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Hassan M, Ali AS, Zubairi ABS, Padhani ZA, Kirmani S, Ahmad H, Fatmi Z, Das JK. Gene polymorphisms and risk of idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Monaldi Arch Chest Dis 2024. [PMID: 39480160 DOI: 10.4081/monaldi.2024.2952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 09/09/2024] [Indexed: 11/02/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) has been widely hypothesized to occur as a result of an interplay between a nexus of environmental and genetic risk factors. However, not much is known about the genetic aspect of this disease. The objective of this review was to identify the genetic polymorphisms associated with the risk of developing IPF. We searched PubMed, EBSCO CINAHL Plus, Web of Science, and Wiley Cochrane Library databases for studies on risk factors of IPF published between March 2000 and November 2023. Studies with an IPF diagnosis based only on the American Thoracic Society and the European Respiratory Society guidelines were included. Thirty-one case-control studies were included with 3997 IPF and 20,925 non-IPF subjects. Two of the studies enrolled biopsy-proven IPF patients; 13 studies diagnosed IPF on the basis of clinical and high-resolution computed tomography (HRCT) findings; and 14 studies diagnosed based on both biopsy and clinical and HRCT findings. 16 studies with MUC5B rs35705950, IL-4 rs2243250, IL-4 rs2070874, and tumor necrosis factor α (TNFα)-308 were eligible for meta-analysis. The allele contrast model (T versus G) for MUC5B rs35705950 revealed statistically significant association of T allele with the risk of IPF [odds ratio (OR) 3.84, 95% confidence interval (CI) 3.20 to 4.61, adjusted p<0.0001), as was the allele contrast model for Asian (OR 2.83, 95% CI 1.51 to 5.32, adjusted p=0.009) and Caucasian (OR 4.11, 95% CI 3.56 to 4.75, adjusted p<0.0001). The allele contrast models for IL-4 rs2243250, IL-4 rs2070874, and TNFα-308 did not demonstrate any significant association with IPF. This review suggests an association of MUC5B rs35705950 T allele with the risk of developing IPF. To our knowledge, this study is the first to aggregate several genetic polymorphisms associated with IPF.
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Affiliation(s)
- Maryam Hassan
- Department of Medicine, Aga Khan University Hospital, Karachi
| | | | - Ali Bin Sarwar Zubairi
- Department of Medicine, Aga Khan University Hospital, Karachi, Pakistan; Department of Medicine, Southern Illinois University School of Medicine, Springfield, IL
| | - Zahra Ali Padhani
- Faculty of Health and Medical Sciences, School of Public Health, University of Adelaide
| | - Salman Kirmani
- Department of Pediatrics and Child Health, Aga Khan University Hospital, Karachi
| | - Huzaifa Ahmad
- Department of Medicine, Aga Khan University Hospital, Karachi
| | - Zafar Fatmi
- Department of Community Health Sciences, Aga Khan University Hospital, Karachi
| | - Jai K Das
- Department of Pediatrics and Child Health, Aga Khan University Hospital, Karachi; Institute of Global Health and Development, Aga Khan University, Karachi
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Long E, Rider CF, Carlsten C. Controlled human exposures: a review and comparison of the health effects of diesel exhaust and wood smoke. Part Fibre Toxicol 2024; 21:44. [PMID: 39444041 PMCID: PMC11515699 DOI: 10.1186/s12989-024-00603-8] [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: 06/14/2024] [Accepted: 09/24/2024] [Indexed: 10/25/2024] Open
Abstract
One of the most pressing issues in global health is air pollution. Emissions from traffic-related air pollution and biomass burning are two of the most common sources of air pollution. Diesel exhaust (DE) and wood smoke (WS) have been used as models of these pollutant sources in controlled human exposure (CHE) experiments. The aim of this review was to compare the health effects of DE and WS using results obtained from CHE studies. A total of 119 CHE-DE publications and 25 CHE-WS publications were identified for review. CHE studies of DE generally involved shorter exposure durations and lower particulate matter concentrations, and demonstrated more potent dysfunctional outcomes than CHE studies of WS. In the airways, DE induces neutrophilic inflammation and increases airway hyperresponsiveness, but the effects of WS are unclear. There is strong evidence that DE provokes systemic oxidative stress and inflammation, but less evidence exists for WS. Exposure to DE was more prothrombotic than WS. DE generally increased cardiovascular dysfunction, but limited evidence is available for WS. Substantial heterogeneity in experimental methodology limited the comparison between studies. In many areas, outcomes of WS exposures tended to trend in similar directions to those of DE, suggesting that the effects of DE exposure may be useful for inferring possible responses to WS. However, several gaps in the literature were identified, predominantly pertaining to elucidating the effects of WS exposure. Future studies should strongly consider performing head-to-head comparisons between DE and WS using a CHE design to determine the differential effects of these exposures.
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Affiliation(s)
- Erin Long
- Faculty of Medicine, University of British Columbia, 317 - 2194 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
| | - Christopher F Rider
- Department of Medicine, Division of Respiratory Medicine, University of British Columbia, 2775 Laurel Street 7th Floor, Vancouver, BC, V5Z 1M9, Canada
| | - Christopher Carlsten
- Department of Medicine, Division of Respiratory Medicine, University of British Columbia, 2775 Laurel Street 7th Floor, Vancouver, BC, V5Z 1M9, Canada.
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Wang L, Wu P, Liu Y, Patel DC, Leonard TB, Zhao H. Clustering-aided prediction of outcomes in patients with idiopathic pulmonary fibrosis. Respir Res 2024; 25:383. [PMID: 39443991 PMCID: PMC11515489 DOI: 10.1186/s12931-024-03015-6] [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: 06/26/2024] [Accepted: 10/15/2024] [Indexed: 10/25/2024] Open
Abstract
BACKGROUND Blood biomarkers predictive of the progression of idiopathic pulmonary fibrosis (IPF) would be of value for research and clinical practice. We used data from the IPF-PRO Registry to investigate whether the addition of "omics" data to risk prediction models based on demographic and clinical characteristics improved prediction of the progression of IPF. METHODS The IPF-PRO Registry enrolled patients with IPF at 46 sites across the US. Patients were followed prospectively. Median follow-up was 27.2 months. Prediction models for disease progression included omics data (proteins and microRNAs [miRNAs]), demographic factors and clinical factors, all assessed at enrollment. Data on proteins and miRNAs were included in the models either as raw values or based on clusters in various combinations. Least absolute shrinkage and selection operator (Lasso) Cox regression was applied for time-to-event composite outcomes and logistic regression with L1 penalty was applied for binary outcomes assessed at 1 year. Model performance was assessed using Harrell's C-index (for time-to-event outcomes) or area under the curve (for binary outcomes). RESULTS Data were analyzed from 231 patients. The models based on demographic and clinical factors, with or without omics data, were the top-performing models for prediction of all the time-to-event outcomes. Relative changes in average C-index after incorporating omics data into models based on demographic and clinical factors ranged from 1.7 to 3.2%. Of the blood biomarkers, surfactant protein-D, serine protease inhibitor A7 and matrix metalloproteinase-9 (MMP-9) were among the top predictors of the outcomes. For the binary outcomes, models based on demographics alone and models based on demographics plus omics data had similar performances. Of the blood biomarkers, CC motif chemokine 11, vascular cell adhesion protein-1, adiponectin, carcinoembryonic antigen and MMP-9 were the most important predictors of the binary outcomes. CONCLUSIONS We identified circulating protein and miRNA biomarkers associated with the progression of IPF. However, the integration of omics data into prediction models that included demographic and clinical factors did not materially improve the performance of the models. TRIAL REGISTRATION ClinicalTrials.gov; No: NCT01915511; registered August 5, 2013; URL: www. CLINICALTRIALS gov .
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Affiliation(s)
- Lijun Wang
- Boehringer Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Road, Ridgefield, CT, 06877, USA.
- Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
| | - Peitao Wu
- Boehringer Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Road, Ridgefield, CT, 06877, USA
| | - Yi Liu
- Boehringer Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Road, Ridgefield, CT, 06877, USA
| | - Divya C Patel
- Boehringer Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Road, Ridgefield, CT, 06877, USA
| | - Thomas B Leonard
- Boehringer Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Road, Ridgefield, CT, 06877, USA
| | - Hongyu Zhao
- Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA
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Lavis P, Garabet A, Cardozo AK, Bondue B. The fibroblast activation protein alpha as a biomarker of pulmonary fibrosis. Front Med (Lausanne) 2024; 11:1393778. [PMID: 39364020 PMCID: PMC11446883 DOI: 10.3389/fmed.2024.1393778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 08/30/2024] [Indexed: 10/05/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a rare, chronic, and progressive interstitial lung disease with an average survival of approximately 3 years. The evolution of IPF is unpredictable, with some patients presenting a relatively stable condition with limited progression over time, whereas others deteriorate rapidly. In addition to IPF, other interstitial lung diseases can lead to pulmonary fibrosis, and up to a third have a progressive phenotype with the same prognosis as IPF. Clinical, biological, and radiological risk factors of progression were identified, but no specific biomarkers of fibrogenesis are currently available. A recent interest in the fibroblast activation protein alpha (FAPα) has emerged. FAPα is a transmembrane serine protease with extracellular activity. It can also be found in a soluble form, also named anti-plasmin cleaving enzyme (APCE). FAPα is specifically expressed by activated fibroblasts, and quinoline-based specific inhibitors (FAPI) were developed, allowing us to visualize its distribution in vivo by imaging techniques. In this review, we discuss the use of FAPα as a useful biomarker for the progression of lung fibrosis, by both its assessment in human fluids and/or its detection by imaging techniques and immunohistochemistry.
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Affiliation(s)
- Philomène Lavis
- Department of Pathology, Hôpital universitaire de Bruxelles, Université libre de Bruxelles, Brussels, Belgium
- IRIBHM, Université libre de Bruxelles, Brussels, Belgium
| | - Ani Garabet
- Inflammation and Cell Death Signalling Group, Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, Brussels, Belgium
| | - Alessandra Kupper Cardozo
- Inflammation and Cell Death Signalling Group, Signal Transduction and Metabolism Laboratory, Université libre de Bruxelles, Brussels, Belgium
| | - Benjamin Bondue
- IRIBHM, Université libre de Bruxelles, Brussels, Belgium
- Department of Pneumology, Hôpital universitaire de Bruxelles, Université libre de Bruxelles, Brussels, Belgium
- European Reference Network for Rare Pulmonary Diseases (ERN-LUNG), Frankfurt, Germany
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Ajaykumar CB, Rajkumar S, Suresh B, Birappa G, Gowda DAA, Jayachandran A, Kim KS, Hong SH, Ramakrishna S. Advances in applications of the CRISPR/Cas9 system for respiratory diseases. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 210:127-147. [PMID: 39824578 DOI: 10.1016/bs.pmbts.2024.07.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/20/2025]
Abstract
Genetic and environmental factors can have an impact on lung and respiratory disorders which are associated with severe symptoms and have high mortality rates. Many respiratory diseases are significantly influenced by genetic or epigenetic factors. Gene therapy offers a powerful approach providing therapeutic treatment for lung diseases. Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (CRISPR/Cas9) are promising gene modifying tool that can edit the genome. The utilization of CRISPR/Cas9 systems in the investigation of respiratory disorders has resulted in advancements such as the rectification of deleterious mutations in patient-derived cells and the alteration of genes in multiple mammalian lung disease models. New avenues of treatment for lung disorders have been opened up by advances in CRISPR/Cas9 research. In this chapter, we discuss the known genes and mutations that cause several common respiratory disorders such as COPD, asthma, IPF, and ARDS. We further review the current research using CRISPR/Cas9 in numerous respiratory disorders and possible therapeutic treatments.
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Affiliation(s)
- C Bindu Ajaykumar
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Sripriya Rajkumar
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Bharathi Suresh
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Girish Birappa
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - D A Ayush Gowda
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
| | - Aparna Jayachandran
- Fiona Elsey Cancer Research Institute, VIC, Australia; Federation University, VIC, Australia
| | - Kye-Seong Kim
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea; College of Medicine, Hanyang University, Seoul, Korea.
| | | | - Suresh Ramakrishna
- Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea; College of Medicine, Hanyang University, Seoul, Korea.
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Maher TM, Jenkins RG, Cottin V, Nishioka Y, Noth I, Selman M, Song JW, Ittrich C, Diefenbach C, Stowasser S, White ES. Circulating biomarkers and progression of idiopathic pulmonary fibrosis: data from the INMARK trial. ERJ Open Res 2024; 10:00335-2023. [PMID: 39040590 PMCID: PMC11261372 DOI: 10.1183/23120541.00335-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 03/16/2024] [Indexed: 07/24/2024] Open
Abstract
Background We used data from the INMARK trial to investigate associations between circulating biomarkers of extracellular matrix (ECM) turnover, inflammation and epithelial dysfunction and disease progression in subjects with idiopathic pulmonary fibrosis (IPF). Methods Subjects with IPF and forced vital capacity (FVC) ≥80% predicted were randomised 1:2 to receive nintedanib 150 mg twice daily or placebo for 12 weeks followed by open-label nintedanib for 40 weeks. Associations between baseline biomarker levels and the proportion of subjects with disease progression (decline in FVC ≥10% predicted or death) over 52 weeks were assessed in subjects randomised to placebo using logistic regression. Associations between baseline demographic/clinical characteristics and biomarker levels and disease progression over 52 weeks were analysed using multivariate models. Results Of 230 subjects who received placebo for 12 weeks then open-label nintedanib for 40 weeks, 70 (30.4%) had disease progression over 52 weeks. Baseline levels of CRPM (C-reactive protein (CRP) degraded by matrix metalloproteinase (MMP)-1/8), C3M (collagen 3 degraded by MMP-9), CRP, KL-6 (Krebs von den Lungen-6) and SP-D (surfactant protein D) were not significantly associated with disease progression over 52 weeks in analyses corrected for multiple comparisons. In models including only baseline demographic/clinical characteristics, 61.2-64.2% of subjects were correctly classified as having or not having disease progression over 52 weeks. When both demographic/clinical characteristics and biomarker levels were included in the models, 50.0-64.5% of the test set were correctly classified. Conclusions Among subjects with IPF and preserved FVC, multivariate models based on demographic/clinical characteristics and biomarker levels at baseline did not provide an accurate prediction of which patients would progress.
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Affiliation(s)
- Toby M. Maher
- National Heart and Lung Institute, Imperial College London, London, UK
- Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - R. Gisli Jenkins
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Vincent Cottin
- National Reference Coordinating Centre for Rare Pulmonary Diseases, Louis Pradel Hospital, Hospices Civils de Lyon, Claude Bernard University Lyon 1, UMR754, Lyon, France
| | - Yasuhiko Nishioka
- Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
| | - Imre Noth
- Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA, USA
| | - Moisés Selman
- Instituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas”, Mexico City, Mexico
| | - Jin Woo Song
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Carina Ittrich
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Claudia Diefenbach
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany
| | - Susanne Stowasser
- Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
| | - Eric S. White
- Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
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Zhong C, Lei Y, Zhang J, Zheng Q, Liu Z, Xu Y, Shan S, Ren T. Prognostic Function and Immunologic Landscape of a Predictive Model Based on Five Senescence-Related Genes in IPF Bronchoalveolar Lavage Fluid. Biomedicines 2024; 12:1246. [PMID: 38927453 PMCID: PMC11201203 DOI: 10.3390/biomedicines12061246] [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: 04/15/2024] [Revised: 05/19/2024] [Accepted: 05/28/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease characterized by unknown causes and a poor prognosis. Recent research indicates that age-related mechanisms, such as cellular senescence, may play a role in the development of this condition. However, the relationship between cellular senescence and clinical outcomes in IPF remains uncertain. METHODS Data from the GSE70867 database were meticulously analyzed in this study. The research employed differential expression analysis, as well as univariate and multivariate Cox regression analysis, to pinpoint senescence-related genes (SRGs) linked to prognosis and construct a prognostic risk model. The model's clinical relevance and its connection to potential biological processes were systematically assessed in training and testing datasets. Additionally, the expression location of prognosis-related SRGs was identified through immunohistochemical staining, and the correlation between SRGs and immune cell infiltration was deduced using the GSE28221 dataset. RESULT The prognostic risk model was constructed based on five SRGs (cellular communication network factor 1, CYR61, stratifin, SFN, megakaryocyte-associated tyrosine kinase, MATK, C-X-C motif chemokine ligand 1, CXCL1, LIM domain, and actin binding 1, LIMA1). Both Kaplan-Meier (KM) curves (p = 0.005) and time-dependent receiver operating characteristic (ROC) analysis affirmed the predictive accuracy of this model in testing datasets, with respective areas under the ROC curve at 1-, 2-, and 3-years being 0.721, 0.802, and 0.739. Furthermore, qRT-RCR analysis and immunohistochemical staining verify the differential expression of SRGs in IPF samples and controls. Moreover, patients in the high-risk group contained higher infiltration levels of neutrophils, eosinophils, and M1 macrophages in BALF, which appeared to be independent indicators of poor prognosis in IPF patients. CONCLUSION Our research reveals the effectiveness of the 5 SRGs model in BALF for risk stratification and prognosis prediction in IPF patients, providing new insights into the immune infiltration of IPF progression.
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Affiliation(s)
| | | | | | | | | | | | - Shan Shan
- Department of Respiratory Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200230, China; (C.Z.)
| | - Tao Ren
- Department of Respiratory Medicine, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200230, China; (C.Z.)
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Oldham JM, Huang Y, Bose S, Ma SF, Kim JS, Schwab A, Ting C, Mou K, Lee CT, Adegunsoye A, Ghodrati S, Pugashetti JV, Nazemi N, Strek ME, Linderholm AL, Chen CH, Murray S, Zemans RL, Flaherty KR, Martinez FJ, Noth I. Proteomic Biomarkers of Survival in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 2024; 209:1111-1120. [PMID: 37847691 PMCID: PMC11092951 DOI: 10.1164/rccm.202301-0117oc] [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: 01/18/2023] [Accepted: 10/16/2023] [Indexed: 10/19/2023] Open
Abstract
Rationale: Idiopathic pulmonary fibrosis (IPF) causes progressive lung scarring and high mortality. Reliable and accurate prognostic biomarkers are urgently needed. Objectives: To identify and validate circulating protein biomarkers of IPF survival. Methods: High-throughput proteomic data were generated using prospectively collected plasma samples from patients with IPF from the Pulmonary Fibrosis Foundation Patient Registry (discovery cohort) and the Universities of California, Davis; Chicago; and Virginia (validation cohort). Proteins associated with three-year transplant-free survival (TFS) were identified using multivariable Cox proportional hazards regression. Those associated with TFS after adjustment for false discovery in the discovery cohort were advanced for testing in the validation cohort, with proteins maintaining TFS association with consistent effect direction considered validated. After combining cohorts, functional analyses were performed, and machine learning was used to derive a proteomic signature of TFS. Measurements and Main Results: Of 2,921 proteins tested in the discovery cohort (n = 871), 231 were associated with differential TFS. Of these, 140 maintained TFS association with consistent effect direction in the validation cohort (n = 355). After cohorts were combined, the validated proteins with the strongest TFS association were latent-transforming growth factor β-binding protein 2 (hazard ratio [HR], 2.43; 95% confidence interval [CI] = 2.09-2.82), collagen α-1(XXIV) chain (HR, 2.21; 95% CI = 1.86-2.39), and keratin 19 (HR, 1.60; 95% CI = 1.47-1.74). In decision curve analysis, a proteomic signature of TFS outperformed a similarly derived clinical prediction model. Conclusions: In the largest proteomic investigation of IPF outcomes performed to date, we identified and validated 140 protein biomarkers of TFS. These results shed important light on potential drivers of IPF progression.
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Affiliation(s)
- Justin M. Oldham
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine
- Department of Epidemiology, and
| | - Yong Huang
- Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia
| | - Swaraj Bose
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
| | - Shwu-Fan Ma
- Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia
| | - John S. Kim
- Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia
| | - Alexandra Schwab
- Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia
| | - Christopher Ting
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine
| | - Kaniz Mou
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine
| | - Cathryn T. Lee
- Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois
| | - Ayodeji Adegunsoye
- Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois
| | - Sahand Ghodrati
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, Davis, California
| | | | - Nazanin Nazemi
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine
| | - Mary E. Strek
- Section of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, Illinois
| | - Angela L. Linderholm
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, Davis, California
| | - Ching-Hsien Chen
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California, Davis, Davis, California
| | - Susan Murray
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan
| | - Rachel L. Zemans
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine
| | - Kevin R. Flaherty
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine
- Pulmonary Fibrosis Foundation, Chicago, Illinois; and
| | | | - Imre Noth
- Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia
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9
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Dare A, King SD, Chen SY. Surfactant protein A promotes western diet-induced hepatic steatosis and fibrosis in mice. Sci Rep 2024; 14:7464. [PMID: 38553537 PMCID: PMC10980756 DOI: 10.1038/s41598-024-58291-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 03/27/2024] [Indexed: 04/02/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) remains the most common cause of liver disease in the United States due to the increased incidence of metabolic dysfunction and obesity. Surfactant protein A (SPA) regulates macrophage function, strongly binds to lipids, and is implicated in renal and idiopathic pulmonary fibrosis (IPF). However, the role of SPA in lipid accumulation, inflammation, and hepatic fibrosis that characterize MASLD remains unknown. SPA deficient (SPA-/-) and age-matched wild-type (WT) control mice were fed a Western diet for 8 weeks to induce MASLD. Blood and liver samples were collected and used to analyze pathological features associated with MASLD. SPA expression was significantly upregulated in livers of mice with MASLD. SPA deficiency attenuated lipid accumulation along with downregulation of genes involved in fatty acid uptake and reduction of hepatic inflammation as evidenced by the diminished macrophage activation, decreased monocyte infiltration, and reduced production of inflammatory cytokines. Moreover, SPA-/- inhibited stellate cell activation, collagen deposit, and liver fibrosis. These results highlight the novel role of SPA in promoting fatty acid uptake into hepatocytes, causing excessive lipid accumulation, inflammation, and fibrosis implicated in the pathogenesis of MASLD.
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Affiliation(s)
- Ayobami Dare
- Department of Surgery, University of Missouri School of Medicine, 1 Hospital Drive, Columbia, MO, 65212, USA
| | - Skylar D King
- Department of Surgery, University of Missouri School of Medicine, 1 Hospital Drive, Columbia, MO, 65212, USA
| | - Shi-You Chen
- Department of Surgery, University of Missouri School of Medicine, 1 Hospital Drive, Columbia, MO, 65212, USA.
- The Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, MO, 65201, USA.
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Ebert C, Walsh AM, Sereda L, Wilson CL, Schafer PH, Fischer A, Zhao L, Ramirez-Valle F, Gordon D, Schnapp LM. Circulating biomarker analyses in a longitudinal cohort of patients with IPF. Am J Physiol Lung Cell Mol Physiol 2024; 326:L303-L312. [PMID: 38226605 PMCID: PMC11281789 DOI: 10.1152/ajplung.00222.2023] [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: 07/17/2023] [Revised: 12/21/2023] [Accepted: 01/05/2024] [Indexed: 01/17/2024] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is an incurable interstitial lung disease characterized by fibrosis. Two FDA-approved drugs, pirfenidone and nintedanib, only modestly prolong survival. In this study, we asked whether levels of select circulating biomarkers in patients with IPF demonstrated changes in response to treatment over time and whether treatment with pirfenidone and nintedanib led to differential biomarker expression. Serial plasma samples from 48 patients with IPF on usual treatment and six healthy volunteers were analyzed to identify differentially expressed blood protein. Hypothesis-driven potential biomarker selection was based on recent literature, internal preclinical data, and the PROLIFIC Consortium (Schafer P. 6th Annual IPF Summit. Boston, MA, 2022) proposed biomarkers of pulmonary fibrosis. We compared our findings to public databases to provide insights into relevant signaling pathways in IPF. Of the 26 proteins measured, we found that 11 (SP-D, TIMP1, MMP7, CYFRA21-1, YKL40, CA125, sICAM, IP-10, MDC, CXCL13) were significantly elevated in patients with IPF compared with healthy volunteers but their levels did not significantly change over time. In the IPF samples, seven proteins were elevated in the treatment group compared with the no-treatment group. However, protein profiles were not distinguishable between patients on pirfenidone versus nintedanib. We demonstrated that most proteins differentially detected in our samples were predicted to be secreted from the lung epithelial or interstitial compartments. However, a significant minority of the proteins are not known to be transcriptionally expressed by lung cells, suggesting an ongoing systemic response. Understanding the contributions of the systemic response in IPF may be important as new therapeutics are developed.NEW & NOTEWORTHY In this study, we confirmed protein expression differences in only a subset of predicted biomarkers from IPF and control subjects. Most differentially expressed proteins were predicted to be secreted from lung cells. However, a significant minority of the proteins are not known to be transcriptionally expressed by lung cells, suggesting an ongoing systemic response. The contributions of the systemic response in IPF may be important as new therapeutics are developed.
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Affiliation(s)
| | - Alice M Walsh
- Bristol Myers Squibb, Princeton, New Jersey, United States
| | - Larisa Sereda
- Bristol Myers Squibb, Princeton, New Jersey, United States
| | - Carole L Wilson
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States
- Medical University of South Carolina, Charleston, South Carolina, United States
| | | | - Aryeh Fischer
- Bristol Myers Squibb, Princeton, New Jersey, United States
| | - Lei Zhao
- Bristol Myers Squibb, Princeton, New Jersey, United States
| | | | - David Gordon
- Bristol Myers Squibb, Princeton, New Jersey, United States
| | - Lynn M Schnapp
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States
- Medical University of South Carolina, Charleston, South Carolina, United States
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11
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Sun Y, Saito K, Ushiki A, Abe M, Saito Y, Kashiwada T, Horimasu Y, Gemma A, Tatsumi K, Hattori N, Tsushima K, Takemoto K, Ishikawa R, Momiyama T, Matsuyama SI, Arakawa N, Akane H, Toyoda T, Ogawa K, Sato M, Takamatsu K, Mori K, Nishiya T, Izumi T, Ohno Y, Saito Y, Hanaoka M. Identification of kynurenine and quinolinic acid as promising serum biomarkers for drug-induced interstitial lung diseases. Respir Res 2024; 25:31. [PMID: 38221627 PMCID: PMC10788992 DOI: 10.1186/s12931-023-02653-6] [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: 08/10/2023] [Accepted: 12/24/2023] [Indexed: 01/16/2024] Open
Abstract
BACKGROUND Drug-induced interstitial lung disease (DILD) is a lung injury caused by various types of drugs and is a serious problem in both clinical practice and drug development. Clinical management of the condition would be improved if there were DILD-specific biomarkers available; this study aimed to meet that need. METHODS Biomarker candidates were identified by non-targeted metabolomics focusing on hydrophilic molecules, and further validated by targeted approaches using the serum of acute DILD patients, DILD recovery patients, DILD-tolerant patients, patients with other related lung diseases, and healthy controls. RESULTS Serum levels of kynurenine and quinolinic acid (and kynurenine/tryptophan ratio) were elevated significantly and specifically in acute DILD patients. The diagnostic potentials of these biomarkers were superior to those of conventional lung injury biomarkers, Krebs von den Lungen-6 and surfactant protein-D, in discriminating between acute DILD patients and patients with other lung diseases, including idiopathic interstitial pneumonia and lung diseases associated with connective tissue diseases. In addition to identifying and evaluating the biomarkers, our data showed that kynurenine/tryptophan ratios (an indicator of kynurenine pathway activation) were positively correlated with serum C-reactive protein concentrations in patients with DILD, suggesting the potential association between the generation of these biomarkers and inflammation. Our in vitro experiments demonstrated that macrophage differentiation and inflammatory stimulations typified by interferon gamma could activate the kynurenine pathway, resulting in enhanced kynurenine levels in the extracellular space in macrophage-like cell lines or lung endothelial cells. Extracellular quinolinic acid levels were elevated only in macrophage-like cells but not endothelial cells owing to the lower expression levels of metabolic enzymes converting kynurenine to quinolinic acid. These findings provide clues about the molecular mechanisms behind their specific elevation in the serum of acute DILD patients. CONCLUSIONS The serum concentrations of kynurenine and quinolinic acid as well as kynurenine/tryptophan ratios are promising and specific biomarkers for detecting and monitoring DILD and its recovery, which could facilitate accurate decisions for appropriate clinical management of patients with DILD.
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Affiliation(s)
- Yuchen Sun
- Division of Medicinal Safety Science, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan
| | - Kosuke Saito
- Division of Medicinal Safety Science, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan
| | - Atsuhito Ushiki
- First Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Mitsuhiro Abe
- Department of Respirology (B2), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8677, Japan
| | - Yoshinobu Saito
- Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan
| | - Takeru Kashiwada
- Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan
| | - Yasushi Horimasu
- Department of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8551, Japan
| | - Akihiko Gemma
- Department of Pulmonary Medicine and Oncology, Graduate School of Medicine, Nippon Medical School, 1-1-5, Sendagi, Bunkyo-ku, Tokyo, 113-8602, Japan
| | - Koichiro Tatsumi
- Department of Respirology (B2), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8677, Japan
| | - Noboru Hattori
- Department of Respiratory Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, Hiroshima, 734-8551, Japan
| | - Kenji Tsushima
- Division of General Internal Medicine, Department of Internal Medicine, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan
| | - Kazuhisa Takemoto
- Division of Medicinal Safety Science, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan
| | - Rika Ishikawa
- Division of Medicinal Safety Science, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan
| | - Toshiko Momiyama
- Division of Medicinal Safety Science, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan
| | - Shin-Ichiro Matsuyama
- Division of Medicinal Safety Science, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan
| | - Noriaki Arakawa
- Division of Medicinal Safety Science, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan
| | - Hirotoshi Akane
- Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan
| | - Takeshi Toyoda
- Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan
| | - Kumiko Ogawa
- Division of Pathology, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan
| | - Motonobu Sato
- Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan
| | - Kazuhiko Takamatsu
- Astellas Pharma Inc., 21, Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan
| | - Kazuhiko Mori
- Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan
| | - Takayoshi Nishiya
- Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo, 134-8630, Japan
| | - Takashi Izumi
- Kihara Memorial Yokohama Foundation, 1-6 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
| | - Yasuo Ohno
- Kihara Memorial Yokohama Foundation, 1-6 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan
| | - Yoshiro Saito
- Division of Medicinal Safety Science, National Institute of Health Sciences, 3-25-26 Tonomachi, Kawasaki-ku, Kawasaki, Kanagawa, 210-9501, Japan.
| | - Masayuki Hanaoka
- First Department of Internal Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
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12
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Abstract
Pulmonary surfactant is a critical component of lung function in healthy individuals. It functions in part by lowering surface tension in the alveoli, thereby allowing for breathing with minimal effort. The prevailing thinking is that low surface tension is attained by a compression-driven squeeze-out of unsaturated phospholipids during exhalation, forming a film enriched in saturated phospholipids that achieves surface tensions close to zero. A thorough review of past and recent literature suggests that the compression-driven squeeze-out mechanism may be erroneous. Here, we posit that a surfactant film enriched in saturated lipids is formed shortly after birth by an adsorption-driven sorting process and that its composition does not change during normal breathing. We provide biophysical evidence for the rapid formation of an enriched film at high surfactant concentrations, facilitated by adsorption structures containing hydrophobic surfactant proteins. We examine biophysical evidence for and against the compression-driven squeeze-out mechanism and propose a new model for surfactant function. The proposed model is tested against existing physiological and pathophysiological evidence in neonatal and adult lungs, leading to ideas for biophysical research, that should be addressed to establish the physiological relevance of this new perspective on the function of the mighty thin film that surfactant provides.
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Affiliation(s)
- Fred Possmayer
- Department of Biochemistry, Western University, London, Ontario N6A 3K7, Canada
- Department of Obstetrics/Gynaecology, Western University, London, Ontario N6A 3K7, Canada
| | - Yi Y Zuo
- Department of Mechanical Engineering, University of Hawaii at Manon, Honolulu, Hawaii 96822, United States
- Department of Pediatrics, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96826, United States
| | - Ruud A W Veldhuizen
- Department of Physiology & Pharmacology, Western University, London, Ontario N6A 5C1, Canada
- Department of Medicine, Western University, London, Ontario N6A 3K7, Canada
- Lawson Health Research Institute, London, Ontario N6A 4V2, Canada
| | - Nils O Petersen
- Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
- Department of Chemistry, Western University, London, Ontario N6A 5B7, Canada
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13
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Rzepka-Wrona P, Skoczyński S, Piotrowski WJ, Jassem E, Ziora D, Barczyk A. Characteristics of Interstitial Pneumonia With Autoimmune Features (IPAF): Protocol for a Multicenter Prospective Study. JMIR Res Protoc 2023; 12:e44802. [PMID: 37976081 PMCID: PMC10692886 DOI: 10.2196/44802] [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: 12/04/2022] [Revised: 03/12/2023] [Accepted: 05/24/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND "Interstitial lung disease" (ILD) is a broad term encompassing diseases of different backgrounds. "Interstitial pneumonia with autoimmune features" (IPAF) is a recent term that implies the presence of autoimmunity. OBJECTIVE This study aims to determine the characteristics of Polish patients with IPAF, compare them with patients with other interstitial pneumonias, and search for the prognostic and diagnostic biomarkers of IPAF in serum and bronchoalveolar lavage fluid (BALF). METHODS This multicenter prospective study plans to recruit 240 participants divided into 1 study group and 2 control groups. Biological fluid samples will be collected according to Polish Respiratory Society management guidelines and stored at -80°C for further tests. Prospective 5-year observations of 60 newly diagnosed individuals are planned. The study will be divided into subsections. First, we plan to characterize Polish patients with IPAF (study group) against their peers with other ILDs (2 control groups). Control group 1 will comprise patients with idiopathic ILDs, including mainly idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia. Control group 2 will comprise patients with connective tissue disease-associated interstitial lung diseases, such as rheumatoid arthritis, systemic sclerosis, polymyositis, dermatomyositis, Sjögren's syndrome, mixed connective tissue disease, and systemic lupus erythematosus. Radiological and functional parameters will be analyzed. Patients will be compared in terms of high-resolution computed tomography results, the 6-minute walking test performance, and pulmonary function test parameters. The diagnosis of IPAF will be reassessed on a regular basis through multidisciplinary discussion in order to determine its clinical stability. In the laboratory arm, inflammation and fibrosis pathways will be assessed. Cytokine levels (interleukin 8, transforming growth factor beta 1, chemokine C-C motif ligand [CXCL]18, CXCL1, surfactant protein [SP]-A, SP-D, Krebs von den Lungen-6 protein, and chitinase 1) will be measured in serum and BALF. A comparative analysis of serum and BALF cytokine levels will be performed in order to establish potential differences between systemic and local inflammatory pathways. In the quality of life (QoL) arm of the study, dyspnea and cough and their impact on various aspects of the QoL will be assessed. Depression and anxiety will be measured with the Hospital Anxiety and Depression Modified Scale and the 9-item Patient Health Questionnaire, and potential correlations with symptom prevalence will be assessed. RESULTS This study will start recruiting patients to phase 1 in October 2023. The final results will be available in 2028. We plan to publish preliminary results after 2-3 years from the start of phase 1. CONCLUSIONS This study will be a step toward a better understanding of IPAF etiopathogenesis and outcomes. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) PRR1-10.2196/44802.
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Affiliation(s)
- Patrycja Rzepka-Wrona
- Department of Pneumonology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
| | - Szymon Skoczyński
- Department of Lung Diseases and Tuberculosis, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | | | - Ewa Jassem
- Department of Pneumonology and Allergology, Medical University of Gdansk, Gdańsk, Poland
| | - Dariusz Ziora
- Department of Lung Diseases and Tuberculosis, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Adam Barczyk
- Department of Pneumonology, School of Medicine in Katowice, Medical University of Silesia, Katowice, Poland
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14
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Lavis P, Pingitore J, Doumont G, Garabet A, Van Simaeys G, Lacroix S, Passon N, Van Heymbeek C, De Maeseneire C, Allard J, Collin A, Huaux F, Decaestecker C, Salmon I, Goldman S, Cardozo AK, Bondue B. Usefulness of FAPα assessment in bronchoalveolar lavage as a marker of fibrogenesis: results of a preclinical study and first report in patients with idiopathic pulmonary fibrosis. Respir Res 2023; 24:254. [PMID: 37880678 PMCID: PMC10601150 DOI: 10.1186/s12931-023-02556-6] [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: 07/20/2023] [Accepted: 10/05/2023] [Indexed: 10/27/2023] Open
Abstract
BACKGROUND Fibroblast activation protein-α (FAPα) is a marker of activated fibroblasts that can be selectively targeted by an inhibitor (FAPI) and visualised by PET/CT imaging. We evaluated whether the measurement of FAPα in bronchoalveolar lavage fluids (BALF) and the uptake of FAPI by PET/CT could be used as biomarkers of fibrogenesis. METHODS The dynamics of lung uptake of 18F-labeled FAPI ([18F]FAPI-74) was assessed in the bleomycin mouse model at various time points and using different concentrations of bleomycin by PET/CT. FAPα was measured in BALFs from these bleomycin-treated and control mice. FAPα levels were also assessed in BALFs from controls and patients with idiopathic pulmonary fibrosis (IPF). RESULTS Bleomycin-treated mice presented a significantly higher uptake of [18F]FAPI-74 during lung fibrinogenesis (days 10 and 16 after instillation) compared to control mice. No significant difference was observed at initial inflammatory phase (3 days) and when fibrosis was already established (28 days). [18F]FAPI-74 tracer was unable to show a dose-response to bleomycin treatment. On the other hand, BALF FAPα levels were steeply higher in bleomycin-treated mice at day 10 and a significant dose-response effect was observed. Moreover, FAPα levels were strongly correlated with lung fibrosis as measured by the modified Aschroft histological analysis, hydroxyproline and the percentage of weight loss. Importantly, higher levels of FAPα were observed in IPF patients where the disease was progressing as compared to stable patients and controls. Moreover, patients with FAPα BALF levels higher than 192.5 pg/mL presented a higher risk of progression, transplantation or death compared to patients with lower levels. CONCLUSIONS Our preclinical data highlight a specific increase of [18F]FAPI-74 lung uptake during the fibrotic phase of the bleomycin murine model. The measurement of FAPα in BALF appears to be a promising marker of the fibrotic activity in preclinical models of lung fibrosis and in IPF patients. Further studies are required to confirm the role of FAPα in BALF as biomarker of IPF activity and assess the relationship between FAPα levels in BALF and [18F]FAPI-74 uptake on PET/CT in patients with fibrotic lung disease.
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Affiliation(s)
- Philomène Lavis
- Department of Pathology, Hôpital universitaire de Bruxelles (Hôpital Erasme), Université libre de Bruxelles, Brussels, Belgium
- I.R.I.B.H.M, Université libre de Bruxelles, Brussels, Belgium
| | - Julien Pingitore
- Department of Pneumology, Hôpital universitaire de Bruxelles (Hôpital Erasme), Université libre de Bruxelles, Brussels, Belgium
| | - Gilles Doumont
- Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Brussels, Belgium
| | - Ani Garabet
- Inflammation and Cell Death Signalling group, Experimental Gastroenterology Laboratory and Endotools, Université libre de Bruxelles, Brussels, Belgium
| | - Gaetan Van Simaeys
- Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Brussels, Belgium
- Department of Nuclear Medicine, Hôpital universitaire de Bruxelles (Hôpital Erasme), Université libre de Bruxelles, Brussels, Belgium
| | - Simon Lacroix
- Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Brussels, Belgium
- Department of Nuclear Medicine, Hôpital universitaire de Bruxelles (Hôpital Erasme), Université libre de Bruxelles, Brussels, Belgium
| | - Nicolas Passon
- Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Brussels, Belgium
| | - Christophe Van Heymbeek
- Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Brussels, Belgium
| | - Coraline De Maeseneire
- Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Brussels, Belgium
| | - Justine Allard
- Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Brussels, Belgium
| | - Amandine Collin
- Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Brussels, Belgium
| | - François Huaux
- Louvain Centre for Toxicology and Applied Pharmacology, Institut de Recherche Expérimentale et Clinique, Université catholique de Louvain, Brussels, Belgium
| | - Christine Decaestecker
- Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Brussels, Belgium
- Laboratory of Image Synthesis and Analysis, Université libre de Bruxelles, Brussels, Belgium
| | - Isabelle Salmon
- Department of Pathology, Hôpital universitaire de Bruxelles (Hôpital Erasme), Université libre de Bruxelles, Brussels, Belgium
- Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Brussels, Belgium
- Centre Universitaire inter Régional d'expertise en Anatomie Pathologique Hospitalière, Jumet, Belgium
| | - Serge Goldman
- Center for Microscopy and Molecular Imaging, Université libre de Bruxelles, Brussels, Belgium
- Department of Nuclear Medicine, Hôpital universitaire de Bruxelles (Hôpital Erasme), Université libre de Bruxelles, Brussels, Belgium
| | - Alessandra Kupper Cardozo
- Inflammation and Cell Death Signalling group, Experimental Gastroenterology Laboratory and Endotools, Université libre de Bruxelles, Brussels, Belgium
| | - Benjamin Bondue
- I.R.I.B.H.M, Université libre de Bruxelles, Brussels, Belgium.
- Department of Pneumology, Hôpital universitaire de Bruxelles (Hôpital Erasme), Université libre de Bruxelles, Brussels, Belgium.
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15
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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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16
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Sonaglioni A, Caminati A, Elia D, Trevisan R, Zompatori M, Grasso E, Lombardo M, Harari S. Comparison of clinical scoring to predict mortality risk in mild-to-moderate idiopathic pulmonary fibrosis. Minerva Med 2023; 114:608-619. [PMID: 37204783 DOI: 10.23736/s0026-4806.23.08585-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
BACKGROUND During the last decade, a number of clinical scores, such as Gender-Age-Physiology (GAP) Index, TORVAN Score and Charlson Comorbidity Index (CCI), have been separately used to measure comorbidity burden in idiopathic pulmonary fibrosis (IPF). However, no previous study compared the prognostic value of these scores to assess mortality risk stratification in IPF patients with mild-to-moderate disease. METHODS All consecutive patients with mild-to-moderate IPF who underwent high-resolution computed tomography, spirometry, transthoracic echocardiography and carotid ultrasonography at our Institution, between January 2016 and December 2018, were retrospectively analyzed. GAP Index, TORVAN Score and CCI were calculated in all patients. Primary endpoint was all-cause mortality, whereas secondary endpoint was the composite of all-cause mortality and rehospitalizations for all-causes, over medium-term follow-up. RESULTS Seventy IPF patients (70.2±7.4 yrs, 74.3% males) were examined. At baseline, GAP Index, TORVAN Score and CCI were 3.4±1.1, 14.7±4.1 and 5.3±2.4, respectively. A strong correlation between coronary artery calcification (CAC) and common carotid artery (CCA) intima-media thickness (IMT) (r=0.88), CCI and CAC (r=0.80), CCI and CCA-IMT (r=0.81), was demonstrated in the study group. Follow-up period was 3.5±1.2 years. During follow-up, 19 patients died and 32 rehospitalizations were detected. CCI (HR 2.39, 95% CI: 1.31-4.35) and heart rate (HR 1.10, 95% CI: 1.04-1.17) were independently associated with primary endpoint. CCI (HR 1.54, 95% CI: 1.15-2.06) predicted secondary endpoint, also. A CCI ≥6 was the optimal cut-off for predicting both outcomes. CONCLUSIONS Due to the increased atherosclerotic and comorbidity burden, IPF patients with CCI ≥6 at an early-stage disease have poor outcome over medium-term follow-up.
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Affiliation(s)
| | - Antonella Caminati
- Semi-Intensive Care Unit, Division of Pneumology, MultiMedica IRCCS, Milan, Italy -
| | - Davide Elia
- Semi-Intensive Care Unit, Division of Pneumology, MultiMedica IRCCS, Milan, Italy
| | | | | | - Enzo Grasso
- Division of Cardiology, MultiMedica IRCCS, Milan, Italy
| | | | - Sergio Harari
- Semi-Intensive Care Unit, Division of Pneumology, MultiMedica IRCCS, Milan, Italy
- Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
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17
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Karampitsakos T, Juan-Guardela BM, Tzouvelekis A, Herazo-Maya JD. Precision medicine advances in idiopathic pulmonary fibrosis. EBioMedicine 2023; 95:104766. [PMID: 37625268 PMCID: PMC10469771 DOI: 10.1016/j.ebiom.2023.104766] [Citation(s) in RCA: 58] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/07/2023] [Accepted: 08/07/2023] [Indexed: 08/27/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a highly heterogeneous, unpredictable and ultimately lethal chronic lung disease. Over the last decade, two anti-fibrotic agents have been shown to slow disease progression, however, both drugs are administered uniformly with minimal consideration of disease severity and inter-individual molecular, genetic, and genomic differences. Advances in biological understanding of disease endotyping and the emergence of precision medicine have shown that "a one-size-fits-all approach" to the management of chronic lung diseases is no longer appropriate. While precision medicine approaches have revolutionized the management of other diseases such as lung cancer and asthma, the implementation of precision medicine in IPF clinical practice remains an unmet need despite several reports demonstrating a large number of diagnostic, prognostic and theragnostic biomarker candidates in IPF. This review article aims to summarize our current knowledge of precision medicine in IPF and highlight barriers to translate these research findings into clinical practice.
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Affiliation(s)
- Theodoros Karampitsakos
- Division of Pulmonary, Critical Care and Sleep Medicine, Ubben Center for Pulmonary Fibrosis Research, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Brenda M Juan-Guardela
- Division of Pulmonary, Critical Care and Sleep Medicine, Ubben Center for Pulmonary Fibrosis Research, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | | | - Jose D Herazo-Maya
- Division of Pulmonary, Critical Care and Sleep Medicine, Ubben Center for Pulmonary Fibrosis Research, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
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18
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Fu S, Song X, Tang X, Qian X, Du Z, Hu Y, Xu X, Zhang M. Synergistic effect of constituent drugs of Baibutang on improving Yin-deficiency pulmonary fibrosis in rats. JOURNAL OF ETHNOPHARMACOLOGY 2023; 306:116050. [PMID: 36535334 DOI: 10.1016/j.jep.2022.116050] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Revised: 11/13/2022] [Accepted: 12/09/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Baibutang (BBT) is an ancient prescription for the treatment of pulmonary fibrosis. Previous experiments have shown that BBT had a good therapeutic effect on pulmonary fibrosis. However, there had been no study on the synergy between drugs composed of BBT. Due to the interaction between the constituent drugs, exploring their synergy profile is of great significance for explaining the essence of BBT's efficacy in improving pulmonary fibrosis. AIM OF THE STUDY Based on the pharmacodynamic value, this study aimed to explore a method for the evaluation of the synergy profile between constituent drugs in traditional Chinese medicine (TCM) compounds. MATERIALS AND METHODS Nine herbs of BBT were divided into Zhikeqingre (ZK), Yangyinyiqi (YY) and Lishijianpi (LS) groups. A rat model of Yin-deficiency pulmonary fibrosis induced by thyroxine-bleomycin was used to evaluate the effects of BBT and the three groups. The pathological changes of lung tissue and the changes of biomarkers associated with fibrosis, Yin-deficiency and water-fluid metabolism were detected. After standardization of pharmacodynamics value (PV), the compatibility coefficient (CC) of the three groups, the relative PV (RPV) and contribution value (CV) of each group on every index were calculated. RESULTS The average CC on fibrosis indexes was 0.44, indicating that 44% of the efficacy of BBT came from the synergistic effect of the three groups. ZK group had the highest RPV (0.80) in improving fibrosis indexes such as histopathological changes, α-SMA, collagen-I and renin-angiotensin system. The average CC on Yin-deficiency indexes was 0.25, and YY group had the highest RPV (0.96) in improving deficiency indexes such as body temperature, cAMP/cGMP ratio, and PDEs, PGE2 and COX-2 levels. The average CC on water-fluid metabolism indexes was 0.15, and LS group had the highest RPV (1.52) in improving water-fluid metabolism indexes such as aquaporins, mucins, and surfactant proteins. The results also showed that 29% of the improvement effect of BBT on all indexes came from the synergistic effect of the three groups, and the contribution of ZK, YY and LS groups to the efficacy of BBT were 25%, 25% and 21%, respectively. CONCLUSION The established semiquantitative method can clearly and simply evaluate the synergy of the three groups in BBT, which will help to promote the research on the synergy of TCM compounds and other multiple-components combinations.
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Affiliation(s)
- San Fu
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
| | - Xianrui Song
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
| | - Xiaoyan Tang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
| | - Xiuhui Qian
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
| | - Zesen Du
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
| | - Yingying Hu
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
| | - Xianghong Xu
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
| | - Mian Zhang
- School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu, China.
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19
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Improved targeting delivery of WED-load immunoliposomes modified with SP-A mAb for the treatment of pulmonary fibrosis. Colloids Surf B Biointerfaces 2023; 224:113237. [PMID: 36871414 DOI: 10.1016/j.colsurfb.2023.113237] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/20/2023] [Accepted: 02/28/2023] [Indexed: 03/05/2023]
Abstract
The epithelial-mesenchymal transition (EMT) of type Ⅱ alveolar epithelial cells (AECS Ⅱ) induced by transforming growth factor (TGF-β1) is a primary pathogenesis of pulmonary fibrosis (PF). To augment the therapeutic potency of wedelolactone (WED) for PF, herein, pulmonary surfactant protein A (SP-A) specifically expressed on AECS Ⅱ was selected as the targeted receptor. Immunoliposomes modified with SP-A monoclonal antibody (SP-A mAb), novel anti-PF drug delivery systems, were developed and investigated in vivo and in vitro. In vivo fluorescence imaging technique was performed to evaluate the pulmonary-targeting effects of immunoliposomes. The result showed that immunoliposomes accumulated more in the lung, compared with non-modified nanoliposomes. Fluorescence detection methods and flow cytometry were used to investigate the function of SP-A mAb and the cellular uptake efficiency of WED-ILP in vitro. SP-A mAb enabled the immunoliposomes to specifically target the A549 cells and increased uptake more effectively. The mean fluorescence intensity (MFI) of cells treated with the targeted immunoliposomes was about 1.4-fold higher than that of cells treated with regular nanoliposomes. The cytotoxicity of nanoliposomes was assessed by the MTT assay, which demonstrated that blank nanoliposomes have no significant effect on A549 cell proliferation even at the SPC concentration of 1000 µg/mL. Additionally, in vitro pulmonary fibrosis model was established to further investigate the anti-pulmonary fibrosis effect of WED-ILP. WED-ILP significantly (**P < 0.01) inhibited the proliferation of A549 cells stimulated by TGF-β1 indicating that WED-ILP has great potential for the clinical treatment of PF.
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20
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Sonaglioni A, Caminati A, Re M, Elia D, Trevisan R, Granato A, Zompatori M, Lombardo M, Harari S. Prognostic role of CHA 2DS 2-VASc score for mortality risk assessment in non-advanced idiopathic pulmonary fibrosis: a preliminary observation. Intern Emerg Med 2023; 18:755-767. [PMID: 36966265 PMCID: PMC10039767 DOI: 10.1007/s11739-023-03219-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/05/2023] [Indexed: 03/27/2023]
Abstract
During the last decade, the CHA2DS2-VASc score has been used for stratifying the mortality risk in both atrial fibrillation (AF) and non-AF patients. However, no previous study considered this score as a prognostic indicator in non-AF patients with mild-to-moderate idiopathic pulmonary fibrosis (IPF). All consecutive non-AF patients with mild-to-moderate IPF, diagnosed between January 2016 and December 2018 at our Institution, entered this study. All patients underwent physical examination, blood tests, spirometry, high-resolution computed tomography and transthoracic echocardiography. CHA2DS2-VASc score, Gender-Age-Physiology (GAP) index and Charlson Comorbidity Index (CCI) were determined in all patients. Primary endpoint was all-cause mortality, while the secondary endpoint was the composite of all-cause mortality and rehospitalizations for all causes over mid-term follow-up. 103 consecutive IPF patients (70.7 ± 7.3 yrs, 79.6% males) were retrospectively analyzed. At the basal evaluation, CHA2DS2-VASc score, GAP index and CCI were 3.7 ± 1.6, 3.6 ± 1.2 and 5.5 ± 2.3, respectively. Mean follow-up was 3.5 ± 1.3 yrs. During the follow-up period, 29 patients died and 43 were re-hospitalized (44.2% due to cardiopulmonary causes). On multivariate Cox regression analysis, CHA2DS2-VASc score (HR 2.15, 95% CI 1.59-2.91) and left ventricular ejection fraction (LVEF) (HR 0.91, 95% CI 0.86-0.97) were independently associated with all-cause mortality in IPF patients. CHA2DS2-VASc score (HR 1.66, 95% CI 1.39-1.99) and LVEF (HR 0.94, 95% CI 0.90-0.98) also predicted the secondary endpoint in the same study group. CHA2DS2-VASc score > 4 was the optimal cut-off for predicting both outcomes. At mid-term follow-up, a CHA2DS2-VASc score > 4 predicts an increased risk of all-cause mortality and rehospitalizations for all causes in non-AF patients with mild-to-moderate IPF.
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Affiliation(s)
| | - Antonella Caminati
- Division of Pneumology, Semi-Intensive Care Unit, MultiMedica IRCCS, Milan, Italy.
| | - Margherita Re
- Division of Internal Medicine, MultiMedica IRCCS, Milan, Italy
| | - Davide Elia
- Division of Pneumology, Semi-Intensive Care Unit, MultiMedica IRCCS, Milan, Italy
| | | | - Alberto Granato
- Department of Veterinary Sciences, University of Turin, Turin, Italy
| | | | | | - Sergio Harari
- Division of Pneumology, Semi-Intensive Care Unit, MultiMedica IRCCS, Milan, Italy
- Division of Internal Medicine, MultiMedica IRCCS, Milan, Italy
- Department of Clinical Sciences and Community Health, Università Di Milano, Milan, Italy
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21
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Stratifin as a novel diagnostic biomarker in serum for diffuse alveolar damage. Nat Commun 2022; 13:5854. [PMID: 36195613 PMCID: PMC9532442 DOI: 10.1038/s41467-022-33160-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 09/05/2022] [Indexed: 11/09/2022] Open
Abstract
Among the various histopathological patterns of drug-induced interstitial lung disease (DILD), diffuse alveolar damage (DAD) is associated with poor prognosis. However, there is no reliable biomarker for its accurate diagnosis. Here, we show stratifin/14-3-3σ (SFN) as a biomarker candidate found in a proteomic analysis. The study includes two independent cohorts (including totally 26 patients with DAD) and controls (total 432 samples). SFN is specifically elevated in DILD patients with DAD, and is superior to the known biomarkers, KL-6 and SP-D, in discrimination of DILD patients with DAD from patients with other DILD patterns or other lung diseases. SFN is also increased in serum from patients with idiopathic DAD, and in lung tissues and bronchoalveolar lavage fluid of patients with DAD. In vitro analysis using cultured lung epithelial cells suggests that extracellular release of SFN occurs via p53-dependent apoptosis. We conclude that serum SFN is a promising biomarker for DAD diagnosis.
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22
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Sonaglioni A, Caminati A, Nicolosi GL, Lombardo M, Harari S. Incremental prognostic value of arterial elastance in mild-to-moderate idiopathic pulmonary fibrosis. THE INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING 2022; 38:1473-1485. [PMID: 35103898 DOI: 10.1007/s10554-022-02541-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 01/25/2022] [Indexed: 11/05/2022]
Abstract
Previous reports suggested that poor pulmonary function was associated with increased arterial elastance (Ea) in patients with chronic obstructive pulmonary disease and systemic sclerosis. The mechanisms connecting pulmonary function and Ea have not yet been accurately studied in patients with idiopathic pulmonary fibrosis (IPF). The present study was designed to assess Ea in IPF patients without chronic severe pulmonary hypertension and to determine its prognostic role over a medium-term follow-up. This retrospective study included 60 consecutive patients with mild-to-moderate IPF (73.8 ± 6.6 years, 75% males) and 60 controls matched by age, sex and cardiovascular risk factors. All patients underwent physical examination, spirometry, blood tests, modified Haller index (MHI, chest transverse diameter over the distance between sternum and spine) assessment, conventional transthoracic echocardiography implemented with speckle tracking analysis of left atrial positive global strain (LA-GSA+ ) and finally carotid Doppler ultrasonography, at basal evaluation. The effective arterial elastance index (EaI) was calculated as the ratio of end-systolic pressure to stroke volume index. During follow-up period, we evaluated the composite endpoint of (1) pulmonary or cardiovascular hospitalizations; (2) all-cause mortality. At baseline, EaI was significantly higher in IPF patients than controls (4.1 ± 1.3 vs 3.5 ± 1.0 mmHg/ml/m2, p = 0.01). EaI was strongly correlated to the following variables: C-reactive protein (CRP) (r = 0.86), forced vital capacity (FVC) (r = - 0.91), E/e' ratio (r = 0.91), LA-GSA+ (r = - 0.92), common carotid artery-cross sectional area (CCA-CSA) (r = 0.89) and MHI (r = 0.86), in IPF patients. Mean follow-up time was 2.4 ± 1.3 years. During follow-up, 12 patients died and 17 were hospitalized due to major adverse clinical events. At univariate Cox analysis, CRP (HR 1.51, 95% CI 1.25-1.82), FVC (HR 0.88, 95% CI 0.85-0.91), LA-GSA+ (HR 0.85, 95% CI 0.77-0.94), CCA-CSA (HR 1.12, 95% CI 1.03-1.22) and EaI (HR 2.43, 95% CI 1.75-3.37) were significantly associated with outcome. At multivariate Cox analysis, only EaI (HR 1.60, 95% CI 1.03-2.50) retained statistical significance. An EaI ≥ 4 mmHg/ml/m2 showed 100% sensitivity and 99.4% specificity for predicting outcome (AUC = 0.98). In patients with mild-to-moderate IPF, an EaI ≥ 4 mmHg/ml/m2 is a negative prognostic factor over a medium-term follow-up.
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Affiliation(s)
- Andrea Sonaglioni
- Division of Cardiology, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy
| | - Antonella Caminati
- Division of Pneumology, Semi-Intensive Care Unit, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy.
| | - Gian Luigi Nicolosi
- Division of Cardiology, Policlinico San Giorgio, Via Agostino Gemelli 10, 33170, Pordenone, Italy
| | - Michele Lombardo
- Division of Cardiology, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy
| | - Sergio Harari
- Division of Pneumology, Semi-Intensive Care Unit, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy
- Department of Clinical Sciences and Community Health, Università Di Milano, Milan, Italy
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23
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Serum Biomarkers in a Radiological Pattern of Non-Fibrotic Hypersensitivity Pneumonitis: Implications for Mechanistic Difference and Differential Diagnosis. Diseases 2022; 10:diseases10030036. [PMID: 35892730 PMCID: PMC9326628 DOI: 10.3390/diseases10030036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 06/15/2022] [Accepted: 06/24/2022] [Indexed: 12/04/2022] Open
Abstract
Hypersensitivity pneumonitis (HP) is a consequence of immune-mediated reactions caused by recurrent exposure to environmental agents. Recently, clinical practice guidelines for the diagnosis of HP were published and increased interest in HP. On the other hand, novel therapies have recently emerged for various diseases, and the management of drug-related pneumonitis (DRP) has become increasingly important. Among DRP, the HP pattern (DRP-HP) shows small, poorly defined centrilobular nodules with or without widespread areas of ground-glass opacity or lobular areas of decreased attenuation and vascularity. A similar radiological pattern of non-fibrotic HP can be induced, irrespective of inhalation (non-fibrotic HP) or intravenous administration (DRP-HP). However, their difference has not been well described, although the distribution of lesions in the lungs was slightly different between these two conditions. In this review, we focus on serum biomarkers of lung epithelial cells in order to investigate the difference between DRP-HP and non-fibrotic HP (common-HP). Serum levels of Krebs von den Lungen 6 (KL-6) might be relatively lower (occasionally normal) in DRP-HP than in common-HP, implying a mechanistic difference. KL-6 could be useful in discriminating between DRP and non-fibrotic HP (common type).
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24
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Kim K, Shin D, Lee G, Bae H. Loss of SP-A in the Lung Exacerbates Pulmonary Fibrosis. Int J Mol Sci 2022; 23:ijms23105292. [PMID: 35628104 PMCID: PMC9141401 DOI: 10.3390/ijms23105292] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/04/2022] [Accepted: 05/07/2022] [Indexed: 02/01/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a devastating and common chronic lung disease that is pathologically characterized by the destruction of lung architecture and the accumulation of extracellular matrix in the lung. Previous studies have shown an association between lung surfactant protein (SP) and the pathogenesis of IPF, as demonstrated by mutations and the altered expression of SP in patients with IPF. However, the role of SP in the development of lung fibrosis is poorly understood. In this study, the role of surfactant protein A (SP-A) was explored in experimental lung fibrosis induced with a low or high dose of bleomycin (BLM) and CRISPR/Cas9-mediated genetic deletion of SP-A. Our results showed that lung SP-A deficiency in mice promoted the development of fibrotic damage and exacerbated inflammatory responses to the BLM challenge. In vitro experiments with murine lung epithelial LA-4 cells demonstrated that in response to transforming growth factor-β1 (TGF-β1), LA-4 cells had a decreased protein expression of SP-A. Furthermore, exogenous SP administration to LA-4 cells inhibited the TGF-β1-induced upregulation of fibrotic markers. Overall, these findings suggest a novel antifibrotic mechanism of SP-A in the development of lung fibrosis, which indicates the therapeutic potential of the lung SP-A in preventing the development of IPF.
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Affiliation(s)
- Kyunghwa Kim
- Department of Health Sciences, The Graduate School of Dong-A University, 840 Hadan-dong, Saha-gu, Busan 49315, Korea; (K.K.); (G.L.)
| | - Dasom Shin
- Department of Physiology, College of Korean Medicine, Kyung Hee University, 26-6 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02453, Korea;
| | - Gaheon Lee
- Department of Health Sciences, The Graduate School of Dong-A University, 840 Hadan-dong, Saha-gu, Busan 49315, Korea; (K.K.); (G.L.)
| | - Hyunsu Bae
- Department of Physiology, College of Korean Medicine, Kyung Hee University, 26-6 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02453, Korea;
- Correspondence:
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25
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Review: Serum Biomarkers of Lung Fibrosis in Interstitial Pneumonia with Autoimmune Features-What Do We Already Know? J Clin Med 2021; 11:jcm11010079. [PMID: 35011819 PMCID: PMC8745166 DOI: 10.3390/jcm11010079] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/13/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
Interstitial pneumonia with autoimmune features (IPAF) belongs to a group of diseases called interstitial lung diseases (ILDs), which are disorders of a varied prognosis and course. Finding sufficiently specific and sensitive biomarkers would enable the progression to be predicted, the natural history to be monitored and patients to be stratified according to their treatment. To assess the significance of pulmonary fibrosis biomarkers studied thus far, we searched the PubMed, Medline and Cochrane Library databases for papers published between January 2015 and June 2021. We focused on circulating biomarkers. A primary review of the databases identified 38 articles of potential interest. Overall, seven articles fulfilled the inclusion criteria. This review aims to assess the diagnostic and prognostic value of molecules such as KL-6, SP-A, SP-D, circulating fibrocytes, CCL2, CXCL13, CXCL9, CXCL10 and CXCL11. All of these biomarkers have previously been studied in idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated interstitial lung disease (CTD-ILD). IPAF is a disorder of a heterogeneous nature. It explains the lack of coherent observations in terms of correlations with functional parameters. There is still no meta-analysis of pulmonary fibrosis biomarkers in IPAF. This is mainly due to the heterogeneity of the methodology and groups analysed in the research. More research in this area is needed.
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26
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Samarelli AV, Masciale V, Aramini B, Coló GP, Tonelli R, Marchioni A, Bruzzi G, Gozzi F, Andrisani D, Castaniere I, Manicardi L, Moretti A, Tabbì L, Guaitoli G, Cerri S, Dominici M, Clini E. Molecular Mechanisms and Cellular Contribution from Lung Fibrosis to Lung Cancer Development. Int J Mol Sci 2021; 22:12179. [PMID: 34830058 PMCID: PMC8624248 DOI: 10.3390/ijms222212179] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/29/2021] [Accepted: 10/30/2021] [Indexed: 12/15/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease (ILD) of unknown aetiology, with a median survival of 2-4 years from the time of diagnosis. Although IPF has unknown aetiology by definition, there have been identified several risks factors increasing the probability of the onset and progression of the disease in IPF patients such as cigarette smoking and environmental risk factors associated with domestic and occupational exposure. Among them, cigarette smoking together with concomitant emphysema might predispose IPF patients to lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer development. To this purpose, IPF and LC share several cellular and molecular processes driving the progression of both pathologies such as fibroblast transition proliferation and activation, endoplasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose IPF patients to LC development. Nintedanib, a tyrosine-kinase inhibitor, was firstly developed as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target molecular pathway. In this review our aim is to describe the updated studies on common cellular and molecular mechanisms between IPF and lung cancer, knowledge of which might help to find novel therapeutic targets for this disease combination.
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Affiliation(s)
- Anna Valeria Samarelli
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena and Reggio Emilia, University of Modena Reggio Emilia, 41100 Modena, Italy;
| | - Valentina Masciale
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, 41100 Modena, Italy;
| | - Beatrice Aramini
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Thoracic Surgery Unit, Department of Diagnostic and Specialty Medicine—DIMES of the Alma Mater Studiorum, University of Bologna, G.B. Morgagni—L. Pierantoni Hospital, 34 Carlo Forlanini Street, 47121 Forlì, Italy
| | - Georgina Pamela Coló
- Laboratorio de Biología del Cáncer INIBIBB-UNS-CONICET-CCT, Bahía Blanca 8000, Argentina;
| | - Roberto Tonelli
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena and Reggio Emilia, University of Modena Reggio Emilia, 41100 Modena, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, 41100 Modena, Italy
| | - Alessandro Marchioni
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena and Reggio Emilia, University of Modena Reggio Emilia, 41100 Modena, Italy;
| | - Giulia Bruzzi
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena and Reggio Emilia, University of Modena Reggio Emilia, 41100 Modena, Italy;
| | - Filippo Gozzi
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena and Reggio Emilia, University of Modena Reggio Emilia, 41100 Modena, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, 41100 Modena, Italy
| | - Dario Andrisani
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena and Reggio Emilia, University of Modena Reggio Emilia, 41100 Modena, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, 41100 Modena, Italy
| | - Ivana Castaniere
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena and Reggio Emilia, University of Modena Reggio Emilia, 41100 Modena, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, 41100 Modena, Italy
| | - Linda Manicardi
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena and Reggio Emilia, University of Modena Reggio Emilia, 41100 Modena, Italy;
| | - Antonio Moretti
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena and Reggio Emilia, University of Modena Reggio Emilia, 41100 Modena, Italy;
| | - Luca Tabbì
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena and Reggio Emilia, University of Modena Reggio Emilia, 41100 Modena, Italy;
| | - Giorgia Guaitoli
- Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, 41100 Modena, Italy;
- Clinical and Experimental Medicine PhD Program, University of Modena Reggio Emilia, 41100 Modena, Italy
| | - Stefania Cerri
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena and Reggio Emilia, University of Modena Reggio Emilia, 41100 Modena, Italy;
| | - Massimo Dominici
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Oncology Unit, University Hospital of Modena and Reggio Emilia, University of Modena and Reggio Emilia, 41100 Modena, Italy;
| | - Enrico Clini
- Laboratory of Cell Therapies and Respiratory Medicine, Department of Medical and Surgical Sciences for Children & Adults, University Hospital of Modena and Reggio Emilia, 41100 Modena, Italy; (A.V.S.); (V.M.); (B.A.); (R.T.); (A.M.); (G.B.); (F.G.); (D.A.); (I.C.); (L.M.); (A.M.); (S.C.); (M.D.)
- Respiratory Diseases Unit, Department of Medical and Surgical Sciences, University Hospital of Modena and Reggio Emilia, University of Modena Reggio Emilia, 41100 Modena, Italy;
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27
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Sonaglioni A, Caminati A, Lipsi R, Lombardo M, Harari S. Association between C-reactive protein and carotid plaque in mild-to-moderate idiopathic pulmonary fibrosis. Intern Emerg Med 2021; 16:1529-1539. [PMID: 33411265 DOI: 10.1007/s11739-020-02607-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Accepted: 12/14/2020] [Indexed: 01/03/2023]
Abstract
An association between C-reactive protein (CRP) levels and carotid plaque has never been investigated in idiopathic pulmonary fibrosis (IPF). The aim of this study was to evaluate the extent of carotid atherosclerosis in mild-to-moderate IPF and to assess its relationship to serum CRP. This observational retrospective case-control study included 60 consecutive IPF patients (73.8 ± 6.6 years, 45 males) and 60 matched controls, examined between Sep 2017 and Jan 2019. All patients underwent CRP assessment and a carotid Doppler ultrasonography. CRP levels were significantly higher in IPF patients than controls (0.2 ± 0.09 mg/dl vs 0.09 ± 0.04 mg/dl, p < 0.0001). A total of 46 plaques were detected, with higher prevalence in IPF patients than controls (38 vs 8, p < 0.0001). On univariate logistic regression the main variables independently associated with carotid plaque were: age (HR 1.09, 95% CI 1.03-1.16, p = 0.006), hypertension duration (HR 1.05, 95% CI 1.01-1.09, p = 0.01), diabetes duration (HR 1.09, 95% CI 1.01-1.18, p = 0.03), LDL-cholesterol (HR 1.07, 95% CI 1.04-1.10, p < 0.0001) and finally CRP levels (HR 1.73, 95% CI 0.59-5.00, p < 0.0001). Multivariate logistic regression analysis revealed that LDL-cholesterol (HR 1.05, 95% CI 1.01-1.08, p = 0.009) and CRP levels (HR 1.43, 95% CI 0.39-5.19, p < 0.0001) retained statistical significance. Common carotid artery-intima media thickness was significantly correlated with CRP levels in IPF patients (r = 0.86). SerumCRP might represent both an early marker and a potential therapeutic target for carotid atherosclerosis in mild-to-moderate IPF.
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Affiliation(s)
- Andrea Sonaglioni
- UO Di Cardiologia, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy
| | - Antonella Caminati
- UO Di Pneumologia E Terapia Semi-Intensiva Respiratoria-Servizio Di Fisiopatologia Respiratoria Ed Emodinamica Polmonare, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy.
| | - Roberto Lipsi
- UO Di Pneumologia E Terapia Semi-Intensiva Respiratoria-Servizio Di Fisiopatologia Respiratoria Ed Emodinamica Polmonare, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy
| | - Michele Lombardo
- UO Di Cardiologia, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy
| | - Sergio Harari
- UO Di Pneumologia E Terapia Semi-Intensiva Respiratoria-Servizio Di Fisiopatologia Respiratoria Ed Emodinamica Polmonare, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy
- Dipartimento Di Scienze Mediche, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy
- Dipartimento Di Scienze Cliniche E Di Comunità, Università Di Milano, Milan, Italy
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28
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Newton CA, Herzog EL. Molecular Markers and the Promise of Precision Medicine for Interstitial Lung Disease. Clin Chest Med 2021; 42:357-364. [PMID: 34024410 DOI: 10.1016/j.ccm.2021.03.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Management of patients with interstitial lung disease (ILD) requires accurate classification. However, this process relies on subjective interpretation of nonspecific and overlapping clinical features that could hamper clinical care. The development and implementation of objective biomarkers reflective of specific disease states could facilitate precision-based approaches based on patient-level biology to improve the health of ILD patients. Omics-based studies allow for the seemingly unbiased and highly efficient screening of candidate biomarkers and offer unprecedented opportunities for discovery. This review outlines representative major omics-based discoveries in a well-studied condition, idiopathic pulmonary fibrosis, to develop a roadmap to personalized medicine in ILD.
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Affiliation(s)
- Chad A Newton
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8558, USA.
| | - Erica L Herzog
- Section of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, Yale School of Medicine, Yale University, 300 Cedar Street TAC441S, New Haven, CT 06520-8057, USA
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29
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Stainer A, Faverio P, Busnelli S, Catalano M, Della Zoppa M, Marruchella A, Pesci A, Luppi F. Molecular Biomarkers in Idiopathic Pulmonary Fibrosis: State of the Art and Future Directions. Int J Mol Sci 2021; 22:6255. [PMID: 34200784 PMCID: PMC8230407 DOI: 10.3390/ijms22126255] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/07/2021] [Accepted: 06/07/2021] [Indexed: 12/12/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF), the most lethal form of interstitial pneumonia of unknown cause, is associated with a specific radiological and histopathological pattern (the so-called "usual interstitial pneumonia" pattern) and has a median survival estimated to be between 3 and 5 years after diagnosis. However, evidence shows that IPF has different clinical phenotypes, which are characterized by a variable disease course over time. At present, the natural history of IPF is unpredictable for individual patients, although some genetic factors and circulating biomarkers have been associated with different prognoses. Since in its early stages, IPF may be asymptomatic, leading to a delayed diagnosis. Two drugs, pirfenidone and nintedanib, have been shown to modify the disease course by slowing down the decline in lung function. It is also known that 5-10% of the IPF patients may be affected by episodes of acute and often fatal decline. The acute worsening of disease is sometimes attributed to identifiable conditions, such as pneumonia or heart failure; but many of these events occur without an identifiable cause. These idiopathic acute worsenings are termed acute exacerbations of IPF. To date, clinical biomarkers, diagnostic, prognostic, and theranostic, are not well characterized. However, they could become useful tools helping facilitate diagnoses, monitoring disease progression and treatment efficacy. The aim of this review is to cover molecular mechanisms underlying IPF and research into new clinical biomarkers, to be utilized in diagnosis and prognosis, even in patients treated with antifibrotic drugs.
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Affiliation(s)
- Anna Stainer
- Department of Medicine and Surgery, University of Milano Bicocca, 20126 Milano, Italy; (A.S.); (P.F.); (M.C.); (A.P.)
- Respiratory Unit, San Gerardo Hospital, 20900 Monza, Italy; (S.B.); (A.M.)
| | - Paola Faverio
- Department of Medicine and Surgery, University of Milano Bicocca, 20126 Milano, Italy; (A.S.); (P.F.); (M.C.); (A.P.)
- Respiratory Unit, San Gerardo Hospital, 20900 Monza, Italy; (S.B.); (A.M.)
| | - Sara Busnelli
- Respiratory Unit, San Gerardo Hospital, 20900 Monza, Italy; (S.B.); (A.M.)
| | - Martina Catalano
- Department of Medicine and Surgery, University of Milano Bicocca, 20126 Milano, Italy; (A.S.); (P.F.); (M.C.); (A.P.)
| | - Matteo Della Zoppa
- Pulmonology Unit, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy;
| | | | - Alberto Pesci
- Department of Medicine and Surgery, University of Milano Bicocca, 20126 Milano, Italy; (A.S.); (P.F.); (M.C.); (A.P.)
- Respiratory Unit, San Gerardo Hospital, 20900 Monza, Italy; (S.B.); (A.M.)
| | - Fabrizio Luppi
- Department of Medicine and Surgery, University of Milano Bicocca, 20126 Milano, Italy; (A.S.); (P.F.); (M.C.); (A.P.)
- Respiratory Unit, San Gerardo Hospital, 20900 Monza, Italy; (S.B.); (A.M.)
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30
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Mayr CH, Simon LM, Leuschner G, Ansari M, Schniering J, Geyer PE, Angelidis I, Strunz M, Singh P, Kneidinger N, Reichenberger F, Silbernagel E, Böhm S, Adler H, Lindner M, Maurer B, Hilgendorff A, Prasse A, Behr J, Mann M, Eickelberg O, Theis FJ, Schiller HB. Integrative analysis of cell state changes in lung fibrosis with peripheral protein biomarkers. EMBO Mol Med 2021; 13:e12871. [PMID: 33650774 PMCID: PMC8033531 DOI: 10.15252/emmm.202012871] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 01/05/2021] [Accepted: 01/19/2021] [Indexed: 12/11/2022] Open
Abstract
The correspondence of cell state changes in diseased organs to peripheral protein signatures is currently unknown. Here, we generated and integrated single-cell transcriptomic and proteomic data from multiple large pulmonary fibrosis patient cohorts. Integration of 233,638 single-cell transcriptomes (n = 61) across three independent cohorts enabled us to derive shifts in cell type proportions and a robust core set of genes altered in lung fibrosis for 45 cell types. Mass spectrometry analysis of lung lavage fluid (n = 124) and plasma (n = 141) proteomes identified distinct protein signatures correlated with diagnosis, lung function, and injury status. A novel SSTR2+ pericyte state correlated with disease severity and was reflected in lavage fluid by increased levels of the complement regulatory factor CFHR1. We further discovered CRTAC1 as a biomarker of alveolar type-2 epithelial cell health status in lavage fluid and plasma. Using cross-modal analysis and machine learning, we identified the cellular source of biomarkers and demonstrated that information transfer between modalities correctly predicts disease status, suggesting feasibility of clinical cell state monitoring through longitudinal sampling of body fluid proteomes.
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Affiliation(s)
- Christoph H Mayr
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC–M bioArchiveHelmholtz Zentrum München, Member of the German Center for Lung Research (DZL)MunichGermany
| | - Lukas M Simon
- Institute of Computational BiologyHelmholtz Zentrum MünchenMunichGermany
| | - Gabriela Leuschner
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC–M bioArchiveHelmholtz Zentrum München, Member of the German Center for Lung Research (DZL)MunichGermany
- Department of Internal Medicine VLudwig‐Maximilians University (LMU) MunichMember of the German Center for Lung Research (DZL), CPC‐M bioArchiveMunichGermany
| | - Meshal Ansari
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC–M bioArchiveHelmholtz Zentrum München, Member of the German Center for Lung Research (DZL)MunichGermany
- Institute of Computational BiologyHelmholtz Zentrum MünchenMunichGermany
| | - Janine Schniering
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC–M bioArchiveHelmholtz Zentrum München, Member of the German Center for Lung Research (DZL)MunichGermany
- Department of RheumatologyCenter of Experimental RheumatologyUniversity & University Hospital ZurichZurichSwitzerland
| | - Philipp E Geyer
- Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany
| | - Ilias Angelidis
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC–M bioArchiveHelmholtz Zentrum München, Member of the German Center for Lung Research (DZL)MunichGermany
| | - Maximilian Strunz
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC–M bioArchiveHelmholtz Zentrum München, Member of the German Center for Lung Research (DZL)MunichGermany
| | - Pawandeep Singh
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC–M bioArchiveHelmholtz Zentrum München, Member of the German Center for Lung Research (DZL)MunichGermany
| | - Nikolaus Kneidinger
- Department of Internal Medicine VLudwig‐Maximilians University (LMU) MunichMember of the German Center for Lung Research (DZL), CPC‐M bioArchiveMunichGermany
| | - Frank Reichenberger
- Asklepios Fachkliniken Munich‐GautingCPC‐M bioArchive, Member of the German Center for Lung Research (DZL)MunichGermany
| | - Edith Silbernagel
- Asklepios Fachkliniken Munich‐GautingCPC‐M bioArchive, Member of the German Center for Lung Research (DZL)MunichGermany
| | - Stephan Böhm
- Faculty of MedicineMax von Pettenkofer‐Institute, VirologyNational Reference Center for RetrovirusesLMU MünchenMunichGermany
| | - Heiko Adler
- Helmholtz Zentrum MünchenResearch Unit Lung Repair and Regeneration, Member of the German Center for Lung Research (DZL)MunichGermany
| | - Michael Lindner
- Asklepios Fachkliniken Munich‐GautingCPC‐M bioArchive, Member of the German Center for Lung Research (DZL)MunichGermany
- University Department of Visceral and Thoracic Surgery SalzburgParacelsus Medical UniversitySalzburgAustria
| | - Britta Maurer
- Department of RheumatologyCenter of Experimental RheumatologyUniversity & University Hospital ZurichZurichSwitzerland
| | - Anne Hilgendorff
- Center for Comprehensive Developmental Care (CDeCLMU)Member of the German Center for Lung Research (DZL)Hospital of the Ludwig‐Maximilians University (LMU)CPC‐M bioArchiveMunichGermany
| | - Antje Prasse
- Department of PneumologyHannover Medical School, Member of the German Center for Lung Research (DZL)HannoverGermany
| | - Jürgen Behr
- Department of Internal Medicine VLudwig‐Maximilians University (LMU) MunichMember of the German Center for Lung Research (DZL), CPC‐M bioArchiveMunichGermany
- Asklepios Fachkliniken Munich‐GautingCPC‐M bioArchive, Member of the German Center for Lung Research (DZL)MunichGermany
| | - Matthias Mann
- Department of Proteomics and Signal TransductionMax Planck Institute of BiochemistryMartinsriedGermany
| | - Oliver Eickelberg
- Division of Pulmonary, Allergy, and Critical Care MedicineDepartment of MedicineUniversity of PittsburghPittsburghPAUSA
| | - Fabian J Theis
- Institute of Computational BiologyHelmholtz Zentrum MünchenMunichGermany
| | - Herbert B Schiller
- Institute of Lung Biology and Disease and Comprehensive Pneumology Center with the CPC–M bioArchiveHelmholtz Zentrum München, Member of the German Center for Lung Research (DZL)MunichGermany
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31
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Casanova NG, Zhou T, Gonzalez-Garay ML, Lussier YA, Sweiss N, Ma SF, Noth I, Knox KS, Garcia JGN. MicroRNA and protein-coding gene expression analysis in idiopathic pulmonary fibrosis yields novel biomarker signatures associated to survival. Transl Res 2021; 228:1-12. [PMID: 32711186 PMCID: PMC7779721 DOI: 10.1016/j.trsl.2020.07.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 07/09/2020] [Accepted: 07/16/2020] [Indexed: 02/04/2023]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology that poses significant challenges in early diagnosis and prediction of progression. Analyses of microRNA and gene expression in IPF have yielded potentially predictive information. However, the relationship between microRNA/gene expression and quantitative phenotypic value in IPF remains controversial, as is the added value of this approach to current molecular signatures in IPF. To identify biomarkers predictive of survival in IPF via a microRNA-driven strategy. We profiled microRNA and protein-coding gene expression in peripheral blood mononuclear cells from 70 IPF subjects in a discovery cohort. We linked the microRNA/gene expression level with the quantitative phenotypic variation in IPF, including diffusing capacity of the lung for carbon monoxide and the forced vital capacity percent predicted. In silico analyses of expression profiles and quantitative phenotypic data allowed the generation of 2 sets of IPF molecular signatures (unique for microRNAs and protein-coding genes) that predict IPF survival. Each signature performed well in a validation cohort comprised of IPF patients aggregated from distinct patient populations recruited from different sites. Resampling test suggests that the protein-coding gene based signature is comparable and potentially superior to published IPF prognostic gene signatures. In conclusion, these results highlight the utility of microRNA-driven peripheral blood molecular signatures as valuable and novel biomarkers associated to individuals at high survival risk and for potentially facilitating individualized therapies in this enigmatic disorder.
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Affiliation(s)
- Nancy G Casanova
- Department of Medicine, University of Arizona Health Sciences, Tucson, Arizona
| | - Tong Zhou
- Department of Physiology and Cell Biology, University of Nevada, Reno School of Medicine, Reno, Nevada
| | | | - Yves A Lussier
- Center for Biomedical Informatics and Biostatistics, University of Arizona, Tucson, Arizona
| | - Nadera Sweiss
- Section of Rheumatology Department of Medicine, University of Illinois at Chicago, Chicago, Illinois
| | - Shwu-Fan Ma
- Section of Pulmonary/Critical Care, Department of Medicine, University of Chicago, Chicago, Illinois
| | - Imre Noth
- Division of Pulmonary and Critical Care Department of Medicine, University of Virginia, Charlottesville, Virginia
| | - Kenneth S Knox
- Department of Medicine, College of Medicine-Phoenix, University of Arizona Health Sciences, Phoenix, Arizona
| | - Joe G N Garcia
- Department of Medicine, University of Arizona Health Sciences, Tucson, Arizona.
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32
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Serum Krebs von den Lungen-6 level predicts disease progression in interstitial lung disease. PLoS One 2020; 15:e0244114. [PMID: 33332430 PMCID: PMC7746162 DOI: 10.1371/journal.pone.0244114] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Accepted: 12/03/2020] [Indexed: 11/22/2022] Open
Abstract
Disease progression (DP) in interstitial lung disease (ILD) is variable and difficult to predict. In previous reports, serum Krebs von den Lungen-6 (KL-6) was suggested to be useful in diagnosing and predicting survival in ILD. The aim of our study was to investigate the usefulness of serum KL-6 as a predictor of DP in ILD. Clinical data of 199 patients with ILD (idiopathic pulmonary fibrosis: 22.8%) were prospectively collected and serum KL-6 levels were measured. DP was defined as a relative decline in forced vital capacity (FVC) ≥ 10%, acute exacerbation, or death during follow-up. The median follow-up period was 11.1 months. The mean age of the subjects was 62.2 years, and 59.8% were male. DP occurred in 21.6% of patients. The progressed group showed lower FVC, lower diffusing capacity for carbon monoxide, lower the minimum oxygen saturation during the 6-minute walk test, higher fibrosis scores on high-resolution computed tomography, and higher KL-6 levels (826.3 vs. 629.0 U/mL; p < 0.001) than those of the non-progressed group. In receiver operating characteristic curve analysis, serum KL-6 levels were a significant predictor of DP in ILD (area under the curve = 0.629, p = 0.009, and the optimal cut-off level was 811 U/mL). In multivariable Cox analysis, high serum KL-6 levels (≥ 800 U/mL) were only independently associated with DP in ILD (HR 2.689, 95% CI 1.445–5.004, P = 0.002). Serum KL-6 levels might be useful to predict DP in patients with ILD.
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Ikeda K, Chiba H, Nishikiori H, Azuma A, Kondoh Y, Ogura T, Taguchi Y, Ebina M, Sakaguchi H, Miyazawa S, Suga M, Sugiyama Y, Nukiwa T, Kudoh S, Takahashi H. Serum surfactant protein D as a predictive biomarker for the efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis: a post-hoc analysis of the phase 3 trial in Japan. Respir Res 2020; 21:316. [PMID: 33256760 PMCID: PMC7706186 DOI: 10.1186/s12931-020-01582-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 11/22/2020] [Indexed: 12/15/2022] Open
Abstract
Background Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease course. The recent advancement of antifibrotic therapy has increased the need for reliable and specific biomarkers. This study aimed to assess alveolar epithelial biomarkers as predictors for the efficacy of the antifibrotic drug pirfenidone. Methods We conducted a post-hoc analysis of the prospective, multicenter, randomized, placebo-controlled, phase 3 trial of pirfenidone in Japan (total, n = 267; pirfenidone, n = 163; placebo, n = 104). Logistic regression analysis was performed to extract parameters that predicted disease progression, defined by a ≥ 10% relative decline in vital capacity (VC) from baseline and/or death, at week 52. For assessment of serum surfactant protein (SP)-D, SP-A and Krebs von den Lungen (KL)-6, all patients were dichotomized by the median concentration of each biomarker at baseline to the high and low biomarker subgroups. Associations of these concentrations were examined with changes in VC at each time point from baseline up to week 52, along with progression-free survival (PFS). Additionally, the effect of pirfenidone treatment on serial longitudinal concentrations of these biomarkers were evaluated. Results In the multivariate logistic regression analysis, body mass index (BMI), %VC and SP-D in the pirfenidone group, and BMI and %VC in the placebo group were indicated as predictors of disease progression. Pirfenidone treatment reduced the decline in VC with statistical significance in the low SP-D and low SP-A subgroups over most of the treatment period, and also prolonged PFS in the low SP-D and low KL-6 subgroups. Furthermore, SP-D levels over time course were reduced in the pirfenidone group from as early as week 8 until the 52-week treatment period compared with the placebo group. Conclusions Serum SP-D was the most consistent biomarker for the efficacy of pirfenidone in the cohort trial of IPF. Serial measurements of SP-D might have a potential for application as a pharmacodynamic biomarker. Trial registration The clinical trial was registered with the Japan Pharmaceutical Information Center (JAPIC) on September 13, 2005 (registration No. JapicCTI-050121; http://Clinicaltrials.jp)
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Affiliation(s)
- Kimiyuki Ikeda
- Department of Respiratory Medicine and Allergology, School of Medicine, Sapporo Medical University, South 1, West 16, Sapporo, 060-8543, Japan
| | - Hirofumi Chiba
- Department of Respiratory Medicine and Allergology, School of Medicine, Sapporo Medical University, South 1, West 16, Sapporo, 060-8543, Japan.
| | - Hirotaka Nishikiori
- Department of Respiratory Medicine and Allergology, School of Medicine, Sapporo Medical University, South 1, West 16, Sapporo, 060-8543, Japan
| | | | | | - Takashi Ogura
- Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan
| | | | - Masahito Ebina
- Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | | | | | | | | | | | - Shoji Kudoh
- Japan Anti-Tuberculosis Association, Tokyo, Japan
| | - Hiroki Takahashi
- Department of Respiratory Medicine and Allergology, School of Medicine, Sapporo Medical University, South 1, West 16, Sapporo, 060-8543, Japan
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Fan Y, He R, Zou L, Meng J. [Clinical value of biomarkers in diagnosis and treatment of idiopathic pulmonary fibrosis]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2020; 40:1062-1065. [PMID: 32895164 DOI: 10.12122/j.issn.1673-4254.2020.07.23] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia characterized by progressive accumulation of fibroblastic foci and destruction of the alveolar structure. Due to an incomplete understanding of the mechanism of the occurrence and progression of IPF, currently no effective means have been available for its early screening or treatment. With a poor overall prognosis, the patients with IPF have a median survival of only 2-4 years. In recent years, several studies have confirmed that dozens of molecules are involved in the development of IPF and can be used as potential biomarkers. These biomarkers play important roles in early diagnosis (such as SP-D, MMP-7, and osteopontin), prognostic evaluation (such as telomerase length, KL-6, mtDNA, HSP-70, LOXL2, CXCL13, miRNA, ICAM-1, and CCL18), and guiding treatment of IPF (such as TOLLIP rs3750920 genotype, SAMS score, and SP-D), and also provide potential therapeutic targets (such as TERT, TERR, RTEC, and PARN).
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Affiliation(s)
- Yubin Fan
- Department of Respiratory and Critical Care Medicine, Xiangya Hospital; Organ Fibrosis Research Center, Central South University, Changsha 410008, China
| | - Rongling He
- Department of Respiratory and Critical Care Medicine, Xiangya Hospital; Organ Fibrosis Research Center, Central South University, Changsha 410008, China
| | - Lijun Zou
- Department of Respiratory and Critical Care Medicine, Xiangya Hospital; Organ Fibrosis Research Center, Central South University, Changsha 410008, China
| | - Jie Meng
- Department of Respiratory and Critical Care Medicine, Xiangya Hospital; Organ Fibrosis Research Center, Central South University, Changsha 410008, China
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35
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Shi S, Liu Y, Qiu X, Cao M, Xiao Y, Yan X. Correlation between serum bilirubin levels and the severity as well as the prognosis of idiopathic pulmonary fibrosis. Chron Respir Dis 2020; 17:1479973120957676. [PMID: 32909821 PMCID: PMC7493269 DOI: 10.1177/1479973120957676] [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] [Indexed: 11/16/2022] Open
Abstract
Bilirubin exerts antioxidant activity that has been associated with respiratory diseases. However, the relationship between serum bilirubin levels and idiopathic pulmonary fibrosis (IPF) is not clear. Therefore, in this study, we evaluated the relationship between serum bilirubin levels and the severity as well as the prognosis of IPF. One hundred and forty-six patients with IPF and 69 healthy individuals as the control group were enrolled as a derivation cohort. Routine blood examination and pulmonary function tests were performed and serum bilirubin levels were measured. To validate the value of serum bilirubin levels to predict the survival of patients with IPF, 40 additional IPF patients were included as a validation cohort. IPF patients were followed-up. Patients with IPF had significantly lower levels of serum total bilirubin (TBIL) and direct bilirubin (DBIL) than those in the control group (P < 0.05). Patients with acute exacerbation of IPF (AE-IPF) had significantly lower levels of serum TBIL and IBIL than those in patients with stable IPF (P < 0.05). The area under the receiver operating characteristic curve (AUROC) of serum TBIL levels for the prediction of the incidence of AE-IPF was 0.72 (95% CI: 0.56–0.87, P = 0.0057). The best cutoff value of serum TBIL level to predict the survival of patients with IPF was 8.8 μmol/l (AUC = 0.75, 95% CI: 0.64–0.87, P = 0.022). The log-rank test showed a significant difference in survival between the two groups (TBIL ≤8.8 μmol/l and TBIL >8.8 μmol/l) in derivation and validation cohort. Cox multiple regression analysis indicated that serum TBIL levels were an independent prognostic factor for IPF prognosis (HR = 0.582, P = 0.026). Serum TBIL levels might be useful for reflecting the severity and predicting the survival of patients with IPF.
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Affiliation(s)
- Shenyun Shi
- Department of Respiratory and Critical Care Medicine, 66506Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Yin Liu
- Department of Respiratory and Critical Care Medicine, 66506Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xiaohua Qiu
- Department of Respiratory and Critical Care Medicine, 66506Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Min Cao
- Department of Respiratory and Critical Care Medicine, 66506Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Yonglong Xiao
- Department of Respiratory and Critical Care Medicine, 66506Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
| | - Xin Yan
- Department of Respiratory and Critical Care Medicine, 66506Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, China
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Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis: Part A. J Clin Med 2020; 9:jcm9061940. [PMID: 32575869 PMCID: PMC7356165 DOI: 10.3390/jcm9061940] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/17/2020] [Accepted: 06/19/2020] [Indexed: 01/21/2023] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease, characterized by fibroblast proliferation and extracellular matrix deposition. CC-chemokine ligand 18 (CCL18) upregulates the production of collagen by lung fibroblasts and is associated with mortality. This study was designed to evaluate the influence of single nucleotide polymorphisms (SNPs) in the CCL18 gene on CCL18 expression and survival in IPF. Serum CCL18 levels and four SNPs in the CCL18 gene were analyzed in 77 Dutch IPF patients and 349 healthy controls (HCs). CCL18 mRNA expression was analyzed in peripheral blood mononuclear cells (PBMCs) from 18 healthy subjects. Survival analysis was conducted, dependent on CCL18-levels and -genotypes and validated in two German IPF cohorts (Part B). IPF patients demonstrated significantly higher serum CCL18 levels than the healthy controls (p < 0.001). Both in IPF patients and HCs, serum CCL18 levels were influenced by rs2015086 C > T genotype, with the highest CCL18-levels with the presence of the C-allele. Constitutive CCL18 mRNA-expression in PBMCs was significantly increased with the C-allele and correlated with serum CCL18-levels. In IPF, high serum levels correlated with decreased survival (p = 0.02). Survival was worse with the CT-genotype compared to the TT genotype (p = 0.01). Concluding, genetic variability in the CCL18-gene accounts for differences in CCL18 mRNA-expression and serum-levels and influences survival in IPF.
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Sonaglioni A, Caminati A, Lipsi R, Nicolosi GL, Lombardo M, Anzà C, Harari S. Early left atrial dysfunction in idiopathic pulmonary fibrosis patients without chronic right heart failure. Int J Cardiovasc Imaging 2020; 36:1711-1723. [PMID: 32448985 DOI: 10.1007/s10554-020-01887-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Accepted: 05/15/2020] [Indexed: 12/17/2022]
Abstract
No data are actually available regarding the left atrial (LA) functional assessment by two-dimensional speckle tracking echocardiography (2D-STE) in early-stage idiopathic pulmonary fibrosis (IPF). The primary end-point of our study was to assess whether global LA peak strain (GLAPS), measured by 2D-STE analysis, may detect early alterations in LA function in IPF patients without right heart failure (RHF). Between September 2017 and January 2019, 50 consecutive IPF patients (73.8 ± 6.8 years, 36 males) without chronic RHF and 30 controls matched by age, sex and cardiovascular risk factors, were enrolled in an observational retrospective case-control study. All patients underwent a complete echocardiographic study implemented with 2D-STE analysis. GLAPS, left ventricular (LV) global longitudinal strain (GLS), right atrial (RA) reservoir strain (GSA+) and right ventricular (RV)-GLS were obtained in each patient. LVFP were significantly increased in IPF patients in comparison to controls (average E/e' ratio 14.4 ± 3.0 vs 9.6 ± 1.5, p < 0.0001), while LV-GLS was slightly reduced in IPF patients compared to controls (19.4 ± 3.6% vs 21.0 ± 2.2%, p = 0.03).Moreover, GLAPS was significantly impaired in IPF patients in comparison to controls (18.4 ± 3.7% vs 28.4 ± 5.6%, p < 0.0001).Finally, the two groups of patients did not show any statistically significant difference in both RA-GSA + (23.9 ± 3.7% vs 24.5 ± 4.0%, p = 0.49) and RV-GLS (- 22.6 ± 3.3% vs - 23.5 ± 3.0%, p = 0.22). Notably, LV-GLS was strongly inversely correlated both with RV/LV basal diameter ratio and TRV in IPF patients (r = - 0.87 and - 0.82, respectively) but not in controls (r = - 0.29 and - 0.27, respectively). This finding highlights a likely process of ventricular interdependence in non-advanced IPF, with consequent LV diastolic dysfunction and secondary impairment in LV-GLS and GLAPS. Early LA reservoir dysfunction in IPF patients may be secondary to LV diastolic dysfunction induced by ventricular interdependence and may develop before RV diastolic and systolic dysfunction.
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Affiliation(s)
- Andrea Sonaglioni
- Department of Cardiology, Ospedale San Giuseppe MultiMedica, Via San Vittore 12, 20123, Milan, Italy
| | - Antonella Caminati
- Semi-Intensive Care Unit, Department of Pneumology, Department of Respiratory Physiopathology and Pulmonary Hemodynamics, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy.
| | - Roberto Lipsi
- Semi-Intensive Care Unit, Department of Pneumology, Department of Respiratory Physiopathology and Pulmonary Hemodynamics, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy
| | - Gian Luigi Nicolosi
- Department of Cardiology, Policlinico San Giorgio, Via Agostino Gemelli 10, 33170, Pordenone, Italy
| | - Michele Lombardo
- Department of Cardiology, Ospedale San Giuseppe MultiMedica, Via San Vittore 12, 20123, Milan, Italy
| | - Claudio Anzà
- Cardiovascular Department, MultiMedica IRCCS, Via Milanese 300, Sesto San Giovanni, 20099, Milan, Italy
| | - Sergio Harari
- Semi-Intensive Care Unit, Department of Pneumology, Department of Respiratory Physiopathology and Pulmonary Hemodynamics, Ospedale San Giuseppe MultiMedica IRCCS, Via San Vittore 12, 20123, Milan, Italy
- Department of Medical Sciences San Giuseppe Hospital MultiMedica IRCCS and Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
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Ni S, Song M, Guo W, Guo T, Shen Q, Peng H. Biomarkers and their potential functions in idiopathic pulmonary fibrosis. Expert Rev Respir Med 2020; 14:593-602. [PMID: 32187497 DOI: 10.1080/17476348.2020.1745066] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic, devastating, and progressive lung disease that is characterized by fibrosis and respiratory failure. IPF holds high morbidity and poor prognosis and still faces considerable problems of reliable diagnosis and valid prognosis. A growing body of literature have reported changes in the level of various biomarkers in IPF patients, which means that they are expected to become a new tool for the clinical practice of IPF.Areas covered: We reviewed the recent literature about biomarkers and focus on the role they play in IPF. We systematically searched Medline/PubMed through February 2020. Many works of literature have shown that a variety of biomolecules and genomics played multiple roles in the diagnosis or differential diagnosis, prognosis, and indication of acute deterioration of IPF and so on.Expert opinion: Significant advances have been made in the role of biomarkers for IPF these years; however, current data indicate that a single biomarker is unlikely to have a transformative effect on clinical practice; therefore, the combined effect of various biomarkers can be considered to improve the accuracy of diagnosis and prognosis. Further research of biomarkers may provide new insights for the diagnosis, prognosis, and even therapy of IPF.
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Affiliation(s)
- Shanshan Ni
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital of Central South University; Research Unit of Respiratory Disease, Central South University; The Respiratory Disease Diagnosis and Treatment Center of Hunan Province, Changsha, Hunan, China
| | - Min Song
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital of Central South University; Research Unit of Respiratory Disease, Central South University; The Respiratory Disease Diagnosis and Treatment Center of Hunan Province, Changsha, Hunan, China
| | - Wei Guo
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital of Central South University; Research Unit of Respiratory Disease, Central South University; The Respiratory Disease Diagnosis and Treatment Center of Hunan Province, Changsha, Hunan, China
| | - Ting Guo
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital of Central South University; Research Unit of Respiratory Disease, Central South University; The Respiratory Disease Diagnosis and Treatment Center of Hunan Province, Changsha, Hunan, China
| | - Qinxue Shen
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital of Central South University; Research Unit of Respiratory Disease, Central South University; The Respiratory Disease Diagnosis and Treatment Center of Hunan Province, Changsha, Hunan, China
| | - Hong Peng
- Department of Respiratory and Critical Care Medicine, the Second Xiangya Hospital of Central South University; Research Unit of Respiratory Disease, Central South University; The Respiratory Disease Diagnosis and Treatment Center of Hunan Province, Changsha, Hunan, China
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Choi B, Kawut SM, Raghu G, Hoffman E, Tracy R, Madahar P, Bernstein EJ, Barr RG, Lederer DJ, Podolanczuk A. Regional distribution of high-attenuation areas on chest computed tomography in the Multi-Ethnic Study of Atherosclerosis. ERJ Open Res 2020; 6:00115-2019. [PMID: 32154292 PMCID: PMC7049731 DOI: 10.1183/23120541.00115-2019] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 12/04/2019] [Indexed: 11/16/2022] Open
Abstract
High-attenuation areas (HAA) are a computed tomography-based quantitative measure of subclinical interstitial lung disease (ILD). We aimed to validate HAA in lung regions that are less subject to artefacts, such as extravascular lung water or dependent atelectasis. We examined the associations of HAA within six lung regions (basilar, non-basilar, peel, core, basilar peel, basilar core) with serum biomarkers of lung remodelling, forced vital capacity (FVC), visually-assessed interstitial lung abnormalities (ILA), and all-cause and ILD-specific mortality. We performed cross-sectional and longitudinal analyses of participants in the Multi-Ethnic Study of Atherosclerosis, a prospective cohort of 6814 adults aged 45–84 years without known cardiovascular disease who underwent cardiac computed tomography. Median regional HAA ranged from 3.8% in the peel to 4.8% in the basilar core. Doubling of regional HAA was associated with greater serum matrix metalloproteinase-7 (range 3.8% to 10.3%; p≤0.01), higher odds of ILA (OR 1.42 to 2.20; p≤0.03), and a higher risk of all-cause mortality (hazard ratio 1.20 to 1.47; p≤0.001). Doubling of regional HAA was associated with greater serum interleukin-6 (4.9% to 10.3%; p≤0.005) and higher risk of ILD-specific mortality (hazard ratio 3.30 to 3.98; p<0.001), except in the basilar core. Doubling of regional HAA was associated with lower FVC in the non-basilar, core and basilar core (113 mL to 186 mL; p<0.001). Associations of HAA with lung remodelling biomarkers, ILA risk and all-cause mortality were consistent across all regions of the lung, including dependent areas where atelectasis may be present. These findings support the validity of HAA as a measure of pathologic subclinical ILD. Evenwhen found in small regions of the lungs, high-attenuation areas, a CT-based quantitative measure of subclinical ILD, are associated with biomarkers of lung remodelling, risk of interstitial lung abnormalities and all-cause mortalityhttp://bit.ly/36psfin
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Affiliation(s)
- Bina Choi
- Columbia University Medical Center, New York, NY, USA
| | - Steven M Kawut
- University of Pennsylvania School of Medicine, Philadelphia, PA, USA
| | - Ganesh Raghu
- University of Washington Medical Center, Seattle, WA, USA
| | - Eric Hoffman
- University of Iowa Carver College of Medicine, Iowa City, IA, USA
| | | | | | | | - R Graham Barr
- Columbia University Medical Center, New York, NY, USA
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Prognostic Value of Serum Osteopontin in Acute Exacerbation of Idiopathic Pulmonary Fibrosis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3424208. [PMID: 32104688 PMCID: PMC7035537 DOI: 10.1155/2020/3424208] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2019] [Revised: 10/30/2019] [Accepted: 11/19/2019] [Indexed: 12/14/2022]
Abstract
Background Acute exacerbation (AE) is a common cause of rapid deterioration and high mortality in idiopathic pulmonary fibrosis (IPF) patients. Osteopontin (OPN) plays an important role in IPF, but the studies about serum OPN in AE-IPF are unclear. We aimed to investigate whether OPN had a potential prognostic value in acute exacerbation and mortality in IPF. Methods Thirty-two patients with AE-IPF, 39 with S-IPF, and 20 healthy controls were included. Serum OPN and KL-6 levels were compared between AE-IPF and S-IPF. Logistic regression analysis was applied to identify the predicted value of OPN for AE. Kaplan-Meier curves were used to display survival, and Cox proportional hazards regression was used to identify risk for mortality. Results In AE-IPF patients, serum OPN levels were significantly higher than in S-IPF subjects (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (p < 0.001) or healthy controls (. Conclusion Elevated OPN could be a potential serum predictor for AE status and survival in IPF patients.
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Yoshikawa T, Otsuka M, Chiba H, Ikeda K, Mori Y, Umeda Y, Nishikiori H, Kuronuma K, Takahashi H. Surfactant protein A as a biomarker of outcomes of anti-fibrotic drug therapy in patients with idiopathic pulmonary fibrosis. BMC Pulm Med 2020; 20:27. [PMID: 32005219 PMCID: PMC6995128 DOI: 10.1186/s12890-020-1060-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 01/23/2020] [Indexed: 01/19/2023] Open
Abstract
Background Idiopathic pulmonary fibrosis (IPF) is a progressive and fibrosing lung disease with poor prognosis. Pirfenidone and nintedanib are anti-fibrotic drugs used for patients with IPF. These drugs reduce the rate of decline in forced vital capacity (FVC). Serum surfactant protein (SP)-A, SP-D, and Krebs von den Lungen-6 (KL-6) are monitoring and prognostic biomarkers in patients with IPF; however, their relationship with the therapeutic outcomes of anti-fibrotic drugs has not been investigated. We aim to clarify whether serum SP-A, SP-D, and KL-6 reflect therapeutic outcomes of pirfenidone and nintedanib administration in patients with IPF. Methods We retrospectively investigated patients with IPF who were initiated on pirfenidone or nintedanib administration between January 2014 and June 2018 at our hospital. Changes in clinical parameters and serum SP-A, SP-D, and KL-6 levels were evaluated. Patients with ≥10% decline in FVC or ≥ 15% decline in diffusing capacity of the lung for carbon monoxide (DLco) from baseline to 6 months were classified as progression group, while the other patients were classified as stable group. Results Forty-nine patients were included (pirfenidone, 23; nintedanib, 26). Stable group comprised 32 patients, while progression group comprised 17 patients. In the stable group, changes in SP-A and KL-6 from baseline to 3 and 6 months significantly decreased compared with the progression group (SP-A: 3 months − 6.0% vs 16.7%, 6 months − 10.2% vs 20.2%, KL-6: 3 months − 9.2% vs 6.7%, 6 months − 15.0% vs 12.1%, p < 0.05). Changes in SP-A and SP-D levels showed significant negative correlations with the change in %FVC (r = − 0.46 and r = − 0.39, p < 0.01, respectively) and %DLco (r = − 0.67 and r = − 0.54, p < 0.01, respectively). Similar results were also seen in subgroup analysis for both pirfenidone and nintedanib groups. On logistic regression analysis, decrease in SP-A from baseline to 3 months and 6 months was found to predict the outcomes at 6 months (odds ratios: 0.89 and 0.88, respectively). Conclusions Changes in serum SP-A reflected the outcomes of anti-fibrotic drug therapy. Serum SP-A has a potential as a biomarker of therapeutic outcomes of anti-fibrotic drugs.
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Affiliation(s)
- Takumi Yoshikawa
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Mitsuo Otsuka
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan.
| | - Hirofumi Chiba
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Kimiyuki Ikeda
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Yuki Mori
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Yasuaki Umeda
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Hirotaka Nishikiori
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Koji Kuronuma
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
| | - Hiroki Takahashi
- Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, 1-37, South 1-West 16, Chuo-ku, Sapporo, Hokkaido, 060-8543, Japan
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Elhai M, Avouac J, Allanore Y. Circulating lung biomarkers in idiopathic lung fibrosis and interstitial lung diseases associated with connective tissue diseases: Where do we stand? Semin Arthritis Rheum 2020; 50:480-491. [PMID: 32089354 DOI: 10.1016/j.semarthrit.2020.01.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 01/09/2020] [Accepted: 01/22/2020] [Indexed: 12/14/2022]
Abstract
Interstitial lung diseases (ILDs) are complex diseases with various courses where personalized medicine is highly expected. Biomarkers are indicators of physiological, pathological processes or of pharmacological response to therapeutic interventions. They can be used for diagnosis, risk-stratification, prediction and monitoring of treatment response. To better delineate the input and pitfalls of biomarkers in ILDs, we performed a systematic review and meta-analysis of literature in MEDLINE and Embase databases from January 1960 to February 2019. We focused on circulating biomarkers as having the highest generalizability. Overall, 70 studies were included in the review and 20 studies could be included in the meta-analysis. This review highlights that ILD associated with connective tissue diseases (CTD-ILD) and idiopathic pulmonary fibrosis (IPF) share common biomarkers, suggesting common pathophysiological pathways. KL-6 and SP-D, could diagnose lung fibrosis in both IPF and CTD-ILD, with KL-6 having the strongest value (OR: 520.95[110.07-2465.58], p<0.001 in IPF and OR:26.43[7.15-97.68], p<0.001 in CTD-ILD), followed by SPD (OR: 33.81[3.20-357.52], p = 0.003 in IPF and 13.24 [3.84-45.71] in SSc-ILD), MMP7 appeared as interesting for IPF diagnosis (p<0.001), whereas in SSc, CCL18 was associated with ILD diagnosis. Both CCL18 and KL-6 were predictive for the outcomes of ILDs, with higher predictive values for CCL18 in both IPF (OR:10.22[4.72-22.16], p<0.001 and in SSc [2.62[1.71-4.03], p<0.001). However, disease specific biomarkers are lacking and large longitudinal studies are needed before the translational use of the potential biomarkers in clinical practice. With the recent availability of new effective therapies in ILDs, further studies should assess response to treatment.
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Affiliation(s)
- Muriel Elhai
- INSERM U1016, Rheumatology A department, Cochin Hospital, Paris Descartes University, 27 rue du Faubourg Saint Jacques, 75014 Paris, France.
| | - Jérôme Avouac
- INSERM U1016, Rheumatology A department, Cochin Hospital, Paris Descartes University, 27 rue du Faubourg Saint Jacques, 75014 Paris, France.
| | - Yannick Allanore
- INSERM U1016, Rheumatology A department, Cochin Hospital, Paris Descartes University, 27 rue du Faubourg Saint Jacques, 75014 Paris, France.
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Aggarwal D. Serum prealbumin as prognostic indicator in idiopathic pulmonary fibrosis. A glimmer of hope. THE CLINICAL RESPIRATORY JOURNAL 2019; 13:659-660. [PMID: 31374160 DOI: 10.1111/crj.13072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Accepted: 07/29/2019] [Indexed: 06/10/2023]
Affiliation(s)
- Deepak Aggarwal
- Department of Pulmonary Medicine, Government Medical College & Hospital, Chandigarh, India
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Jee AS, Sahhar J, Youssef P, Bleasel J, Adelstein S, Nguyen M, Corte TJ. Review: Serum biomarkers in idiopathic pulmonary fibrosis and systemic sclerosis associated interstitial lung disease – frontiers and horizons. Pharmacol Ther 2019; 202:40-52. [DOI: 10.1016/j.pharmthera.2019.05.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Accepted: 05/24/2019] [Indexed: 02/02/2023]
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Somogyi V, Chaudhuri N, Torrisi SE, Kahn N, Müller V, Kreuter M. The therapy of idiopathic pulmonary fibrosis: what is next? Eur Respir Rev 2019; 28:190021. [PMID: 31484664 PMCID: PMC9488691 DOI: 10.1183/16000617.0021-2019] [Citation(s) in RCA: 172] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 05/16/2019] [Indexed: 12/21/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung disease, characterised by progressive scarring of the lung and associated with a high burden of disease and early death. The pathophysiological understanding, clinical diagnostics and therapy of IPF have significantly evolved in recent years. While the recent introduction of the two antifibrotic drugs pirfenidone and nintedanib led to a significant reduction in lung function decline, there is still no cure for IPF; thus, new therapeutic approaches are needed. Currently, several clinical phase I-III trials are focusing on novel therapeutic targets. Furthermore, new approaches in nonpharmacological treatments in palliative care, pulmonary rehabilitation, lung transplantation, management of comorbidities and acute exacerbations aim to improve symptom control and quality of life. Here we summarise new therapeutic attempts and potential future approaches to treat this devastating disease.
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Affiliation(s)
- Vivien Somogyi
- Center for Interstitial and Rare Lung Diseases, Thoraxklinik, University of Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany
- Dept of Pulmonology, Semmelweis University, Budapest, Hungary
| | - Nazia Chaudhuri
- Manchester University NHS Foundation Trust, Wythenshawe Hospital, Manchester, UK
| | - Sebastiano Emanuele Torrisi
- Center for Interstitial and Rare Lung Diseases, Thoraxklinik, University of Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany
- Regional Referral Centre for Rare Lung Diseases, University Hospital "Policlinico", Dept of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Nicolas Kahn
- Center for Interstitial and Rare Lung Diseases, Thoraxklinik, University of Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany
| | - Veronika Müller
- Dept of Pulmonology, Semmelweis University, Budapest, Hungary
| | - Michael Kreuter
- Center for Interstitial and Rare Lung Diseases, Thoraxklinik, University of Heidelberg, German Center for Lung Research (DZL), Heidelberg, Germany
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Ballester B, Milara J, Cortijo J. Mucins as a New Frontier in Pulmonary Fibrosis. J Clin Med 2019; 8:jcm8091447. [PMID: 31514468 PMCID: PMC6780288 DOI: 10.3390/jcm8091447] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 09/05/2019] [Accepted: 09/09/2019] [Indexed: 12/15/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pulmonary disease with a median survival of 3–5 years after diagnosis. Recent evidence identifies mucins as key effectors in cell growth and tissue remodeling processes compatible with the processes observed in IPF. Mucins are classified in two groups depending on whether they are secreted (secreted mucins) or tethered to cell membranes (transmembrane mucins). Secreted mucins (MUC2, MUC5AC, MUC5B, MUC6-8 and MUC19) are released to the extracellular medium and recent evidence has shown that a promoter polymorphism in the secreted mucin MUC5B is associated with IPF risk. Otherwise, transmembrane mucins (MUC1, MUC3, MUC4, MUC12-17 and MUC20) have a receptor-like structure, sensing the external environment and activating intracellular signal transduction pathways essential for mucosal maintenance and damage repair. In this context, the extracellular domain can be released to the external environment by metalloproteinase action, increased in IPF, thus activating fibrotic processes. For example, several studies have reported increased serum extracellular secreted KL6/MUC1 during IPF acute exacerbation. Moreover, MUC1 and MUC4 overexpression in the main IPF cells has been observed. In this review we summarize the current knowledge of mucins as promising druggable targets for IPF.
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Affiliation(s)
- Beatriz Ballester
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain.
- CIBERES, Health Institute Carlos III, 46010 Valencia, Spain.
| | - Javier Milara
- CIBERES, Health Institute Carlos III, 46010 Valencia, Spain.
- Institute of Health Research-INCLIVA, 46010 Valencia, Spain.
| | - Julio Cortijo
- Department of Pharmacology, Faculty of Medicine, University of Valencia, 46010 Valencia, Spain
- CIBERES, Health Institute Carlos III, 46010 Valencia, Spain
- Research and teaching Unit, University General Hospital Consortium of Valencia, 46014 Valencia, Spain
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Sivakumar P, Thompson JR, Ammar R, Porteous M, McCoubrey C, Cantu E, Ravi K, Zhang Y, Luo Y, Streltsov D, Beers MF, Jarai G, Christie JD. RNA sequencing of transplant-stage idiopathic pulmonary fibrosis lung reveals unique pathway regulation. ERJ Open Res 2019; 5:00117-2019. [PMID: 31423451 PMCID: PMC6689672 DOI: 10.1183/23120541.00117-2019] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 06/15/2019] [Indexed: 11/05/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF), the scarring of lung parenchyma resulting in the loss of lung function, remains a fatal disease with a significant unmet medical need. Patients with severe IPF often develop acute exacerbations resulting in the rapid deterioration of lung function, requiring transplantation. Understanding the pathophysiological mechanisms contributing to IPF is key to develop novel therapeutic approaches for end-stage disease. We report here RNA-sequencing analyses of lung tissues from a cohort of patients with transplant-stage IPF (n=36), compared with acute lung injury (ALI) (n=11) and nondisease controls (n=19), that reveal a robust gene expression signature unique to end-stage IPF. In addition to extracellular matrix remodelling pathways, we identified pathways associated with T-cell infiltration/activation, tumour development, and cholesterol homeostasis, as well as novel alternatively spliced transcripts that are differentially regulated in the advanced IPF lung versus ALI or nondisease controls. Additionally, we show a subset of genes that are correlated with percent predicted forced vital capacity and could reflect disease severity. Our results establish a robust transcriptomic fingerprint of an advanced IPF lung that is distinct from previously reported microarray signatures of moderate, stable or progressive IPF and identifies hitherto unknown candidate targets and pathways for therapeutic intervention in late-stage IPF as well as biomarkers to characterise disease progression and enable patient stratification.
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Affiliation(s)
- Pitchumani Sivakumar
- Fibrosis Translational Research and Development, Bristol-Myers Squibb Research and Development, Princeton NJ, USA
| | - John Ryan Thompson
- Translational Bioinformatics, Bristol-Myers Squibb Research and Development, Princeton NJ, USA
| | - Ron Ammar
- Translational Bioinformatics, Bristol-Myers Squibb Research and Development, Princeton NJ, USA
| | - Mary Porteous
- Pulmonary and Critical Care Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Carly McCoubrey
- Pulmonary and Critical Care Medicine, University of Pennsylvania, Philadelphia PA, USA
| | - Edward Cantu
- Surgery Dept, University of Pennsylvania, Philadelphia PA, USA
| | - Kandasamy Ravi
- Integrated Genomics, Bristol-Myers Squibb Research and Development, Princeton NJ, USA
| | - Yan Zhang
- Integrated Genomics, Bristol-Myers Squibb Research and Development, Princeton NJ, USA
| | - Yi Luo
- Clinical Biomarkers, Bristol-Myers Squibb Research and Development, Princeton NJ, USA
| | - Denis Streltsov
- Fibrosis Translational Research and Development, Bristol-Myers Squibb Research and Development, Princeton NJ, USA
| | - Michael F Beers
- Pulmonary and Critical Care Medicine, University of Pennsylvania, Philadelphia PA, USA.,PENN Center for Pulmonary Biology, University of Pennsylvania, Philadelphia PA, USA
| | - Gabor Jarai
- Fibrosis Translational Research and Development, Bristol-Myers Squibb Research and Development, Princeton NJ, USA
| | - Jason D Christie
- Pulmonary and Critical Care Medicine, University of Pennsylvania, Philadelphia PA, USA.,PENN Center for Pulmonary Biology, University of Pennsylvania, Philadelphia PA, USA
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Li B, Zhang X, Xu G, Zhang S, Song H, Yang K, Dai H, Wang C. Serum prealbumin is a prognostic indicator in idiopathic pulmonary fibrosis. CLINICAL RESPIRATORY JOURNAL 2019; 13:493-498. [PMID: 31102566 DOI: 10.1111/crj.13050] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 05/01/2019] [Accepted: 05/02/2019] [Indexed: 01/19/2023]
Abstract
INTRODUCTION Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by variable progression. The prealbumin (PA) is a parameter in a routine blood biochemistry examination. We sought to investigate the prognostic value in IPF patients. OBJECTIVES To evaluate the prognosis value in patients with IPF. METHODS Blood biochemistry examination, demographics, pulmonary function data from patients with IPF consulted in Beijing Chao-Yang Hospital and China-Japan Friendship Hospital between July 2012 and December 2016 were collected. Infection, liver and kidney dysfunction and lung transplantation are excluded from the cohort. RESULTS The result of multivariate Cox analysis showed that PA was significant prognostic indicator of survival along with BMI, FVC, serum albumin protein and serum global protein. The patients with PA concentration <0.2 mg/L had shorter survival compared with those whose PA were normal. Although the survival had no significant difference between the patients with PA concentration < 0.2 mg/L and albumin < 35 g/L and those with PA concentration < 0.2 mg/L, the average survival time of patients with PA concentration < 0.2 mg/L and albumin < 35 g/L were shorter. CONCLUSIONS Our study indicated that IPF patients with PA concentration < 0.2 mg/L have poorer outcome. Further studies are warranted to indentify PA as a predictor for IPF patients outcomes and explore the role of PA in the pathogenesis of IPF.
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Affiliation(s)
- Biyun Li
- Department of Pulmonary and Critical Care Medicine, Perking University China-Japan Friendship School of Clinical Medicine, Beijing, China
| | - Xinran Zhang
- Institute of Clinical Medical Sciences, Center of Respiratory Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Beijing, China
| | - Guodong Xu
- Institute of Clinical Medical Sciences, Center of Respiratory Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Beijing, China
| | - Shu Zhang
- Department of Pulmonary and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Huifang Song
- Department of Pulmonary and Critical Care Medicine, Inner Mongolia People's Hospital, Hohhot, China
| | - Kaiyuan Yang
- Department of Pulmonary and Critical Care Medicine, Beijing Lu-He Hospital, Capital Medical University, Beijing, China
| | - Huaping Dai
- Department of Pulmonary and Critical Care Medicine, Perking University China-Japan Friendship School of Clinical Medicine, Beijing, China.,Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Perking University Health Science Center, Beijing, China
| | - Chen Wang
- Department of Pulmonary and Critical Care Medicine, Perking University China-Japan Friendship School of Clinical Medicine, Beijing, China.,Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, National Clinical Research Center for Respiratory Diseases, Perking University Health Science Center, Beijing, China
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Kishaba T. Evaluation and management of Idiopathic Pulmonary Fibrosis. Respir Investig 2019; 57:300-311. [PMID: 30853366 DOI: 10.1016/j.resinv.2019.02.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 01/09/2019] [Accepted: 02/04/2019] [Indexed: 02/02/2023]
Abstract
Idiopathic Pulmonary Fibrosis (IPF) is a most common progressive interstitial lung disease (ILD) of unknown etiology, although majority of patients are elderly male smokers. The main pathogenesis is aberrant recovery of epithelial injury and collagen deposition. Fibrotic nonspecific interstitial pneumonia, connective tissue disease (CTD) especially rheumatoid arthritis (RA) associated ILD, and chronic hypersensitivity pneumonia(CHP) are important differential diagnosis. Main symptoms are non-productive cough and progressive exertional dyspnea. Crucial physical findings are scalene muscle hypertrophy, bibasilar fine crackles, and finger clubbing. The serum markers such as lactate dehydrogenase (LDH) and Krebs von den Lungen-6 (KL-6) are sensitive for ILD detection and activity. Both pulmonary function test (PFT) and the 6-minute walk test (6MWT) are useful tool for evaluation of disease progression of IPF. Serial changes of forced vital capacity (FVC) and 6MWT distance predict mortality in IPF effectively. Recently published international IPF guidelines highlight the importance of chest high resolution computed tomography (HRCT) findings such as honeycombing, traction bronchiectasis (TBE), and sub-pleural reticular opacity. IPF is chronic and progressive; therefore, tracking disease behavior is crucial. Unifying clinical, physiological, and imaging information over time is useful. With regard to its management, two anti-fibrotic drugs such as pirfenidone and nintedanib have been available. These drugs can slow the decline of FVC and prevent acute exacerbation (AE). In this review, I outline the clinical characteristics of IPF, physiological, imaging, pathological findings and review diagnosis process and management.
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Affiliation(s)
- Tomoo Kishaba
- Department of Respiratory Medicine, Okinawa Chubu Hospital, Miyazato 281, Uruma City, Okinawa 〒904-2293, Japan.
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Hayton C, Terrington D, Wilson AM, Chaudhuri N, Leonard C, Fowler SJ. Breath biomarkers in idiopathic pulmonary fibrosis: a systematic review. Respir Res 2019; 20:7. [PMID: 30634961 PMCID: PMC6329167 DOI: 10.1186/s12931-019-0971-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 01/01/2019] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Exhaled biomarkers may be related to disease processes in idiopathic pulmonary fibrosis (IPF) however their clinical role remains unclear. We performed a systematic review to investigate whether breath biomarkers discriminate between patients with IPF and healthy controls. We also assessed correlation with lung function, ability to distinguish diagnostic subgroups and change in response to treatment. METHODS MEDLINE, EMBASE and Web of Science databases were searched. Study selection was limited to adults with a diagnosis of IPF as per international guidelines. RESULTS Of 1014 studies screened, fourteen fulfilled selection criteria and included 257 IPF patients. Twenty individual biomarkers discriminated between IPF and controls and four showed correlation with lung function. Meta-analysis of three studies indicated mean (± SD) alveolar nitric oxide (CalvNO) levels were significantly higher in IPF (8.5 ± 5.5 ppb) than controls (4.4 ± 2.2 ppb). Markers of oxidative stress in exhaled breath condensate, such as hydrogen peroxide and 8-isoprostane, were also discriminatory. Two breathomic studies have isolated discriminative compounds using mass spectrometry. There was a lack of studies assessing relevant treatment and none assessed differences in diagnostic subgroups. CONCLUSIONS Evidence suggests CalvNO is higher in IPF, although studies were limited by small sample size. Further breathomic work may identify biomarkers with diagnostic and prognostic potential.
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Affiliation(s)
- Conal Hayton
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.
- North West Lung Centre, Manchester University NHS Foundation Trust, Manchester, UK.
| | | | - Andrew M Wilson
- Norwich Medical School, University of East Anglia, Norwich, UK
| | - Nazia Chaudhuri
- North West Lung Centre, Manchester University NHS Foundation Trust, Manchester, UK
| | - Colm Leonard
- North West Lung Centre, Manchester University NHS Foundation Trust, Manchester, UK
| | - Stephen J Fowler
- Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- North West Lung Centre, Manchester University NHS Foundation Trust, Manchester, UK
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