023]
Abstract
Pulmonary fibrosis (PF) is a heterogeneous disease with a poor prognosis. Therefore, identifying additional therapeutic modalities is required to improve outcome. However, the lack of biomarkers of disease progression hampers the preclinical to clinical translational process. Here, this work assesses and identifies progressive alterations in pulmonary function, transcriptomics, and metabolomics in the mouse lung at 7, 14, 21, and 28 days after a single dose of oropharyngeal bleomycin. By integrating multi-omics data, this work identifies two central gene subnetworks associated with multiple critical pathological changes in transcriptomics and metabolomics as well as pulmonary function. This work presents a multi-omics-based framework to establish a translational link between the bleomycin-induced PF model in mice and human idiopathic pulmonary fibrosis to identify druggable targets and test therapeutic candidates. This work also indicates peripheral cannabinoid receptor 1 (CB1 R) antagonism as a rational therapeutic target for clinical translation in PF. Mouse Lung Fibrosis Atlas can be accessed freely at https://niaaa.nih.gov/mouselungfibrosisatlas.
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Affiliation(s)
- Muhammad Arif
- Section on Fibrotic DisordersNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMD20852USA
- Laboratory of Cardiovascular Physiology and Tissue InjuryNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMD20852USA
| | - Abhishek Basu
- Section on Fibrotic DisordersNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMD20852USA
| | - Kaelin M. Wolf
- Section on Fibrotic DisordersNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMD20852USA
| | - Joshua K. Park
- Laboratory of Physiologic StudiesNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMD20852USA
| | - Lenny Pommerolle
- Section on Fibrotic DisordersNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMD20852USA
| | - Madeline Behee
- Section on Fibrotic DisordersNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMD20852USA
| | - Bernadette R. Gochuico
- Medical Genetics BranchNational Human Genome Research InstituteNational Institutes of Health (NIH)BethesdaMD20892USA
| | - Resat Cinar
- Section on Fibrotic DisordersNational Institute on Alcohol Abuse and AlcoholismNational Institutes of HealthRockvilleMD20852USA
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Zhang Y, Mo Y, Zhang Y, Yuan J, Zhang Q. MMP-3-mediated cleavage of OPN is involved in copper oxide nanoparticle-induced activation of fibroblasts. Part Fibre Toxicol 2023; 20:22. [PMID: 37217992 PMCID: PMC10201731 DOI: 10.1186/s12989-023-00532-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 05/08/2023] [Indexed: 05/24/2023] Open
Abstract
BACKGROUND Copper oxide nanoparticles (Nano-CuO) are one of the most produced and used nanomaterials. Previous studies have shown that exposure to Nano-CuO caused acute lung injury, inflammation, and fibrosis. However, the mechanisms underlying Nano-CuO-induced lung fibrosis are still unclear. Here, we hypothesized that exposure of human lung epithelial cells and macrophages to Nano-CuO would upregulate MMP-3, which cleaved osteopontin (OPN), resulting in fibroblast activation and lung fibrosis. METHODS A triple co-culture model was established to explore the mechanisms underlying Nano-CuO-induced fibroblast activation. Cytotoxicity of Nano-CuO on BEAS-2B, U937* macrophages, and MRC-5 fibroblasts were determined by alamarBlue and MTS assays. The expression or activity of MMP-3, OPN, and fibrosis-associated proteins was determined by Western blot or zymography assay. Migration of MRC-5 fibroblasts was evaluated by wound healing assay. MMP-3 siRNA and an RGD-containing peptide, GRGDSP, were used to explore the role of MMP-3 and cleaved OPN in fibroblast activation. RESULTS Exposure to non-cytotoxic doses of Nano-CuO (0.5 and 1 µg/mL) caused increased expression and activity of MMP-3 in the conditioned media of BEAS-2B and U937* cells, but not MRC-5 fibroblasts. Nano-CuO exposure also caused increased production of cleaved OPN fragments, which was abolished by MMP-3 siRNA transfection. Conditioned media from Nano-CuO-exposed BEAS-2B, U937*, or the co-culture of BEAS-2B and U937* caused activation of unexposed MRC-5 fibroblasts. However, direct exposure of MRC-5 fibroblasts to Nano-CuO did not induce their activation. In a triple co-culture system, exposure of BEAS-2B and U937* cells to Nano-CuO caused activation of unexposed MRC-5 fibroblasts, while transfection of MMP-3 siRNA in BEAS-2B and U937* cells significantly inhibited the activation and migration of MRC-5 fibroblasts. In addition, pretreatment with GRGDSP peptide inhibited Nano-CuO-induced activation and migration of MRC-5 fibroblasts in the triple co-culture system. CONCLUSIONS Our results demonstrated that Nano-CuO exposure caused increased production of MMP-3 from lung epithelial BEAS-2B cells and U937* macrophages, which cleaved OPN, resulting in the activation of lung fibroblasts MRC-5. These results suggest that MMP-3-cleaved OPN may play a key role in Nano-CuO-induced activation of lung fibroblasts. More investigations are needed to confirm whether these effects are due to the nanoparticles themselves and/or Cu ions.
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Affiliation(s)
- Yuanbao Zhang
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY 40202 USA
| | - Yiqun Mo
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY 40202 USA
| | - Yue Zhang
- Northwestern University Feinberg School of Medicine, Chicago, IL 60611 USA
| | - Jiali Yuan
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY 40202 USA
| | - Qunwei Zhang
- Department of Epidemiology and Population Health, School of Public Health and Information Sciences, University of Louisville, 485 E. Gray Street, Louisville, KY 40202 USA
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Coulis G, Jaime D, Guerrero-Juarez C, Kastenschmidt JM, Farahat PK, Nguyen Q, Pervolarakis N, McLinden K, Thurlow L, Movahedi S, Duarte J, Sorn A, Montoya E, Mozaffar I, Dragan M, Othy S, Joshi T, Hans CP, Kimonis V, MacLean AL, Nie Q, Wallace LM, Harper SQ, Mozaffar T, Hogarth MW, Bhattacharya S, Jaiswal JK, Golann DR, Su Q, Kessenbrock K, Stec M, Spencer MJ, Zamudio JR, Villalta SA. Single-cell and spatial transcriptomics identify a macrophage population associated with skeletal muscle fibrosis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.18.537253. [PMID: 37131694 PMCID: PMC10153153 DOI: 10.1101/2023.04.18.537253] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
The monocytic/macrophage system is essential for skeletal muscle homeostasis, but its dysregulation contributes to the pathogenesis of muscle degenerative disorders. Despite our increasing knowledge of the role of macrophages in degenerative disease, it still remains unclear how macrophages contribute to muscle fibrosis. Here, we used single-cell transcriptomics to determine the molecular attributes of dystrophic and healthy muscle macrophages. We identified six novel clusters. Unexpectedly, none corresponded to traditional definitions of M1 or M2 macrophage activation. Rather, the predominant macrophage signature in dystrophic muscle was characterized by high expression of fibrotic factors, galectin-3 and spp1. Spatial transcriptomics and computational inferences of intercellular communication indicated that spp1 regulates stromal progenitor and macrophage interactions during muscular dystrophy. Galectin-3 + macrophages were chronically activated in dystrophic muscle and adoptive transfer assays showed that the galectin-3 + phenotype was the dominant molecular program induced within the dystrophic milieu. Histological examination of human muscle biopsies revealed that galectin-3 + macrophages were also elevated in multiple myopathies. These studies advance our understanding of macrophages in muscular dystrophy by defining the transcriptional programs induced in muscle macrophages, and reveal spp1 as a major regulator of macrophage and stromal progenitor interactions.
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Affiliation(s)
- Gerald Coulis
- Department of Physiology and Biophysics, University of California Irvine, USA
- Institute for Immunology, University of California Irvine, USA
| | - Diego Jaime
- Department of Physiology and Biophysics, University of California Irvine, USA
- Institute for Immunology, University of California Irvine, USA
| | - Christian Guerrero-Juarez
- Department of Mathematics, University of California Irvine, USA
- Department of Developmental and Cell Biology, University of California Irvine, USA
| | - Jenna M. Kastenschmidt
- Department of Physiology and Biophysics, University of California Irvine, USA
- Institute for Immunology, University of California Irvine, USA
| | - Philip K. Farahat
- Department of Physiology and Biophysics, University of California Irvine, USA
- Institute for Immunology, University of California Irvine, USA
| | - Quy Nguyen
- Department of Biological Chemistry, University of California Irvine, USA
| | | | - Katherine McLinden
- Department of Molecular Cell and Developmental Biology, University of California Los Angeles, USA
| | - Lauren Thurlow
- Department of Molecular Cell and Developmental Biology, University of California Los Angeles, USA
| | - Saba Movahedi
- Department of Physiology and Biophysics, University of California Irvine, USA
| | - Jorge Duarte
- Department of Physiology and Biophysics, University of California Irvine, USA
| | - Andrew Sorn
- Department of Physiology and Biophysics, University of California Irvine, USA
| | - Elizabeth Montoya
- Department of Physiology and Biophysics, University of California Irvine, USA
| | - Izza Mozaffar
- Department of Physiology and Biophysics, University of California Irvine, USA
| | - Morgan Dragan
- Department of Molecular Cell and Developmental Biology, University of California Los Angeles, USA
| | - Shivashankar Othy
- Department of Physiology and Biophysics, University of California Irvine, USA
- Institute for Immunology, University of California Irvine, USA
| | - Trupti Joshi
- Department of Health Management and Informatics, University of Missouri, Columbia, USA
| | - Chetan P. Hans
- Department of Cardiovascular Medicine, University of Missouri, Columbia, USA
| | | | - Adam L. MacLean
- Department of Quantitative and Computational Biology, University of Southern California, Los Angeles, USA
| | - Qing Nie
- Department of Mathematics, University of California Irvine, USA
- Department of Developmental and Cell Biology, University of California Irvine, USA
| | - Lindsay M. Wallace
- Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Children’s Hospital
| | - Scott Q. Harper
- Department of Pediatrics, The Ohio State University, Columbus, OH, USA
- Center for Gene Therapy, The Abigail Wexner Research Institute at Nationwide Children’s Hospital
| | - Tahseen Mozaffar
- Department of Neurology, University of California Irvine, USA
- Department of Pathology and Laboratory Medicine, University of California Irvine, USA
| | - Marshall W. Hogarth
- Children’s National Hospital, Research Center for Genetic Medicine, Washington, DC, USA
| | - Surajit Bhattacharya
- Children’s National Hospital, Research Center for Genetic Medicine, Washington, DC, USA
| | - Jyoti K. Jaiswal
- Children’s National Hospital, Research Center for Genetic Medicine, Washington, DC, USA
| | | | - Qi Su
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
| | - Kai Kessenbrock
- Department of Biological Chemistry, University of California Irvine, USA
| | - Michael Stec
- Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA
| | | | - Jesse R. Zamudio
- Department of Molecular Cell and Developmental Biology, University of California Los Angeles, USA
| | - S. Armando Villalta
- Department of Physiology and Biophysics, University of California Irvine, USA
- Institute for Immunology, University of California Irvine, USA
- Department of Neurology, University of California Irvine, USA
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Rizzi M, D'Onghia D, Tonello S, Minisini R, Colangelo D, Bellan M, Castello LM, Gavelli F, Avanzi GC, Pirisi M, Sainaghi PP. COVID-19 Biomarkers at the Crossroad between Patient Stratification and Targeted Therapy: The Role of Validated and Proposed Parameters. Int J Mol Sci 2023; 24:ijms24087099. [PMID: 37108262 PMCID: PMC10138390 DOI: 10.3390/ijms24087099] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/06/2023] [Accepted: 04/10/2023] [Indexed: 04/29/2023] Open
Abstract
Clinical knowledge about SARS-CoV-2 infection mechanisms and COVID-19 pathophysiology have enormously increased during the pandemic. Nevertheless, because of the great heterogeneity of disease manifestations, a precise patient stratification at admission is still difficult, thus rendering a rational allocation of limited medical resources as well as a tailored therapeutic approach challenging. To date, many hematologic biomarkers have been validated to support the early triage of SARS-CoV-2-positive patients and to monitor their disease progression. Among them, some indices have proven to be not only predictive parameters, but also direct or indirect pharmacological targets, thus allowing for a more tailored approach to single-patient symptoms, especially in those with severe progressive disease. While many blood test-derived parameters quickly entered routine clinical practice, other circulating biomarkers have been proposed by several researchers who have investigated their reliability in specific patient cohorts. Despite their usefulness in specific contexts as well as their potential interest as therapeutic targets, such experimental markers have not been implemented in routine clinical practice, mainly due to their higher costs and low availability in general hospital settings. This narrative review will present an overview of the most commonly adopted biomarkers in clinical practice and of the most promising ones emerging from specific population studies. Considering that each of the validated markers reflects a specific aspect of COVID-19 evolution, embedding new highly informative markers into routine clinical testing could help not only in early patient stratification, but also in guiding a timely and tailored method of therapeutic intervention.
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Affiliation(s)
- Manuela Rizzi
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Davide D'Onghia
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Stelvio Tonello
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Donato Colangelo
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Mattia Bellan
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Luigi Mario Castello
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Francesco Gavelli
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Gian Carlo Avanzi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
| | - Pier Paolo Sainaghi
- Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy
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Uehara Y, Tanaka Y, Zhao S, Nikolaidis NM, Pitstick LB, Wu H, Yu JJ, Zhang E, Hasegawa Y, Noel JG, Gardner JC, Kopras EJ, Haffey WD, Greis KD, Guo J, Woods JC, Wikenheiser-Brokamp KA, Kyle JE, Ansong C, Teitelbaum SL, Inoue Y, Altinişik G, Xu Y, McCormack FX. Insights into pulmonary phosphate homeostasis and osteoclastogenesis emerge from the study of pulmonary alveolar microlithiasis. Nat Commun 2023; 14:1205. [PMID: 36864068 PMCID: PMC9981730 DOI: 10.1038/s41467-023-36810-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 02/17/2023] [Indexed: 03/04/2023] Open
Abstract
Pulmonary alveolar microlithiasis is an autosomal recessive lung disease caused by a deficiency in the pulmonary epithelial Npt2b sodium-phosphate co-transporter that results in accumulation of phosphate and formation of hydroxyapatite microliths in the alveolar space. The single cell transcriptomic analysis of a pulmonary alveolar microlithiasis lung explant showing a robust osteoclast gene signature in alveolar monocytes and the finding that calcium phosphate microliths contain a rich protein and lipid matrix that includes bone resorbing osteoclast enzymes and other proteins suggested a role for osteoclast-like cells in the host response to microliths. While investigating the mechanisms of microlith clearance, we found that Npt2b modulates pulmonary phosphate homeostasis through effects on alternative phosphate transporter activity and alveolar osteoprotegerin, and that microliths induce osteoclast formation and activation in a receptor activator of nuclear factor-κB ligand and dietary phosphate dependent manner. This work reveals that Npt2b and pulmonary osteoclast-like cells play key roles in pulmonary homeostasis and suggest potential new therapeutic targets for the treatment of lung disease.
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Affiliation(s)
- Yasuaki Uehara
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
| | - Yusuke Tanaka
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Shuyang Zhao
- Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Nikolaos M Nikolaidis
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lori B Pitstick
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Huixing Wu
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jane J Yu
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Erik Zhang
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Yoshihiro Hasegawa
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - John G Noel
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jason C Gardner
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Elizabeth J Kopras
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Wendy D Haffey
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Kenneth D Greis
- Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jinbang Guo
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Jason C Woods
- Center for Pulmonary Imaging Research, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | | | - Jennifer E Kyle
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Charles Ansong
- Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA
| | - Steven L Teitelbaum
- Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA
| | - Yoshikazu Inoue
- Department of Diffuse Lung Diseases and Respiratory Failure, Clinical Research Center, National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japan
| | - Göksel Altinişik
- Department of Chest Diseases, Faculty of Medicine, Pamukkale University, Pamukkale, Turkey
| | - Yan Xu
- Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
- Departments of Pediatrics and Biomedical Informatics, University of Cincinnati School of Medicine, Cincinnati, OH, USA.
| | - Francis X McCormack
- Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Karabulut Uzunçakmak S, Aksakal A, Kerget F, Aydın P, Halıcı Z. Evaluation of IGFBP5 expression and plasma osteopontin level in COVID-19 patients. Adv Med Sci 2023; 68:31-37. [PMID: 36427358 PMCID: PMC9640409 DOI: 10.1016/j.advms.2022.11.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 10/07/2022] [Accepted: 11/02/2022] [Indexed: 11/09/2022]
Abstract
PURPOSE The aim of this study is to investigate insulin-like growth factor binding protein 5 (IGFBP5) expression in coronavirus disease 2019 (COVID-19) patients and its relationships with COVID-19 laboratory findings and plasma osteopontin (OPN) levels. MATERIALS AND METHODS We enrolled 60 patients with COVID-19 and 30 healthy individuals in this study. mRNA expression of IGFBP5 was measured by RT-PCR. Plasma OPN levels were measured via the ELISA method. RESULTS Plasma OPN levels were higher and IGFBP5 expression levels were lower in COVID-19 patients than in the healthy individuals (p = 0.0057 and p = 0.0142, respectively). Critically ill patients had higher OPN and lower IGFBP5 than non-critically ill patients. Patients with affected lungs demonstrated increased OPN and decreased IGFBP5 (p = 0.00032 and p = 0.044, respectively). Receiver operating characteristic (ROC) analysis indicated that IGFBP5 expression and OPN levels can be used discriminate non-critically from critically ill patients (p = 0.049; p = 0.0016, respectively). CONCLUSION This study demonstrated that patients with a poor prognosis had increased OPN and decreased IGFBP5. High values of OPN and low values of IGFBP5 may be considered as signs of disease severity. Tissue-specific IGFBP5 expression may contribute to understanding the role of IGFBP5 in the lungs in COVID-19 cases.
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Affiliation(s)
- Sevgi Karabulut Uzunçakmak
- Health Services Vocational School, Bayburt University, Bayburt, Turkey,Corresponding author. Health Services Vocational School, Bayburt University, Gençosman Street, Bayburt, 69000, Turkey
| | - Alperen Aksakal
- Department of Chest Diseases, Erzurum Regional Education and Research Hospital, Erzurum, Turkey
| | - Ferhan Kerget
- Department of Infectious and Clinical Microbiology Diseases, Erzurum Regional Education and Research Hospital, Erzurum, Turkey
| | - Pelin Aydın
- Department of Anesthesiology and Reanimation, Erzurum Regional Training and Research Hospital, Erzurum, Turkey
| | - Zekai Halıcı
- Faculty of Medicine, Department of Pharmacology, Ataturk University, Erzurum, Turkey,Clinical Research, Development and Design Application and Research Center, Ataturk University, Erzurum, Turkey
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Chang M. Matrix metalloproteinase profiling and their roles in disease. RSC Adv 2023; 13:6304-6316. [PMID: 36825288 PMCID: PMC9942564 DOI: 10.1039/d2ra07005g] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 01/24/2023] [Indexed: 02/25/2023] Open
Abstract
Matrix metalloproteinases (MMPs) play roles in remodelling of the extracellular matrix that occurs during morphogenesis, repair, and angiogenesis. Dysregulation of extracellular matrix remodelling can lead to cell proliferation, invasion, and tissue fibrosis. Identification of a specific MMP(s) in a disease has been challenging due to the presence of 24 closely-related human MMPs, each existing in three forms, of which only one is active and capable of catalysis. This review focuses on methods for MMP profiling, with particular emphasis on the batimastat affinity resin that binds only to the active forms of MMPs and related ADAMs (a disintegrin and metalloproteinases), which are then identified by mass spectrometry. Use of the batimastat affinity resin has identified targets for intervention in several human diseases.
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Affiliation(s)
- Mayland Chang
- Department of Chemistry and Biochemistry, University of Notre Dame Notre Dame IN 46556 USA
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50
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Bao S, Chen Z, Qin D, Xu H, Deng X, Zhang R, Ma J, Lu Z, Jiang S, Zhang X. Single-cell profiling reveals mechanisms of uncontrolled inflammation and glycolysis in decidual stromal cell subtypes in recurrent miscarriage. Hum Reprod 2023; 38:57-74. [PMID: 36355621 DOI: 10.1093/humrep/deac240] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 10/08/2022] [Indexed: 11/12/2022] Open
Abstract
STUDY QUESTION Do distinct subpopulations of decidual stromal cells (DSCs) exist and if so, are given subpopulations enriched in recurrent miscarriage (RM)? SUMMARY ANSWER Three subpopulations of DSCs were identified from which inflammatory DSCs (iDSCs) and glycolytic DSCs (glyDSCs) are significantly enriched in RM, with implicated roles in driving decidual inflammation and immune dysregulation. WHAT IS KNOWN ALREADY DSCs play crucial roles in establishing and maintaining a successful pregnancy; dysfunction of DSCs has been considered as one of the key reasons for the development of RM. STUDY DESIGN, SIZE, DURATION We collected 15 early decidual samples from five healthy donors (HDs) and ten RM patients to perform single-cell RNA sequencing (scRNA-seq). A total of 43 RM patients and 37 HDs were enrolled in the validation cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS Non-immune cells and immune cells of decidual tissues were sorted by flow cytometry to perform scRNA-seq. We used tissue microarrays (TMA) to validate three distinct subpopulations of DSCs. The expression of inflammatory and glycolytic proteins by DSCs was validated by immunohistochemistry (IHC) and multiplex immunohistochemistry (mIHC). Different subsets of decidual NK (dNK) cells and macrophages were also validated by multicolor flow cytometry and mIHC. Cell ligand-receptor and spatial analyses between DSCs and immune cells were analyzed by mIHC. MAIN RESULTS AND THE ROLE OF CHANCE We classify the DSCs into three subtypes based on scRNA-seq data: myofibroblastic (myDSCs), inflammatory (iDSCs) and glycolytic (glyDSCs), with the latter two being significantly enriched in RM patients. The distribution patterns of DSC subtypes in the RM and HD groups were validated by mIHC. Single-cell analyses indicate that the differentiation of iDSCs and glyDSCs may be coupled with the degrees of hypoxia. Consequently, we propose a pathological model in which a vicious circle is formed and fueled by hypoxic stress, uncontrolled inflammation and aberrant glycolysis. Furthermore, our results show that the inflammatory SPP1+ macrophages and CD18+ dNK cells are preferentially increased in the decidua of RM patients. Cell ligand-receptor and mIHC spatial analyses uncovered close interactions between pathogenic DSCs and inflammatory SPP1+ macrophages and CD18+ NK cells in RM patients. LARGE SCALE DATA The raw single-cell sequence data reported in this paper were deposited at the National Omics Data Encyclopedia (www.biosino.org), under the accession number OEP002901. LIMITATIONS, REASONS FOR CAUTION The number of decidual samples for scRNA-seq was limited and in-depth functional studies on DSCs are warranted in future studies. WIDER IMPLICATIONS OF THE FINDINGS Identification of three DSC subpopulations opens new avenues for further investigation of their roles in RM patients. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Strategic Priority Research Program (No. XDB29030302), Frontier Science Key Research Project (QYZDB-SSW-SMC036), Chinese Academy of Sciences; National Key Research and Development Program of China (2021YFE0200600), National Natural Science Foundation of China (No. 31770960), Shanghai Municipal Science and Technology Major Project (No. 2019SHZDZX02, HS2021SHZX001), and Shanghai Committee of Science and Technology (17411967800). All authors report no conflict of interest.
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Affiliation(s)
- Shihua Bao
- Department of Reproductive Immunology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.,Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Zechuan Chen
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences/University of Chinese Academy of Sciences, Shanghai, China
| | - Dengke Qin
- Department of Reproductive Immunology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.,Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Huihui Xu
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences/University of Chinese Academy of Sciences, Shanghai, China
| | - Xujing Deng
- Department of Reproductive Immunology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.,Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Ruixiu Zhang
- Department of Reproductive Immunology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.,Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Jiaqiang Ma
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences/University of Chinese Academy of Sciences, Shanghai, China
| | - Zhouping Lu
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.,Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Shan Jiang
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences/University of Chinese Academy of Sciences, Shanghai, China
| | - Xiaoming Zhang
- The Center for Microbes, Development and Health, Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences/University of Chinese Academy of Sciences, Shanghai, China.,Shanghai Huashen Institute of Microbes and Infections, Shanghai, China
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