|
1
|
Kawasaki H. A mechanistic review-regulation of silica-induced pulmonary inflammation by IL-10 and exacerbation by Type I IFN. Inhal Toxicol 2025; 37:59-73. [PMID: 39955624 DOI: 10.1080/08958378.2025.2465378] [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: 04/12/2024] [Accepted: 02/05/2025] [Indexed: 02/17/2025]
Abstract
Occupational exposure to crystalline silica (CS) is known to induce silicosis, a chronic lung disease characterized by the formation of granulomas and severe lung fibrosis. Specifically, individuals exposed to low doses of CS may develop silicosis after a decade or more of exposure. Similarly, in rat silicosis models exposed to occupationally relevant doses of α-quartz, there is an initial phase characterized by minimal and well-controlled pulmonary inflammation, followed by the development of robust and persistent inflammation. During the initial phase, the inflammation provoked by α-quartz is subdued by two mechanisms. Firstly, α-quartz particles are engulfed by alveolar macrophages (AMs) of the alternatively activated (M2) subtype and interstitial macrophages (IMs), limiting their interaction with other lung cells. Secondly, the anti-inflammatory cytokine, interleukin (IL)-10, is constitutively expressed by these macrophages, further dampening the inflammatory response. In the later inflammatory phase, IL-10-dependent anti-inflammatory state is disrupted by Type I interferons (IFNs), leading to the production of pro-inflammatory cytokines in response to α-quartz, aided by lipopolysaccharides (LPS). This review delves into the complex pathways involving IL-10, LPS, and Type I IFNs in α-quartz-induced pulmonary inflammation, offering a detailed analysis of the underlying mechanisms and identifying areas for future research.
Collapse
|
|
2
|
Elsheikh AA, Shalaby AM, Alabiad MA, Abd-Almotaleb NA, Khayal EES. Perfluorooctanoic acid induced lung toxicity via TGF-β1/Smad pathway, crosstalk between airway hyperresponsiveness and fibrosis: withdrawal impact. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2025; 32:4989-5007. [PMID: 39900883 DOI: 10.1007/s11356-025-36005-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Accepted: 01/22/2025] [Indexed: 02/05/2025]
Abstract
Perfluorooctanoic acid (PFOA) is an environmental persistent agent to which humans are exposed daily through food and water. This study investigated the lung toxic effects induced by ingested PFOA (30 mg/kg/day) for 8 weeks in adult male rats and the impact following 8 weeks of its withdrawal. PFOA increased MDA and reduced TAC inducing oxidative stress. It induced airway hyperresponsiveness (AHR) via increased bronchoalveolar lavage fluid (BALF) IL-4, IL-5, IL-13, IL-9, eosinophil count, TNF-α, and IL-1ß; reduced IL-12; increased serum IgE; and increased urocortin expression in lung tissues. Moreover, it induced pulmonary fibrosis via increased serum KL-6, and SFTP-D, altered pulmonary structure, and increased deposition of collagen fibers in lung tissues. Furthermore, it increased TGF-β1, Smad2, and Smad3 and reduced Smad7 gene expression in lung tissues. These gene alterations were positively correlated with AHR and fibrosis-related factors. The recovered lung upon PFOA withdrawal showed complete resolution of oxidative stress and slight amelioration of other studying parameters. Exposure to PFOA induced lung toxicity by disrupting the TGF-β1/Smad signaling pathway, which acts as a crosstalk between AHR and fibrosis. Additionally, PFOA altered pulmonary architecture, triggered inflammation, and caused oxidative stress. The lung exhibited partial alleviation upon recovery.
Collapse
Affiliation(s)
- Arwa A Elsheikh
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Amany Mohamed Shalaby
- Histology and Cell Biology Department, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mohamed Ali Alabiad
- Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Noha Ali Abd-Almotaleb
- Anatomy and Embryology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
| | - Eman El-Sayed Khayal
- Forensic Medicine and Clinical Toxicology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
| |
Collapse
|
|
3
|
Li Y, Jiang C, Zhu W, Lu S, Yu H, Meng L. Exploring therapeutic targets for molecular therapy of idiopathic pulmonary fibrosis. Sci Prog 2024; 107:368504241247402. [PMID: 38651330 PMCID: PMC11036936 DOI: 10.1177/00368504241247402] [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] [Indexed: 04/25/2024]
Abstract
Idiopathic pulmonary fibrosis is a chronic and progressive interstitial lung disease with a poor prognosis. Idiopathic pulmonary fibrosis is characterized by repeated alveolar epithelial damage leading to abnormal repair. The intercellular microenvironment is disturbed, leading to continuous activation of fibroblasts and myofibroblasts, deposition of extracellular matrix, and ultimately fibrosis. Moreover, pulmonary fibrosis was also found as a COVID-19 complication. Currently, two drugs, pirfenidone and nintedanib, are approved for clinical therapy worldwide. However, they can merely slow the disease's progression rather than rescue it. These two drugs have other limitations, such as lack of efficacy, adverse effects, and poor pharmacokinetics. Consequently, a growing number of molecular therapies have been actively developed. Treatment options for IPF are becoming increasingly available. This article reviews the research platform, including cell and animal models involved in molecular therapy studies of idiopathic pulmonary fibrosis as well as the promising therapeutic targets and their development progress during clinical trials. The former includes patient case/control studies, cell models, and animal models. The latter includes transforming growth factor-beta, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, lysophosphatidic acid, interleukin-13, Rho-associated coiled-coil forming protein kinase family, and Janus kinases/signal transducers and activators of transcription pathway. We mainly focused on the therapeutic targets that have not only entered clinical trials but were publicly published with their clinical outcomes. Moreover, this work provides an outlook on some promising targets for further validation of their possibilities to cure the disease.
Collapse
Affiliation(s)
- Yue Li
- National Regional Children's Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi'an Key Laboratory of Children's Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
- First Department of Respiratory Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
| | - Congshan Jiang
- National Regional Children's Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi'an Key Laboratory of Children's Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Wenhua Zhu
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, People's Republic of China
| | - Shemin Lu
- National Regional Children's Medical Center (Northwest), Key Laboratory of Precision Medicine to Pediatric Diseases of Shaanxi Province, Xi'an Key Laboratory of Children's Health and Diseases, Shaanxi Institute for Pediatric Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, People's Republic of China
| | - Hongchuan Yu
- First Department of Respiratory Diseases, Xi'an Children's Hospital, Affiliated Children's Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Liesu Meng
- Institute of Molecular and Translational Medicine (IMTM), and Department of Biochemistry and Molecular Biology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China
- Key Laboratory of Environment and Genes Related to Diseases, Xi'an Jiaotong University, Ministry of Education, Xi'an, Shaanxi, People's Republic of China
| |
Collapse
|
|
4
|
Lequain H, Dégletagne C, Streichenberger N, Valantin J, Simonet T, Schaeffer L, Sève P, Leblanc P. Spatial Transcriptomics Reveals Signatures of Histopathological Changes in Muscular Sarcoidosis. Cells 2023; 12:2747. [PMID: 38067175 PMCID: PMC10706822 DOI: 10.3390/cells12232747] [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: 11/09/2023] [Revised: 11/25/2023] [Accepted: 11/27/2023] [Indexed: 12/18/2023] Open
Abstract
Sarcoidosis is a multisystemic disease characterized by non-caseating granuloma infiltrating various organs. The form with symptomatic muscular involvement is called muscular sarcoidosis. The impact of immune cells composing the granuloma on the skeletal muscle is misunderstood. Here, we investigated the granuloma-skeletal muscle interactions through spatial transcriptomics on two patients affected by muscular sarcoidosis. Five major transcriptomic clusters corresponding to perigranuloma, granuloma, and three successive muscle tissue areas (proximal, intermediate, and distal) around the granuloma were identified. Analyses revealed upregulated pathways in the granuloma corresponding to the activation of T-lymphocytes and monocytes/macrophages cytokines, the upregulation of extracellular matrix signatures, and the induction of the TGF-β signaling in the perigranuloma. A comparison between the proximal and distal muscles to the granuloma revealed an inverse correlation between the distance to the granuloma and the upregulation of cellular response to interferon-γ/α, TNF-α, IL-1,4,6, fibroblast proliferation, epithelial to mesenchymal cell transition, and the downregulation of muscle gene expression. These data shed light on the intercommunications between granulomas and the muscle tissue and provide pathophysiological mechanisms by showing that granuloma immune cells have a direct impact on proximal muscle tissue by promoting its progressive replacement by fibrosis via the expression of pro-inflammatory and profibrosing signatures. These data could possibly explain the evolution towards a state of disability for some patients.
Collapse
Affiliation(s)
- Hippolyte Lequain
- Département de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69004 Lyon, France;
- Institut NeuroMyoGène INMG-PGNM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, Inserm U1315, Faculté de Médecine Rockefeller, Université Claude Bernard UCBL-Lyon 1, 69008 Lyon, France; (N.S.); (T.S.)
| | - Cyril Dégletagne
- CRCL Core Facilities, Centre de Recherche en Cancérologie de Lyon (CRCL) INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, 69008 Lyon, France; (C.D.); (J.V.)
| | - Nathalie Streichenberger
- Institut NeuroMyoGène INMG-PGNM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, Inserm U1315, Faculté de Médecine Rockefeller, Université Claude Bernard UCBL-Lyon 1, 69008 Lyon, France; (N.S.); (T.S.)
- Service d’Anatomopathologie, Centre de Biologie et Pathologie Est (CBPE), Hospices Civils de Lyon, 69500 Bron, France
| | - Julie Valantin
- CRCL Core Facilities, Centre de Recherche en Cancérologie de Lyon (CRCL) INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, 69008 Lyon, France; (C.D.); (J.V.)
| | - Thomas Simonet
- Institut NeuroMyoGène INMG-PGNM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, Inserm U1315, Faculté de Médecine Rockefeller, Université Claude Bernard UCBL-Lyon 1, 69008 Lyon, France; (N.S.); (T.S.)
| | - Laurent Schaeffer
- Institut NeuroMyoGène INMG-PGNM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, Inserm U1315, Faculté de Médecine Rockefeller, Université Claude Bernard UCBL-Lyon 1, 69008 Lyon, France; (N.S.); (T.S.)
- Centre de Biotechnologie Cellulaire, CHU de Lyon—HCL Groupement Est, 69677 Bron, France
| | - Pascal Sève
- Département de Médecine Interne, Hôpital de la Croix-Rousse, Hospices Civils de Lyon, 69004 Lyon, France;
- Pôle IMER, HESPER EA 7425, 69002 Lyon, France
| | - Pascal Leblanc
- Institut NeuroMyoGène INMG-PGNM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, Inserm U1315, Faculté de Médecine Rockefeller, Université Claude Bernard UCBL-Lyon 1, 69008 Lyon, France; (N.S.); (T.S.)
| |
Collapse
|
|
5
|
Woo S, Gandhi S, Ghincea A, Saber T, Lee CJ, Ryu C. Targeting the NLRP3 inflammasome and associated cytokines in scleroderma associated interstitial lung disease. Front Cell Dev Biol 2023; 11:1254904. [PMID: 37849737 PMCID: PMC10577231 DOI: 10.3389/fcell.2023.1254904] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Accepted: 09/19/2023] [Indexed: 10/19/2023] Open
Abstract
SSc-ILD (scleroderma associated interstitial lung disease) is a complex rheumatic disease characterized in part by immune dysregulation leading to the progressive fibrotic replacement of normal lung architecture. Because improved treatment options are sorely needed, additional study of the fibroproliferative mechanisms mediating this disease has the potential to accelerate development of novel therapies. The contribution of innate immunity is an emerging area of investigation in SSc-ILD as recent work has demonstrated the mechanistic and clinical significance of the NLRP3 inflammasome and its associated cytokines of TNFα (tumor necrosis factor alpha), IL-1β (interleukin-1 beta), and IL-18 in this disease. In this review, we will highlight novel pathophysiologic insights afforded by these studies and the potential of leveraging this complex biology for clinical benefit.
Collapse
Affiliation(s)
| | | | | | | | | | - Changwan Ryu
- Department of Internal Medicine, Yale School of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, New Haven, CT, United States
| |
Collapse
|
|
6
|
Shi M, Cui H, Shi J, Mei Y. mmu-microRNA-92a-3p attenuates pulmonary fibrosis by modulating Cpeb4-mediated Smad2/3 signaling pathway. Funct Integr Genomics 2022; 22:1297-1306. [PMID: 35909199 DOI: 10.1007/s10142-022-00879-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 04/02/2022] [Accepted: 06/23/2022] [Indexed: 11/26/2022]
Abstract
Pulmonary fibrosis (PF) is a chronic lung disorder, in which the mechanism of mmu-microRNA (miR)-92a-3p is not elucidated clearly. The present work was proposed to disclose mmu-miR-92a-3p-focused mechanism in PF with cytoplasmic polyadenylation element-binding protein 4 (Cpeb4)/Smad2/3 axis. PF was induced in mice by the intratracheal injection of bleomycin (BLM). Then, the BLM-treated mice were injected with mmu-miR-92a-3p- and/or Cpeb4-related adenovirus vectors. mmu-miR-92a-3p, Cpeb4, and Smad2/3 expression in lung tissues were examined. Alveolar cell apoptosis and collagen deposition in lung tissues and inflammatory factors in serum were observed. The interaction between mmu-miR-92a-3p and Cpeb4 was explored. Lowly expressed mmu-miR-92a-3p and highly expressed Cpeb4 and Smad2/3 were manifested in BLM-induced PF mice. BLM-induced PF mice exhibited enhanced inflammation, alveolar cell apoptosis, and collagen deposition, which would be attenuated by upregulating mmu-miR-92a-3p or downregulating Cpeb4. mmu-miR-92a-3p targeted Cpeb4. Upregulating mmu-miR-92a-3p or downregulating Cpeb4 inactivated the Smad2/3 signaling pathway in BLM-induced PF mice. It is elaborated that mmu-miR-92a-3p attenuates the process of PF by modulating Cpeb4-mediated Smad2/3 signaling pathway, renewing the molecular mechanism of PF.
Collapse
Affiliation(s)
- Mengkun Shi
- Department of Cardiothoracic Surgery, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Putuo District, Shanghai, 200092, China
| | - Huixia Cui
- Department of Medical Institution Conducting Clinical Trials for Human Used Drug, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, 046099, Shanxi, China
| | - Jialun Shi
- Department of Cardiothoracic Surgery, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, 046099, Shanxi, China
| | - Yunqing Mei
- Department of Cardiothoracic Surgery, Tongji Hospital, School of Medicine, Tongji University, No. 389 Xincun Road, Putuo District, Shanghai, 200092, China.
| |
Collapse
|
|
7
|
Park S, Avera AD, Kim Y. BIOMANUFACTURING OF GLIOBLASTOMA ORGANOIDS EXHIBITING HIERARCHICAL AND SPATIALLY ORGANIZED TUMOR MICROENVIRONMENT VIA TRANSDIFFERENTIATION. Biotechnol Bioeng 2022; 119:3252-3274. [DOI: 10.1002/bit.28191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 07/14/2022] [Accepted: 07/20/2022] [Indexed: 11/11/2022]
Affiliation(s)
- Seungjo Park
- Department of Chemical and Biological EngineeringThe University of AlabamaTuscaloosaAlabama
| | - Alexandra D. Avera
- Department of Chemical and Biological EngineeringThe University of AlabamaTuscaloosaAlabama
| | - Yonghyun Kim
- Department of Chemical and Biological EngineeringThe University of AlabamaTuscaloosaAlabama
| |
Collapse
|
|
8
|
Wilson SE, Shiju TM, Sampaio LP, Hilgert GL. Corneal fibroblast collagen type IV negative feedback modulation of TGF beta: A fibrosis modulating system likely active in other organs. Matrix Biol 2022; 109:162-172. [PMID: 35421526 DOI: 10.1016/j.matbio.2022.04.002] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 04/02/2022] [Accepted: 04/05/2022] [Indexed: 12/15/2022]
Abstract
Collagen type IV (COL IV) is a major component of basement membranes (BM) in all organs. It serves functions related to BM organization and modulates the passage of growth factors from one tissue compartment to another. COL IV binds transforming growth factor (TGF) beta-1 and TGF beta-2 and, therefore, is a major modulator of TGF beta pro-fibrotic functions. After fibrotic corneal injury, TGF beta enters into the stroma from the tears, epithelium, endothelium and/or aqueous humor and markedly upregulates COL IV production in corneal fibroblasts in the adjacent stroma far removed from BMs. It is hypothesized this non-BM stromal COL IV binds TGF beta-1 (and likely TGF beta-2) in competition with the binding of the growth factors to TGF beta cognate receptors and serves as a negative feedback regulatory pathway to mitigate the effects of TGF beta on stromal cells, including reducing the developmental transition of corneal fibroblasts and fibrocytes into myofibroblasts. Losartan, a known TGF beta signaling inhibitor, when applied topically to the cornea after fibrotic injury, alters this COL IV-TGF beta pathway by down-regulating COL IV production by corneal fibroblasts. Non-BM COL IV produced in response to injuries in other organs, including the lung, skin, liver, kidney, and gut, may participate in similar COL IV-TGF beta pathways and have an important role in controlling TGF beta pro-fibrotic effects in these organs.
Collapse
|
|
9
|
Abstract
Pulmonary fibrosis is the end stage of a broad range of heterogeneous interstitial lung diseases and more than 200 factors contribute to it. In recent years, the relationship between virus infection and pulmonary fibrosis is getting more and more attention, especially after the outbreak of SARS-CoV-2 in 2019, however, the mechanisms underlying the virus-induced pulmonary fibrosis are not fully understood. Here, we review the relationship between pulmonary fibrosis and several viruses such as Human T-cell leukemia virus (HTLV), Human immunodeficiency virus (HIV), Cytomegalovirus (CMV), Epstein–Barr virus (EBV), Murine γ-herpesvirus 68 (MHV-68), Influenza virus, Avian influenza virus, Middle East Respiratory Syndrome (MERS)-CoV, Severe acute respiratory syndrome (SARS)-CoV and SARS-CoV-2 as well as the mechanisms underlying the virus infection induced pulmonary fibrosis. This may shed new light on the potential targets for anti-fibrotic therapy to treat pulmonary fibrosis induced by viruses including SARS-CoV-2.
Collapse
Affiliation(s)
- Wei Jie Huang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Xiao Xiao Tang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. .,Guangzhou Laboratory, Bio-island, Guangzhou, China.
| |
Collapse
|
|
10
|
Main actors behind the endometrial receptivity and successful implantation. Tissue Cell 2021; 73:101656. [PMID: 34634636 DOI: 10.1016/j.tice.2021.101656] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 09/21/2021] [Accepted: 09/23/2021] [Indexed: 12/23/2022]
Abstract
Embryo implantation occurs during a short period of time, the implantation window, in the mid-secretory phase of the menstrual cycle. The cross-talk between the endometrium and the embryo, at the stage of blastocyst, is a necessary condition for successful implantation. Till now, no single molecule or receptor has been identified to play an essential role on embryo implantation but a huge number of mediators, including cytokines, lipids, adhesion molecules, growth factors, and others, are reported to support the establishment of pregnancy. Therefore, the aim of this review is not only to describe the different actors involved in the implantation process, but also to try to characterize the relationships between these factors as well as their time-regulated activation. Moreover, the availability of in vitro culture systems to study the interactions between embryo and endometrium as well as the paracrine communication regulated by exosomal vesicles will be investigated, as an innovative approach for a more precise characterization of the interactions between the different molecules involved in this process. The in-depth knowledge of all these complex mechanisms will allow to address the reasons of implantation failure and infertility, thus providing new avenues for promoting the successful establishment of a pregnancy.
Collapse
|
|
11
|
Duckworth A, Longhurst HJ, Paxton JK, Scotton CJ. The Role of Herpes Viruses in Pulmonary Fibrosis. Front Med (Lausanne) 2021; 8:704222. [PMID: 34368196 PMCID: PMC8339799 DOI: 10.3389/fmed.2021.704222] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 06/24/2021] [Indexed: 12/29/2022] Open
Abstract
Pulmonary fibrosis (PF) is a serious lung disease which can result from known genetic or environmental exposures but is more commonly idiopathic (IPF). In familial PF (FPF), the majority of identified causal genes play key roles in the maintenance of telomeres, the protective end structures of chromosomes. Recent evidence suggests that short telomeres may also be implicated causally in a significant proportion of idiopathic cases. The possible involvement of herpes viruses in PF disease incidence and progression has been examined for many years, with some studies showing strong, statistically significant associations and others reporting no involvement. Evidence is thus polarized and remains inconclusive. Here we review the reported involvement of herpes viruses in PF in both animals and humans and present a summary of the evidence to date. We also present several possible mechanisms of action of the different herpes viruses in PF pathogenesis, including potential contributions to telomere attrition and cellular senescence. Evidence for antiviral treatment in PF is very limited but suggests a potential benefit. Further work is required to definitely answer the question of whether herpes viruses impact PF disease onset and progression and to enable the possible use of targeted antiviral treatments to improve clinical outcomes.
Collapse
Affiliation(s)
- Anna Duckworth
- College of Medicine and Health, University of Exeter, Exeter, United Kingdom
| | - Hilary J. Longhurst
- Department of Medicine, University of Auckland, Auckland, New Zealand
- Dyskeratosis Congenita (DC) Action, London, United Kingdom
| | - Jane K. Paxton
- Dyskeratosis Congenita (DC) Action, London, United Kingdom
| | - Chris J. Scotton
- College of Medicine and Health, University of Exeter, Exeter, United Kingdom
| |
Collapse
|
|
12
|
Balberova OV, Bykov EV, Shnayder NA, Petrova MM, Gavrilyuk OA, Kaskaeva DS, Soloveva IA, Petrov KV, Mozheyko EY, Medvedev GV, Nasyrova RF. The "Angiogenic Switch" and Functional Resources in Cyclic Sports Athletes. Int J Mol Sci 2021; 22:ijms22126496. [PMID: 34204341 PMCID: PMC8234968 DOI: 10.3390/ijms22126496] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 06/08/2021] [Accepted: 06/10/2021] [Indexed: 12/22/2022] Open
Abstract
Regular physical activity in cyclic sports can influence the so-called “angiogenic switch”, which is considered as an imbalance between proangiogenic and anti-angiogenic molecules. Disruption of the synthesis of angiogenic molecules can be caused by local changes in tissues under the influence of excessive physical exertion and its consequences, such as chronic oxidative stress and associated hypoxia, metabolic acidosis, sports injuries, etc. A review of publications on signaling pathways that activate and inhibit angiogenesis in skeletal muscles, myocardium, lung, and nervous tissue under the influence of intense physical activity in cyclic sports. Materials: We searched PubMed, SCOPUS, Web of Science, Google Scholar, Clinical keys, and e-LIBRARY databases for full-text articles published from 2000 to 2020, using keywords and their combinations. Results: An important aspect of adaptation to training loads in cyclic sports is an increase in the number of capillaries in muscle fibers, which improves the metabolism of skeletal muscles and myocardium, as well as nervous and lung tissue. Recent studies have shown that myocardial endothelial cells not only respond to hemodynamic forces and paracrine signals from neighboring cells, but also take an active part in heart remodeling processes, stimulating the growth and contractility of cardiomyocytes or the production of extracellular matrix proteins in myofibroblasts. As myocardial vascularization plays a central role in the transition from adaptive heart hypertrophy to heart failure, further study of the signaling mechanisms involved in the regulation of angiogenesis in the myocardium is important in sports practice. The study of the “angiogenic switch” problem in the cerebrovascular and cardiovascular systems allows us to claim that the formation of new vessels is mediated by a complex interaction of all growth factors. Although the lungs are one of the limiting systems of the body in cyclic sports, their response to high-intensity loads and other environmental stresses is often overlooked. Airway epithelial cells are the predominant source of several growth factors throughout lung organogenesis and appear to be critical for normal alveolarization, rapid alveolar proliferation, and normal vascular development. There are many controversial questions about the role of growth factors in the physiology and pathology of the lungs. The presented review has demonstrated that when doing sports, it is necessary to give a careful consideration to the possible positive and negative effects of growth factors on muscles, myocardium, lung tissue, and brain. Primarily, the “angiogenic switch” is important in aerobic sports (long distance running). Conclusions: Angiogenesis is a physiological process of the formation of new blood capillaries, which play an important role in the functioning of skeletal muscles, myocardium, lung, and nervous tissue in athletes. Violation of the “angiogenic switch” as a balance between proangiogenic and anti-angiogenic molecules can lead to a decrease in the functional resources of the nervous, musculoskeletal, cardiovascular, and respiratory systems in athletes and, as a consequence, to a decrease in sports performance.
Collapse
Affiliation(s)
- Olga V. Balberova
- Research Institute of Olympic Sports, Ural State University of Physical Culture, 454091 Chelyabinsk, Russia;
- Correspondence: (O.V.B.); (N.A.S.); (R.F.N.)
| | - Evgeny V. Bykov
- Research Institute of Olympic Sports, Ural State University of Physical Culture, 454091 Chelyabinsk, Russia;
| | - Natalia A. Shnayder
- V.M. Bekhterev National Medical Research Center for Neurology and Psychiatry, Department of Personalized Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- Department of Outpatient Therapy and Family Medicine with a Postgraduate Course, Shared Core Facilities Molecular and Cell Technologies, Professor V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia; (M.M.P.); (D.S.K.)
- Correspondence: (O.V.B.); (N.A.S.); (R.F.N.)
| | - Marina M. Petrova
- Department of Outpatient Therapy and Family Medicine with a Postgraduate Course, Shared Core Facilities Molecular and Cell Technologies, Professor V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia; (M.M.P.); (D.S.K.)
| | - Oksana A. Gavrilyuk
- The Department of Polyclinic Therapy and Family Medicine and Healthy Lifesttyle with a Course of PE, V. F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia;
| | - Daria S. Kaskaeva
- Department of Outpatient Therapy and Family Medicine with a Postgraduate Course, Shared Core Facilities Molecular and Cell Technologies, Professor V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia; (M.M.P.); (D.S.K.)
| | - Irina A. Soloveva
- Department of Hospital Therapy and Immunology with a Postgraduate Course, Shared Core Facilities Molecular and Cell Technologies, Professor V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia;
| | - Kirill V. Petrov
- Department of Physical and Rehabilitation Medicine with a Postgraduate Course, Shared Core Facilities Molecular and Cell Technologies, Professor V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia; (K.V.P.); (E.Y.M.)
| | - Elena Y. Mozheyko
- Department of Physical and Rehabilitation Medicine with a Postgraduate Course, Shared Core Facilities Molecular and Cell Technologies, Professor V.F. Voino-Yasenetsky Krasnoyarsk State Medical University, 660022 Krasnoyarsk, Russia; (K.V.P.); (E.Y.M.)
| | - German V. Medvedev
- R. R. Vreden National Medical Research Center for Traumatology and Orthopedics, Department of Hand Surgery with Microsurgical Equipment, 195427 Saint-Petersburg, Russia;
| | - Regina F. Nasyrova
- V.M. Bekhterev National Medical Research Center for Neurology and Psychiatry, Department of Personalized Psychiatry and Neurology, 192019 Saint Petersburg, Russia
- Correspondence: (O.V.B.); (N.A.S.); (R.F.N.)
| |
Collapse
|
|
13
|
Smith JNP, Witkin MD, Jogasuria AP, Christo KF, Raffay TM, Markowitz SD, Desai AB. Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis. Sci Rep 2020; 10:11657. [PMID: 32669620 PMCID: PMC7363833 DOI: 10.1038/s41598-020-68336-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 06/23/2020] [Indexed: 12/31/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by interstitial remodeling and pulmonary dysfunction. The etiology of IPF is not completely understood but involves pathologic inflammation and subsequent failure to resolve fibrosis in response to epithelial injury. Treatments for IPF are limited to anti-inflammatory and immunomodulatory agents, which are only partially effective. Prostaglandin E2 (PGE2) disrupts TGFβ signaling and suppresses myofibroblast differentiation, however practical strategies to raise tissue PGE2 during IPF have been limited. We previously described the discovery of a small molecule, (+)SW033291, that binds with high affinity to the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and increases PGE2 levels. Here we evaluated pulmonary 15-PGDH expression and activity and tested whether pharmacologic 15-PGDH inhibition (PGDHi) is protective in a mouse model of bleomycin-induced pulmonary fibrosis (PF). Long-term PGDHi was well-tolerated, reduced the severity of pulmonary fibrotic lesions and extracellular matrix remodeling, and improved pulmonary function in bleomycin-treated mice. Moreover, PGDHi attenuated both acute inflammation and weight loss, and decreased mortality. Endothelial cells and macrophages are likely targets as these cell types highly expressed 15-PGDH. In conclusion, PGDHi ameliorates inflammatory pathology and fibrosis in murine PF, and may have clinical utility to treat human disease.
Collapse
Affiliation(s)
- Julianne N P Smith
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Matthew D Witkin
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Alvin P Jogasuria
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Kelsey F Christo
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Thomas M Raffay
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA
| | - Sanford D Markowitz
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA. .,University Hospitals Seidman Cancer Center, Cleveland, OH, 44106, USA.
| | - Amar B Desai
- Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA.
| |
Collapse
|
|
14
|
Kardas G, Daszyńska-Kardas A, Marynowski M, Brząkalska O, Kuna P, Panek M. Role of Platelet-Derived Growth Factor (PDGF) in Asthma as an Immunoregulatory Factor Mediating Airway Remodeling and Possible Pharmacological Target. Front Pharmacol 2020; 11:47. [PMID: 32116722 PMCID: PMC7033439 DOI: 10.3389/fphar.2020.00047] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 01/14/2020] [Indexed: 12/22/2022] Open
Abstract
Asthma is a chronic and heterogenic disease of the respiratory system, one of the most common lung diseases worldwide. The underlying pathologies, which are chronic inflammatory process and airway remodeling (AR), are mediated by numerous cells and cytokines. Particularly interesting in this field is the platelet-derived growth factor (PDGF), one of the members of the human growth factor family. In this article, the authors analyze the available data on the role of PDGF in asthma in experimental models and in human research. PDGF is expressed in airway by various cells contributing to asthma pathogenesis—mast cells, eosinophils, and airway epithelial cells. Research confirms the thesis that this factor is also secreted by these cells in the course of asthma. The main effects of PDGF on bronchi are the proliferation of airway smooth muscle (ASM) cells, migration of ASM cells into the epithelium and enhanced collagen synthesis by lung fibroblasts. The importance of AR in asthma is well recognized and new therapies should also aim to manage it, possibly targeting PDGFRs. Further studies on new and already existing drugs, mediating the PDGF signaling and related to asthma are necessary. Several promising drugs from the tyrosine kinase inhibitors group, including nilotinib, imatinib masitinib, and sunitinib, are currently being clinically tested and other molecules are likely to emerge in this field.
Collapse
Affiliation(s)
- Grzegorz Kardas
- Clinic of Internal Diseases, Asthma and Allergy, Medical University of Lodz, Łódź, Poland
| | | | - Mateusz Marynowski
- Clinic of Internal Diseases, Asthma and Allergy, Medical University of Lodz, Łódź, Poland
| | - Oliwia Brząkalska
- Clinic of Internal Diseases, Asthma and Allergy, Medical University of Lodz, Łódź, Poland
| | - Piotr Kuna
- Clinic of Internal Diseases, Asthma and Allergy, Medical University of Lodz, Łódź, Poland
| | - Michał Panek
- Clinic of Internal Diseases, Asthma and Allergy, Medical University of Lodz, Łódź, Poland
| |
Collapse
|
|
15
|
Liu G, Zhai H, Zhang T, Li S, Li N, Chen J, Gu M, Qin Z, Liu X. New therapeutic strategies for IPF: Based on the "phagocytosis-secretion-immunization" network regulation mechanism of pulmonary macrophages. Biomed Pharmacother 2019; 118:109230. [PMID: 31351434 DOI: 10.1016/j.biopha.2019.109230] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 06/19/2019] [Accepted: 07/15/2019] [Indexed: 12/15/2022] Open
Abstract
Pulmonary fibrosis is a chronic and progressive interstitial lung disease of known and unknown etiology. Over the past decades, macrophages have been recognized to play a significant role in IPF pathogenesis. According to their anatomical loci, macrophages can be divided to alveolar macrophages (AMs) subtypes and interstitial macrophages subtypes (IMs) with different responsibility in the damage defense response. Depending on diverse chemokines and cytokines in local microenvironments, macrophages can be induced and polarized to either classically activated (M1) or alternatively activated (M2) phenotypes in different stages of immunity. Therefore, we hypothesize that there is a "phagocytosis-secretion-immunization" network regulation of pulmonary macrophages related to a number of chemokines and cytokines. In this paper, we summarize and discuss the role of chemokines and cytokines involved in the "phagocytosis-secretion-immunization" network regulation mechanism of pulmonary macrophages, pointing toward novel therapeutic approaches based on the network target regulation in the field. Therapeutic strategies focused on modifying the chemokines, cytokines and the network are promising for the pharmacotherapy of IPF. Some Traditional Chinese medicines may have more superiorities in delaying the progression of pulmonary fibrosis for their multi-target activities of this network regulation.
Collapse
Affiliation(s)
- Guoxiu Liu
- Beijing University of Chinese Medicine, China
| | | | | | - Siyu Li
- Beijing University of Chinese Medicine, China
| | - Ningning Li
- Beijing University of Chinese Medicine, China
| | - Jiajia Chen
- Beijing University of Chinese Medicine, China
| | - Min Gu
- Beijing University of Chinese Medicine, China
| | - Zinan Qin
- Beijing University of Chinese Medicine, China
| | - Xin Liu
- Beijing University of Chinese Medicine, China.
| |
Collapse
|
|
16
|
Affiliation(s)
- Arnold R. Brody
- Department of Pathology, Tulane University Medical School, New Orleans, LA, United States
| |
Collapse
|
|
17
|
Umezawa K, Nagano T, Kobayashi K, Dokuni R, Katsurada M, Yamamoto M, Yoshikawa Y, Kataoka T, Nishimura Y. Phospholipase Cε plays a crucial role in neutrophilic inflammation accompanying acute lung injury through augmentation of CXC chemokine production from alveolar epithelial cells. Respir Res 2019; 20:9. [PMID: 30634975 PMCID: PMC6330467 DOI: 10.1186/s12931-019-0975-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Accepted: 01/02/2019] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND We have shown that phospholipase Cε (PLCε), an effector of Ras and Rap1 small GTPases, plays pivotal roles in inflammation and inflammation-associated carcinogenesis by augmenting proinflammatory cytokine production from epithelial cells of various organs. The purpose of this study is to analyze its role in neutrophilic alveolar inflammation accompanying acute lung injury (ALI), focusing on that in alveolar epithelial cells (AECs), which are known to make a major contribution to the pathogenesis of ALI. METHODS We examine the effect of the PLCε genotypes on the development of ALI induced by intratracheal administration of lipopolysaccharide (LPS) to PLCε wild-type (PLCε+/+) and knockout (PLCεΔX/ΔX) mice. Pathogenesis of ALI is analyzed by histological examination of lung inflammation and measurements of the levels of various cytokines, in particular neutrophil-attracting chemokines such as Cxcl5, by quantitative reverse transcription-polymerase chain reaction and immunostaining. Primary cultures of AECs, established from PLCε+/+ and PLCεΔX/ΔX mice, are used to analyze the roles of PLCε, protein kinase D (PKD) and nuclear factor-κB (NF-κB) in augmentation of LPS-induced Cxcl5 expression. RESULTS Compared to PLCε+/+ mice, PLCεΔX/ΔX mice exhibit marked alleviation of lung inflammation as shown by great reduction in lung wet/dry weight ratios, accumulation of inflammatory cells in the alveolar space and thickening of alveolar walls as well as the number of neutrophils and the protein concentration in bronchoalveolar lavage fluid. Also, LPS-induced expression of the CXC family of chemokines, in particular Cxcl5, is substantially diminished in the total lung and AECs of PLCεΔX/ΔX mice. Moreover, LPS-induced Cxcl5 expression in primary cultured AECs is markedly suppressed on the PLCεΔX/ΔX background (p < 0.05 versus PLCε+/+ AECs), which is accompanied by the reduction in phosphorylation of inhibitor κB (IκB), PKD and nuclear translocation of NF-κB p65. Also, it is suppressed by the treatment with inhibitors of PKD and IκB kinase, suggesting the involvement of the PLCε-PKD-IκB-NF-κB pathway. CONCLUSIONS PLCε-mediated augmentation of the production of the CXC family of chemokines, in particular Cxcl5, in AECs plays a crucial role in neutrophilic alveolar inflammation accompanying ALI, suggesting that PLCε may be a potential molecular target for the treatment of acute respiratory distress syndrome.
Collapse
Affiliation(s)
- Kanoko Umezawa
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Tatsuya Nagano
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
| | - Kazuyuki Kobayashi
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Ryota Dokuni
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Masahiro Katsurada
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Masatsugu Yamamoto
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yoko Yoshikawa
- Division of Molecular Biology, Department of Biochemistry and Molecular and Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Tohru Kataoka
- Division of Molecular Biology, Department of Biochemistry and Molecular and Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.,Kobe University Incubation Center, 1-5-6 Miyakojima Minami-cho, Chuo-ku, Kobe, 650-0047, Japan
| | - Yoshihiro Nishimura
- Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| |
Collapse
|
|
18
|
Kramer EL, Hardie WD, Madala SK, Davidson C, Clancy JP. Subacute TGFβ expression drives inflammation, goblet cell hyperplasia, and pulmonary function abnormalities in mice with effects dependent on CFTR function. Am J Physiol Lung Cell Mol Physiol 2018; 315:L456-L465. [PMID: 29877096 DOI: 10.1152/ajplung.00530.2017] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Cystic fibrosis (CF) produces variable lung disease phenotypes that are, in part, independent of the CF transmembrane conductance regulator ( CFTR) genotype. Transforming growth factor-β (TGFβ) is the best described genetic modifier of the CF phenotype, but its mechanism of action is unknown. We hypothesized that TGFβ is sufficient to drive pathognomonic features of CF lung disease in vivo and that CFTR deficiency enhances susceptibility to pathological TGFβ effects. A CF mouse model and littermate controls were exposed intratracheally to an adenoviral vector containing the TGFβ1 cDNA (Ad-TGFβ), empty vector, or PBS only. Studies were performed 1 wk after treatment, including lung mechanics, collection of bronchoalveolar lavage fluid, and analysis of lung histology, RNA, and protein. CF and non-CF mice showed similar weight loss, inflammation, goblet cell hyperplasia, and Smad pathway activation after Ad-TGFβ treatment. Ad-TGFβ produced greater abnormalities in lung mechanics in CF versus control mice, which was uniquely associated with induction of phosphoinositide 3-kinase and mitogen-activated protein kinase signaling. CFTR transcripts were reduced, and epithelial sodium channel transcripts were increased in CF and non-CF mice, whereas the goblet cell transcription factors, forkhead ortholog A3 and SAM-pointed domain-containing ETS-like factor, were increased in non-CF but not CF mice following Ad-TGFβ treatment. Pulmonary TGFβ1 expression was sufficient to produce pulmonary remodeling and abnormalities in lung mechanics that were associated with both shared and unique cell signaling pathway activation in CF and non-CF mice. These results highlight the multifunctional impact of TGFβ on pulmonary pathology in vivo and identify cellular-response differences that may impact CF lung pathology.
Collapse
Affiliation(s)
- Elizabeth L Kramer
- Department of Pediatrics, University of Cincinnati College of Medicine , Cincinnati, Ohio.,Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - William D Hardie
- Department of Pediatrics, University of Cincinnati College of Medicine , Cincinnati, Ohio.,Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Satish K Madala
- Department of Pediatrics, University of Cincinnati College of Medicine , Cincinnati, Ohio.,Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - Cynthia Davidson
- Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| | - John P Clancy
- Department of Pediatrics, University of Cincinnati College of Medicine , Cincinnati, Ohio.,Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center , Cincinnati, Ohio
| |
Collapse
|
|
19
|
Tubastatin ameliorates pulmonary fibrosis by targeting the TGFβ-PI3K-Akt pathway. PLoS One 2017; 12:e0186615. [PMID: 29045477 PMCID: PMC5646855 DOI: 10.1371/journal.pone.0186615] [Citation(s) in RCA: 88] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 10/04/2017] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal disease. Histone deacetylase 6 (HDAC6) alters function and fate of various proteins via deacetylation of lysine residues, and is implicated in TGF-β1-induced EMT (epithelial-mesenchymal transition). However, the role of HDAC6 in pulmonary fibrosis is unknown. METHODS HDAC6 expression in IPF and control lungs was assessed by quantitative real-time PCR (qRT-PCR) and immunoblots. Lung fibroblasts were treated with TGF-β1 ± HDAC6 inhibitors (Tubacin, Tubastatin, ACY1215, or MC1568), and fibrotic markers such as type I collagen were assessed using qRT-PCR and immunoblots. Mice were treated with bleomycin (oropharyngeal aspiration; single dose) ± Tubastatin (intraperitoneally injection; daily for 21 days), and lung collagen expression was gauged using immunoblots and trichrome staining. In a separate experiment, HDAC6 wild-type (WT) and knockout (KO) mice were administered bleomycin, and lungs were evaluated in the same manner. RESULTS HDAC6 expression was deregulated in IPF lungs. Among the HDAC6 inhibitors tested, only Tubastatin significantly repressed TGF-β1-induced expression of type-1 collagen in lung fibroblasts, and this finding was coupled with decreased Akt phosphorylation and increased Akt-PHLPP (PH domain and Leucine rich repeat Protein Phosphatase) association. Tubastatin repressed TGF-β1-induced S6K phosphorylation, HIF-1α expression, and VEGF expression. Tubastatin also repressed TGF-β1-induced inhibition of LC3B-II (a marker of autophagosome formation). In bleomycin-treated mouse lungs, HDAC6 expression was increased, and Tubastatin repressed type-1 collagen expression. However, in HDAC6 KO mice, bleomycin-induced type-1 collagen expression was not repressed compared to WT mice. Knockdown of HDAC6, as well as HDAC10, another potential Tubastatin target, did not inhibit TGF-β1-induced collagen expression in lung fibroblasts. CONCLUSIONS HDAC6 expression is altered during lung fibrogenesis. Tubastatin represses TGF-β1-induced collagen expression, by diminishing Akt phosphorylation and regulating downstream targets such as HIF-1α-VEGF axis and autophagy. Tubastatin-treated WT mice are protected against bleomycin-induced fibrosis, but HDAC6 KO mice are not. Our data suggest that Tubastatin ameliorates pulmonary fibrosis, by targeting the TGFβ-PI3K-Akt pathway, likely via an HDAC6-independent mechanism.
Collapse
|
|
20
|
Nan J, Zhongyan Z. Bone marrow mesenchymal stem cells inhibited bleomycin-induced lung fibrosis. RSC Adv 2017. [DOI: 10.1039/c7ra03971a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The present study was performed to evaluate the protective effect of bone marrow mesenchymal stem cells (BMSCs), TLR2-silencing BMSCs (BMSCTLR2−/−), on bleomycin (BLM)-induced lung fibrosis and elucidate the critical role of TLR2 during the process.
Collapse
Affiliation(s)
- Jiang Nan
- The Third Teaching Hospital
- Jilin University
- Changchun 130033
- China
| | - Zhao Zhongyan
- The Third Teaching Hospital
- Jilin University
- Changchun 130033
- China
| |
Collapse
|
|
21
|
Shi Y, Chen Q, Yan H, Gu W. The effect of a liver-X-receptor ligand on bleomycin induced pulmonary fibrosis in mice. Int Immunopharmacol 2016; 41:116-121. [PMID: 27838587 DOI: 10.1016/j.intimp.2016.10.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 10/13/2016] [Accepted: 10/21/2016] [Indexed: 11/19/2022]
Abstract
The liver-X-receptors have shown anti-fibrosis ability in several animal models. Our purpose was to investigate the effect of LXRs in bleomycin induced lung fibrosis in mice. Bleomycin was intratracheally delivered to mice. Some mice were administered a LXR agonist, T0901317. Then mice were evaluated for the development of lung inflammation and fibrosis. T0901317 was able to attenuate the inflammation and fibrosis induced by bleomycin. T0901317 treatment evidently abolished the high level of TGF-β1 and inhibited NF-κB DNA-binding activity in lung. So LXRs may attenuate the progressing of lung fibrosis, providing a potential treatment of IPF.
Collapse
Affiliation(s)
- Ying Shi
- Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Qiongju Chen
- Yancheng City No. 1 People's Hospital, Yan Cheng, China
| | - Haijun Yan
- Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Wei Gu
- Department of Respiratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| |
Collapse
|
|
22
|
Vietti G, Lison D, van den Brule S. Mechanisms of lung fibrosis induced by carbon nanotubes: towards an Adverse Outcome Pathway (AOP). Part Fibre Toxicol 2016; 13:11. [PMID: 26926090 PMCID: PMC4772332 DOI: 10.1186/s12989-016-0123-y] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Accepted: 02/12/2016] [Indexed: 12/17/2022] Open
Abstract
Several experimental studies have shown that carbon nanotubes (CNT) can induce respiratory effects, including lung fibrosis. The cellular and molecular events through which these effects develop are, however, not clearly elucidated. The purpose of the present review was to analyze the key events involved in the lung fibrotic reaction induced by CNT and to assess their relationships. We thus address current knowledge and gaps with a view to draft an Adverse Outcome Pathway (AOP) concerning the fibrotic potential of CNT. As for many inhaled particles, CNT can indirectly activate fibroblasts through the release of pro-inflammatory (IL-1β) and pro-fibrotic (PDGF and TGF-β) mediators by inflammatory cells (macrophages and epithelial cells) via the induction of oxidative stress, inflammasome or NF-kB. We also highlight here direct effects of CNT on fibroblasts, which appear as a new mode of toxicity relatively specific for CNT. Direct effects of CNT on fibroblasts include the induction of fibroblast proliferation, differentiation and collagen production via ERK 1/2 or Smad signaling. We also point out the physico-chemical properties of CNT important for their toxicity and the relationship between in vitro and in vivo effects. This knowledge provides evidence to draft an AOP for the fibrogenic activity of CNT, which allows developing simple in vitro models contributing to predict the CNT effects in lung fibrosis, and risk assessment tools for regulatory decision.
Collapse
Affiliation(s)
- Giulia Vietti
- Louvain centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Avenue E. Mounier, 52 - bte B1.52.12, 1200, Brussels, Belgium.
| | - Dominique Lison
- Louvain centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Avenue E. Mounier, 52 - bte B1.52.12, 1200, Brussels, Belgium.
| | - Sybille van den Brule
- Louvain centre for Toxicology and Applied Pharmacology, Université Catholique de Louvain, Avenue E. Mounier, 52 - bte B1.52.12, 1200, Brussels, Belgium.
| |
Collapse
|
|
23
|
Palaniyandi S, Liu X, Periasamy S, Ma A, Tang J, Jenkins M, Tuo W, Song W, Keegan AD, Conrad DH, Zhu X. Inhibition of CD23-mediated IgE transcytosis suppresses the initiation and development of allergic airway inflammation. Mucosal Immunol 2015; 8:1262-74. [PMID: 25783969 PMCID: PMC4575230 DOI: 10.1038/mi.2015.16] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Accepted: 02/02/2015] [Indexed: 02/04/2023]
Abstract
The epithelial lining of the airway tract and allergen-specific IgE are considered essential controllers of inflammatory responses to allergens. The human low affinity IgE receptor, CD23 (FcɛRII), is capable of transporting IgE or IgE-allergen complexes across the polarized human airway epithelial cell (AEC) monolayer in vitro. However, it remains unknown whether the CD23-dependent IgE transfer pathway in AECs initiates and facilitates allergic inflammation in vivo, and whether inhibition of this pathway attenuates allergic inflammation. To this end, we show that in wild-type (WT) mice, epithelial CD23 transcytosed both IgE and ovalbumin (OVA)-IgE complexes across the airway epithelial barrier, whereas neither type of transcytosis was observed in CD23 knockout (KO) mice. In chimeric mice, OVA sensitization and aerosol challenge of WT/WT (bone-marrow transfer from the WT to WT) or CD23KO/WT (CD23KO to WT) chimeric mice, which express CD23 on radioresistant airway structural cells (mainly epithelial cells) resulted in airway eosinophilia, including collagen deposition and a significant increase in goblet cells, and increased airway hyperreactivity. In contrast, the absence of CD23 expression on airway structural or epithelial cells, but not on hematopoietic cells, in WT/CD23KO (the WT to CD23KO) chimeric mice significantly reduced OVA-driven allergic airway inflammation. In addition, inhalation of the CD23-blocking B3B4 antibody in sensitized WT mice before or during airway challenge suppressed the salient features of asthma, including bronchial hyperreactivity. Taken together, these results identify a previously unproven mechanism in which epithelial CD23 plays a central role in the development of allergic inflammation. Further, our study suggests that functional inhibition of CD23 in the airway is a potential therapeutic approach to inhibit the development of asthma.
Collapse
Affiliation(s)
- Senthilkumar Palaniyandi
- Division of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742, USA,Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA
| | - Xiaoyang Liu
- Division of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742, USA
| | - Sivakumar Periasamy
- Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY, USA
| | - Aiying Ma
- Division of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742, USA
| | | | - Mark Jenkins
- Animal Parasitic Diseases Laboratory, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD 20705, USA
| | - Wenbin Tuo
- Animal Parasitic Diseases Laboratory, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD 20705, USA
| | - Wenxia Song
- Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA,Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA
| | - Achsah D. Keegan
- Center for Vascular and Inflammatory Diseases and Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Daniel H. Conrad
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA
| | - Xiaoping Zhu
- Division of Immunology, Virginia-Maryland College of Veterinary Medicine, University of Maryland, College Park, MD 20742, USA,Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA,To whom all correspondence should be addressed: Dr. Xiaoping Zhu, VA-MD Regional College of Veterinary Medicine, University of Maryland, 8075 Greenmead Drive, College Park, MD 20742, USA, Telephone: (301)314-6814; Fax: (301)314-6855,
| |
Collapse
|
|
24
|
Breakdown of Epithelial Barrier Integrity and Overdrive Activation of Alveolar Epithelial Cells in the Pathogenesis of Acute Respiratory Distress Syndrome and Lung Fibrosis. BIOMED RESEARCH INTERNATIONAL 2015; 2015:573210. [PMID: 26523279 PMCID: PMC4615219 DOI: 10.1155/2015/573210] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/19/2015] [Revised: 09/05/2015] [Accepted: 09/15/2015] [Indexed: 12/29/2022]
Abstract
Individual alveolar epithelial cells (AECs) collaboratively form a tight barrier between atmosphere and fluid-filled tissue to enable normal gas exchange. The tight junctions of AECs provide intercellular sealing and are integral to the maintenance of the AEC barrier integrity. Disruption and failure of reconstitution of AEC barrier result in catastrophic consequences, leading to alveolar flooding and subsequent devastating fibrotic scarring. Recent evidences reveal that many of the fibrotic lung diseases involve AECs both as a frequent target of injury and as a driver of ongoing pathological processes. Aberrantly activated AECs express most of the growth factors and chemokines responsible for the proliferation, migration, and activation of fibroblasts. Current evidences suggest that AECs may acquire overdrive activation in the initial step of fibrosis by several mechanisms, including abnormal recapitulation of the developmental pathway, defects of the molecules essential for epithelial integrity, and acceleration of aging-related properties. Among these initial triggering events, epithelial Pten, a multiple phosphatase that negatively regulates the PI3K/Akt pathway and is crucial for lung development, is essential for the prevention of alveolar flooding and lung fibrosis through the regulation of AEC barrier integrity after injury. Reestablishment of AEC barrier integrity also involves the deployment of specialized stem/progenitor cells.
Collapse
|
|
25
|
Marten E, Nielsen HC, Dammann CEL. Interdependent TTF1 - ErbB4 interactions are critical for surfactant protein-B homeostasis in primary mouse lung alveolar type II cells. J Cell Commun Signal 2015. [PMID: 26198867 DOI: 10.1007/s12079-015-0299-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
ErbB4 receptor and thyroid transcription factor (TTF)-1 are important modulators of fetal alveolar type II (ATII) cell development and injury. ErbB4 is an upstream regulator of TTF-1, promoting its expression in MLE-12 cells, an ATII cell line. Both proteins are known to promote surfactant protein-B gene (SftpB) and protein (SP-B) expression, but their feedback interactions on each other are not known. We hypothesized that TTF-1 expression has a feedback effect on ErbB4 expression in an in-vitro model of isolated mouse ATII cells. We tested this hypothesis by analyzing the effects of overexpressing HER4 and Nkx2.1, the genes of ErbB4 and TTF-1 on TTF-1 and ErbB4 protein expression, respectively, as well as SP-B protein expression in primary fetal mouse lung ATII cells. Transient ErbB4 protein overexpression upregulated TTF-1 protein expression in primary fetal ATII cells, similarly to results previously shown in MLE-12 cells. Transient TTF-1 protein overexpression down regulated ErbB4 protein expression in both cell types. TTF-1 protein was upregulated in primary transgenic ErbB4-depleted adult ATII cells, however SP-B protein expression in these adult transgenic ATII cells was not affected by the absence of ErbB4. The observation that TTF-1 is upregulated in fetal ATII cells by ErbB4 overexpression and also in ErbB4-deleted adult ATII cells suggests additional factors interact with ErbB4 to regulate TTF-1 levels. We conclude that the interdependency of TTF-1 and ErbB4 is important for surfactant protein levels. The interactive regulation of ErbB4 and TTF-1 needs further elucidation.
Collapse
Affiliation(s)
- Elger Marten
- Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA.,Hannover Medical School, Hannover, 30625, Germany
| | - Heber C Nielsen
- Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA.,Sackler School for Biomedical Sciences, Tufts University, Boston, MA, 02111, USA
| | - Christiane E L Dammann
- Division of Newborn Medicine, Floating Hospital for Children at Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA. .,Hannover Medical School, Hannover, 30625, Germany. .,Sackler School for Biomedical Sciences, Tufts University, Boston, MA, 02111, USA.
| |
Collapse
|
|
26
|
|
|
27
|
Polyhexamethylene guanidine phosphate aerosol particles induce pulmonary inflammatory and fibrotic responses. Arch Toxicol 2015; 90:617-32. [PMID: 25716161 DOI: 10.1007/s00204-015-1486-9] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 02/12/2015] [Indexed: 12/18/2022]
Abstract
Polyhexamethylene guanidine (PHMG) phosphate was used as a disinfectant for the prevention of microorganism growth in humidifiers, without recognizing that a change of exposure route might cause significant health effects. Epidemiological studies reported that the use of humidifier disinfectant containing PHMG-phosphate can provoke pulmonary fibrosis. However, the pulmonary toxicity of PHMG-phosphate aerosol particles is unknown yet. This study aimed to elucidate the toxicological relationship between PHMG-phosphate aerosol particles and pulmonary fibrosis. An in vivo nose-only exposure system and an in vitro air-liquid interface (ALI) co-culture model were applied to confirm whether PHMG-phosphate induces inflammatory and fibrotic responses in the respiratory tract. Seven-week-old male Sprague-Dawley rats were exposed to PHMG-phosphate aerosol particles for 3 weeks and recovered for 3 weeks in a nose-only exposure chamber. In addition, three human lung cells (Calu-3, differentiated THP-1 and HMC-1 cells) were cultured at ALI condition for 12 days and were treated with PHMG-phosphate at set concentrations and times. The reactive oxygen species (ROS) generation, airway barrier injuries and inflammatory and fibrotic responses were evaluated in vivo and in vitro. The rats exposed to PHMG-phosphate aerosol particles in nanometer size showed pulmonary inflammation and fibrosis including inflammatory cytokines and fibronectin mRNA increase, as well as histopathological changes. In addition, PHMG-phosphate triggered the ROS generation, airway barrier injuries and inflammatory responses in a bronchial ALI co-culture model. Those results demonstrated that PHMG-phosphate aerosol particles cause pulmonary inflammatory and fibrotic responses. All features of fibrogenesis by PHMG-phosphate aerosol particles closely resembled the pathology of fibrosis that was reported in epidemiological studies. Finally, we expected that PHMG-phosphate infiltrated into the lungs in the form of aerosol particles would induce an airway barrier injury via ROS, release fibrotic inflammatory cytokines, and trigger a wound-healing response, leading to pulmonary fibrosis. A simultaneous state of tissue destruction and inflammation caused by PHMG-phosphate had whipped up a "perfect storm" in the respiratory tract.
Collapse
|
|
28
|
Wong AP, Chin S, Xia S, Garner J, Bear CE, Rossant J. Efficient generation of functional CFTR-expressing airway epithelial cells from human pluripotent stem cells. Nat Protoc 2015; 10:363-81. [DOI: 10.1038/nprot.2015.021] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
|
|
29
|
Wang Z, Guo QY, Zhang XJ, Li X, Li WT, Ma XT, Ma LJ. Corilagin attenuates aerosol bleomycin-induced experimental lung injury. Int J Mol Sci 2014; 15:9762-79. [PMID: 24886817 PMCID: PMC4100119 DOI: 10.3390/ijms15069762] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Revised: 03/16/2014] [Accepted: 05/22/2014] [Indexed: 11/16/2022] Open
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressing lethal disease with few clinically effective therapies. Corilagin is a tannin derivative which shows anti-inflammatory and antifibrotics properties and is potentiated in treating IPF. Here, we investigated the effect of corilagin on lung injury following bleomycin exposure in an animal model of pulmonary fibrosis. Corilagin abrogated bleomycin-induced lung fibrosis as assessed by H&E; Masson's trichrome staining and lung hydroxyproline content in lung tissue. Corilagin reduced the number of apoptotic lung cells and prevented lung epithelial cells from membrane breakdown, effluence of lamellar bodies and thickening of the respiratory membrane. Bleomycin exposure induced expression of MDA, IKKα, phosphorylated IKKα (p-IKKα), NF-κB P65, TNF-α and IL-1β, and reduced I-κB expression in mice lung tissue or in BALF. These changes were reversed by high-dose corilagin (100 mg/kg i.p) more dramatically than by low dose (10 mg/kg i.p). Last, corilagin inhibits TGF-β1 production and α-SMA expression in lung tissue samples. Taken together, these findings confirmed that corilagin attenuates bleomycin-induced epithelial injury and fibrosis via inactivation of oxidative stress, proinflammatory cytokine release and NF-κB and TGF-β1 signaling. Corilagin may serve as a promising therapeutic agent for pulmonary fibrosis.
Collapse
Affiliation(s)
- Zheng Wang
- Department of Respiratory and Critical Medicine, the People's Hospital of Zhengzhou University, Zhengzhou 450003, China.
| | - Qiong-Ya Guo
- Department of Gastroenterology, the People's Hospital of Zhengzhou University, Zhengzhou 450003, China.
| | - Xiao-Ju Zhang
- Department of Respiratory and Critical Medicine, the People's Hospital of Zhengzhou University, Zhengzhou 450003, China.
| | - Xiao Li
- Department of Respiratory and Critical Medicine, the People's Hospital of Zhengzhou University, Zhengzhou 450003, China.
| | - Wen-Ting Li
- Department of Infectious Disease, Anhui Provincial Hospital, Hefei 230001, China.
| | - Xi-Tao Ma
- Department of Respiratory and Critical Medicine, the People's Hospital of Zhengzhou University, Zhengzhou 450003, China.
| | - Li-Jun Ma
- Department of Respiratory and Critical Medicine, the People's Hospital of Zhengzhou University, Zhengzhou 450003, China.
| |
Collapse
|
|
30
|
Sunaga H, Matsui H, Ueno M, Maeno T, Iso T, Syamsunarno MRAA, Anjo S, Matsuzaka T, Shimano H, Yokoyama T, Kurabayashi M. Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice. Nat Commun 2014; 4:2563. [PMID: 24113622 DOI: 10.1038/ncomms3563] [Citation(s) in RCA: 79] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2013] [Accepted: 09/04/2013] [Indexed: 11/09/2022] Open
Abstract
Despite the established role of alveolar type II epithelial cells for the maintenance of pulmonary function, little is known about the deregulation of lipid composition in the pathogenesis of pulmonary fibrosis. The elongation of long-chain fatty acids family member 6 (Elovl6) is a rate-limiting enzyme catalysing the elongation of saturated and monounsaturated fatty acids. Here we show that Elovl6 expression is significantly downregulated after an intratracheal instillation of bleomycin (BLM) and in human lung with idiopathic pulmonary fibrosis. Elovl6-deficient (Elovl6⁻/⁻) mice treated with BLM exhibit severe fibroproliferative response and derangement of fatty acid profile compared with wild-type mice. Furthermore, Elovl6 knockdown induces a change in fatty acid composition similar to that in Elovl6⁻/⁻ mice, resulting in induction of apoptosis, TGF-β1 expression and reactive oxygen species generation. Our findings demonstrate a previously unappreciated role for Elovl6 in the regulation of lung homeostasis, and in pathogenesis and exacerbation of BLM-induced pulmonary fibrosis.
Collapse
Affiliation(s)
- Hiroaki Sunaga
- 1] Department of Laboratory Sciences, Gunma University Graduate School of Health Sciences, 3-39-22, Showa-machi, Maebashi 371-8514, Japan [2]
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Vittal R, Fisher A, Gu H, Mickler EA, Panitch A, Lander C, Cummings OW, Sandusky GE, Wilkes DS. Peptide-mediated inhibition of mitogen-activated protein kinase-activated protein kinase-2 ameliorates bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 2013; 49:47-57. [PMID: 23470623 DOI: 10.1165/rcmb.2012-0389oc] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2, or MK2), a serine/threonine kinase downstream of p38 mitogen-activated protein kinase, has been implicated in inflammation and fibrosis. Compared with pathologically normal lung tissue, significantly higher concentrations of activated MK2 are evident in lung biopsies of patients with idiopathic pulmonary fibrosis (IPF). Expression is localized to fibroblasts and epithelial cells. In the murine bleomycin model of pulmonary fibrosis, we observed robust, activated MK2 expression on Day 7 (prefibrotic stage) and Day 14 (postfibrotic stage). To determine the effects of MK2 inhibition during the postinflammatory/prefibrotic and postfibrotic stages, C57BL/6 mice received intratracheal bleomycin instillation (0.025 U; Day 0), followed by PBS or the MK2 inhibitor (MK2i; 37.5 μg/kg), administered via either local (nebulized) or systemic (intraperitoneal) routes. MK2i or PBS was dosed daily for 14 days subsequent to bleomycin injury, beginning on either Day 7 or Day 14. Regardless of mode of administration or stage of intervention, MK2i significantly abrogated collagen deposition, myofibroblast differentiation and activated MK2 expression. MK2i also decreased circulating TNF-α and IL-6 concentrations, and modulated the local mRNA expression of profibrotic cytokine il-1β, matrix-related genes col1a2, col3a1, and lox, and transforming growth factor-β family members, including smad3, serpine1 (pai1), and smad6/7. In vitro, MK2i dose-dependently attenuated total MK2, myofibroblast differentiation, the secretion of collagen Type I, fibronectin, and the activation of focal adhesion kinase, whereas activated MK2 was attenuated at optimal doses. The peptide-mediated inhibition of MK2 affects both inflammatory and fibrotic responses, and thus may offer a promising therapeutic target for IPF.
Collapse
Affiliation(s)
- Ragini Vittal
- Center for Immunobiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Im SK, Jeong H, Jeong HW, Kim KT, Hwang D, Ikegami M, Kong YY. Disruption of sorting nexin 5 causes respiratory failure associated with undifferentiated alveolar epithelial type I cells in mice. PLoS One 2013; 8:e58511. [PMID: 23526992 PMCID: PMC3602295 DOI: 10.1371/journal.pone.0058511] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 02/05/2013] [Indexed: 01/16/2023] Open
Abstract
Sorting nexin 5 (Snx5) has been posited to regulate the degradation of epidermal growth factor receptor and the retrograde trafficking of cation-independent mannose 6-phosphate receptor/insulin-like growth factor II receptor. Snx5 has also been suggested to interact with Mind bomb-1, an E3 ubiquitin ligase that regulates the activation of Notch signaling. However, the in vivo functions of Snx5 are largely unknown. Here, we report that disruption of the Snx5 gene in mice (Snx5-/- mice) resulted in partial perinatal lethality; 40% of Snx5-/- mice died shortly after birth due to cyanosis, reduced air space in the lungs, and respiratory failure. Histological analysis revealed that Snx5-/- mice exhibited thickened alveolar walls associated with undifferentiated alveolar epithelial type I cells. In contrast, alveolar epithelial type II cells were intact, exhibiting normal surfactant synthesis and secretion. Although the expression levels of surfactant proteins and saturated phosphatidylcholine in the lungs of Snx5-/- mice were comparable to those of Snx5+/+ mice, the expression levels of T1α, Aqp5, and Rage, markers for distal alveolar epithelial type I cells, were significantly decreased in Snx5-/- mice. These results demonstrate that Snx5 is necessary for the differentiation of alveolar epithelial type I cells, which may underlie the adaptation to air breathing at birth.
Collapse
Affiliation(s)
- Sun-Kyoung Im
- School of Biological Science, College of Natural Sciences, Seoul National University, Seoul, South Korea
- Department of Life Science, Division of Molecular and Life Science, POSTECH, Pohang, South Korea
| | - HyoBin Jeong
- School of Interdisciplinary Biosciences and Bioengineering, POSTECH, Pohang, South Korea
| | - Hyun-Woo Jeong
- School of Biological Science, College of Natural Sciences, Seoul National University, Seoul, South Korea
| | - Kyong-Tai Kim
- Department of Life Science, Division of Molecular and Life Science, POSTECH, Pohang, South Korea
| | - Daehee Hwang
- School of Interdisciplinary Biosciences and Bioengineering, POSTECH, Pohang, South Korea
| | - Machiko Ikegami
- Division of Pulmonary Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, United States of America
| | - Young-Yun Kong
- School of Biological Science, College of Natural Sciences, Seoul National University, Seoul, South Korea
- * E-mail:
| |
Collapse
|
|
33
|
Martino RB, Coelho AMM, Kubrusly MS, Leitão R, Sampietre SN, Machado MCC, Bacchella T, D'Albuquerque LAC. Pentoxifylline improves liver regeneration through down-regulation of TNF-α synthesis and TGF-β1 gene expression. World J Gastrointest Surg 2012; 4:146-51. [PMID: 22816029 PMCID: PMC3400043 DOI: 10.4240/wjgs.v4.i6.146] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Revised: 06/20/2012] [Accepted: 06/23/2012] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the mechanism of pentoxifylline (PTX) improvement in liver regeneration.
RESULTS: Rats were randomized into 4 groups: Control rats; Sham - sham-operation rats; Saline - 70% hepatectomy plus saline solution; PTX - 70% hepatectomy plus PTX. At 2 and 6 h after hepatectomy, aspartate aminotransferase, alanine aminotransferase, tumor necrosis factor (TNF)-α and interleukin-6 (IL-6) serum and hepatic tissue levels were determined. Tumor growth factor (TGF)-β1 gene expression in liver tissue was evaluated 24 h after hepatectomy by quantitative reverse transcriptase polymerase chain reaction analysis. Proliferation was analyzed by mitotic index and proliferating cell nuclear antigen (PCNA) staining 48 h after hepatectomy.
RESULTS: TNF-α and IL-6 serum levels increased at 2 and 6 h after hepatectomy. At 2 h after hepatectomy serum PTX was reduced but not hepatic levels of TNF-α and IL-6. A decrease in liver TGF-β1 gene expression and an increase in mitotic index and PCNA after hepatectomy were observed in the PTX treatment group in comparison to the saline group.
CONCLUSION: PTX improves liver regeneration by a mechanism related to down regulation of TNF-α production and TGF-β1 gene expression.
Collapse
Affiliation(s)
- Rodrigo Bronze Martino
- Rodrigo Bronze Martino, Ana Maria Mendonça Coelho, Márcia Saldanha Kubrusly, Regina Leitão, Sandra Nassa Sampietre, Marcel Cerqueira Cesar Machado, Telesforo Bacchella, Luiz Augusto Carneiro D'Albuquerque, Department of Gastroenterology (LIM/37), and Department of Surgery, Medical School, University of Sao Paulo, Sao Paulo 01246903, Brazil
| | | | | | | | | | | | | | | |
Collapse
|
|
34
|
Roszell BR, Tao JQ, Yu KJ, Huang S, Bates SR. Characterization of the Niemann-Pick C pathway in alveolar type II cells and lamellar bodies of the lung. Am J Physiol Lung Cell Mol Physiol 2012; 302:L919-32. [PMID: 22367786 DOI: 10.1152/ajplung.00383.2011] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The Niemann-Pick C (NPC) pathway plays an essential role in the intracellular trafficking of cholesterol by facilitating the release of lipoprotein-derived sterol from the lumen of lysosomes. Regulation of cellular cholesterol homeostasis is of particular importance to lung alveolar type II cells because of the need for production of surfactant with an appropriate lipid composition. We performed microscopic and biochemical analysis of NPC proteins in isolated rat type II pneumocytes. NPC1 and NPC2 proteins were present in the lung, isolated type II cells in culture, and alveolar macrophages. The glycosylated and nonglycosylated forms of NPC1 were prominent in the lung and the lamellar body organelles. Immunocytochemical analysis of isolated type II pneumocytes showed localization of NPC1 to the limiting membrane of lamellar bodies. NPC2 and lysosomal acid lipase were found within these organelles, as confirmed by z-stack analysis of confocal images. All three proteins also were identified in small, lysosome-like vesicles. In the presence of serum, pharmacological inhibition of the NPC pathway with compound U18666A resulted in doubling of the cholesterol content of the type II cells. Filipin staining revealed a striking accumulation of cholesterol within lamellar bodies. Thus the NPC pathway functions to control cholesterol accumulation in lamellar bodies of type II pneumocytes and, thereby, may play a role in the regulation of surfactant cholesterol content.
Collapse
Affiliation(s)
- Blair R Roszell
- Institute for Environmental Medicine, Univ. of Pennsylvania, Philadelphia, PA 19104-6068, USA
| | | | | | | | | |
Collapse
|
|
35
|
Helmig S, Stephan P, Döhrel J, Schneider J. TNF-α mRNA expression correlates with TGF-β mRNA expression in vivo. Inflammation 2011; 34:255-9. [PMID: 20652825 DOI: 10.1007/s10753-010-9231-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
TNF-α is postulated to play a significant role in regulating TGF-β(1) expression. In lung fibroblasts, for example, TNF-α is supposed to induce TGF-β(1) via AP-1 activation. TNF-α receptor, knock-out mice are resistant to induced fibrosis and over-expression of TNF-α causes increased TGF-β(1) production in mice. Therefore, we investigated whether TNF-α mRNA levels are associated with the TGF-β(1) mRNA levels of blood leucocytes in humans. Quantitative real-time PCR of TNF-α and TGF-β(1) was performed in 118 Germans. Calculations of expression were made with the 2(-ΔΔCT) method. When the investigated population was divided in two groups (TNF-α low and TNF-α high) by the median of the determined TNF-α expression, highly significant (p < 0.0001) differences of TGF-β1 mRNA expression were revealed. Additionally, dividing the investigated population into quartiles of the determined TNF-α expression showed significantly different TGF-β1 mRNA expressions. Comparing the determined CT-values of TNF-α in context with these of TGF-β1, a coefficient of determination R(2) = 0.4635 was calculated. In this study we demonstrated in vivo a significant association of the relative TNF-α/B2M mRNA expression and the relative TGF-β(1)/B2M mRNA expression in 118 Germans.
Collapse
Affiliation(s)
- Simone Helmig
- Institut und Poliklinik für Arbeits- und Sozialmedizin, Justus-Liebig-Universität, Aulweg 129, 35392, Giessen, Germany.
| | | | | | | |
Collapse
|
|
36
|
Hsieh WY, Chou CC, Ho CC, Yu SL, Chen HY, Chou HYE, Chen JJW, Chen HW, Yang PC. Single-walled carbon nanotubes induce airway hyperreactivity and parenchymal injury in mice. Am J Respir Cell Mol Biol 2011; 46:257-67. [PMID: 21960547 DOI: 10.1165/rcmb.2011-0010oc] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Inhalation of single-walled carbon nanotubes (SWCNTs) has raised serious concerns related to potential toxic effects in the respiratory system. This study examined possible SWCNT-induced toxic mechanisms in vivo in mice. The results indicated that a single intratracheal instillation of SWCNTs could induce airway hyperreactivity and airflow obstruction and confirmed previous findings of granulomatous changes in the lung parenchyma that persisted from 7 days to 6 months after exposure. The irreversible lung pathology and functional airway alterations in the mouse model mimicked obstructive airway disease in humans. Transcriptomic analysis showed that SWCNTs might up-regulate proteinases (cathepsin K and matrix metalloproteinase [MMP]12), chemokines C-C motif ligands (CCL2 and CCL3), and several macrophage receptors (Toll-like receptor 2, macrophage scavenger receptor 1). Pathway analyses showed that NF-κB-related inflammatory responses and downstream signals affecting tissue remodeling dominated the pathologic process. The NF-κB inhibitor pyrrolidine dithiocarbamate attenuated SWCNT-induced airway hyperreactivity, chronic airway inflammation, and MMP12 and cathepsin K expression when administered in vivo, whereas a cathepsin K inhibitor could partially reduce airway hyperreactivity and granulomatous changes in the SWCNT-treated group. The up-regulation of cathepsin K and MMP12 by SWCNTs was further confirmed via in vitro coculture of bronchoalveolar macrophages with lung epithelial/mesenchymal cells but not in macrophages without coculture, indicating that SWCNT-induced MMP12 and cathespin K were cell-type specific and cell-cell interaction dependent. In conclusion, exposure to SWCNTs may cause irreversible obstructive airway disease. Nanotoxicogenomics uncovered novel mechanisms underlying SWCNT-induced lung diseases, implicating MMP12 and cathepsin K in the pathologic injury as potential biomarkers or therapeutic targets.
Collapse
Affiliation(s)
- Wan-Yu Hsieh
- Graduate Institute of Toxicology, National Taiwan University College of Medicine, No. 1 Sec. 1 Ren-Ai Road, Taipei, Taiwan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Voloshenyuk TG, Hart AD, Khoutorova E, Gardner JD. TNF-α increases cardiac fibroblast lysyl oxidase expression through TGF-β and PI3Kinase signaling pathways. Biochem Biophys Res Commun 2011; 413:370-5. [PMID: 21893029 DOI: 10.1016/j.bbrc.2011.08.109] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2011] [Accepted: 08/20/2011] [Indexed: 12/01/2022]
Abstract
TNF-α is a proinflammatory cytokine that is upregulated in many cardiac diseases. The increase of TNF-α expression affects both heart function and the structure of the extracellular matrix. Lysyl oxidase (LOX) is a key enzyme responsible for the maturation of extracellular matrix proteins, including collagens type I and III. In this study, we investigated the regulation of LOX expression and activity by TNF-α using adult rat cardiac fibroblasts. Our results indicate that TNF-α has a dichotomous effect on LOX expression by cardiac fibroblasts. Low dose TNF-α (1-5 ng/ml) decreased LOX expression, whereas higher doses (10-30 ng/ml) increased expression. The higher dose TNF-α effect on LOX expression was attenuated by the inhibition of PI3Kinase/Akt pathway. TGF-β1 signaling played a significant role in mediating the TNF-α effect. TNF-α increased the expression of TGF-β, and TGF-β receptors type I and II, and also stimulated Smad3 phosphorylation. Inhibition of TGF-β receptor I or Smad3 prevented increased LOX expression by TNF-α. These findings indicate that TNF-α stimulated LOX expression may play an important role in progressive cardiac fibrosis.
Collapse
Affiliation(s)
- Tetyana G Voloshenyuk
- Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA, United States
| | | | | | | |
Collapse
|
|
38
|
Helmig S, Aliahmadi N, Stephan P, Döhrel J, Schneider J. TNF-α −308 genotypes are associated with TNF-α and TGF-β1 mRNA expression in blood leucocytes of humans. Cytokine 2011; 53:306-10. [DOI: 10.1016/j.cyto.2010.11.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2010] [Revised: 11/04/2010] [Accepted: 11/19/2010] [Indexed: 11/17/2022]
|
|
39
|
Mesenchymal cell survival in airway and interstitial pulmonary fibrosis. FIBROGENESIS & TISSUE REPAIR 2010; 3:15. [PMID: 20738867 PMCID: PMC2940818 DOI: 10.1186/1755-1536-3-15] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2010] [Accepted: 08/25/2010] [Indexed: 02/06/2023]
Abstract
Fibrotic reactions in the airways of the lung or the pulmonary interstitium are a common pathologic outcome after exposure to a wide variety of toxic agents, including metals, particles or fibers. The survival of mesenchymal cells (fibroblasts and myofibroblasts) is a key factor in determining whether a fibroproliferative response that occurs after toxic injury to the lung will ultimately resolve or progress to a pathologic state. Several polypeptide growth factors, including members of the platelet-derived growth factor (PDGF) family and the epidermal growth factor (EGF) family, are prosurvival factors that stimulate a replicative and migratory mesenchymal cell phenotype during the early stages of lung fibrogenesis. This replicative phenotype can progress to a matrix synthetic phenotype in the presence of transforming growth factor-β1 (TGF-β1). The resolution of a fibrotic response requires growth arrest and apoptosis of mesenchymal cells, whereas progressive chronic fibrosis has been associated with mesenchymal cell resistance to apoptosis. Mesenchymal cell survival or apoptosis is further influenced by cytokines secreted during Th1 inflammation (e.g., IFN-γ) or Th2 inflammation (e.g., IL-13) that modulate the expression of growth factor activity through the STAT family of transcription factors. Understanding the mechanisms that regulate the survival or death of mesenchymal cells is central to ultimately developing therapeutic strategies for lung fibrosis.
Collapse
|
|
40
|
Sullivan DE, Ferris M, Nguyen H, Abboud E, Brody AR. TNF-alpha induces TGF-beta1 expression in lung fibroblasts at the transcriptional level via AP-1 activation. J Cell Mol Med 2010. [PMID: 20141610 DOI: 10.1111/j.1582-4934.2008.00647.x] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta(1) (TGF-beta(1)) are peptides with multiple biological activities that influence neoplastic, immunologic and fibroproliferative diseases. There are clear interrelationships and overlap between the actions of TNF-alpha and TGF-beta(1) in lung fibrosis; therefore, we postulated that TNF-alpha may play a significant role in regulating TGF-beta(1) expression in lungs. We recently reported that TNF-alpha activates the extracellular regulated kinase (ERK)-specific pathway in fibroblasts resulting in stabilization of TGF-beta(1) mRNA and increased expression of TGF-beta(1). In the current study, we further investigated the molecular mechanisms involved in TNF-alpha regulation of TGF-beta(1) expression. Nuclear run-on assays showed that treatment of Swiss 3T3 fibroblasts with TNF-alpha increased transcription of the TGF-beta(1) gene in an ERK independent manner. Pre-treatment with the activator protein-1 (AP-1) inhibitor curcumin attenuated TNF-alpha induced transcription of the TGF-beta(1) gene. TNF-alpha induced increased levels of c-Jun and C-Fos in the nucleus accompanied by phosphorylation of c-Jun. In electrophoretic mobility shift assays, AP-1 binding to an AP-1 binding site found within the TGF-beta(1) promoter was increased in nuclear extracts from Swiss 3T3 fibroblasts treated with TNF-alpha. Together, these results suggest that TNF-alpha induces expression and DNA binding of AP-1 resulting in increased transcription of the TGF-beta(1) gene. It is essential to know which transcription pathways are activated because of the wide distribution of TNF-alpha and TGF-beta(1), the general lack of effective treatments for fibroproliferative disease and the possibility that targeting the correct transcription factors could be palliative.
Collapse
Affiliation(s)
- Deborah E Sullivan
- Department of Microbiology and Immunology, Biomedical Sciences Graduate Program, Tulane University School of Medicine, New Orleans, LA, USA
| | | | | | | | | |
Collapse
|
|
41
|
Sullivan DE, Ferris M, Nguyen H, Abboud E, Brody AR. TNF-alpha induces TGF-beta1 expression in lung fibroblasts at the transcriptional level via AP-1 activation. J Cell Mol Med 2010; 13:1866-76. [PMID: 20141610 DOI: 10.1111/j.1582-4934.2009.00647.x] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta(1) (TGF-beta(1)) are peptides with multiple biological activities that influence neoplastic, immunologic and fibroproliferative diseases. There are clear interrelationships and overlap between the actions of TNF-alpha and TGF-beta(1) in lung fibrosis; therefore, we postulated that TNF-alpha may play a significant role in regulating TGF-beta(1) expression in lungs. We recently reported that TNF-alpha activates the extracellular regulated kinase (ERK)-specific pathway in fibroblasts resulting in stabilization of TGF-beta(1) mRNA and increased expression of TGF-beta(1). In the current study, we further investigated the molecular mechanisms involved in TNF-alpha regulation of TGF-beta(1) expression. Nuclear run-on assays showed that treatment of Swiss 3T3 fibroblasts with TNF-alpha increased transcription of the TGF-beta(1) gene in an ERK independent manner. Pre-treatment with the activator protein-1 (AP-1) inhibitor curcumin attenuated TNF-alpha induced transcription of the TGF-beta(1) gene. TNF-alpha induced increased levels of c-Jun and C-Fos in the nucleus accompanied by phosphorylation of c-Jun. In electrophoretic mobility shift assays, AP-1 binding to an AP-1 binding site found within the TGF-beta(1) promoter was increased in nuclear extracts from Swiss 3T3 fibroblasts treated with TNF-alpha. Together, these results suggest that TNF-alpha induces expression and DNA binding of AP-1 resulting in increased transcription of the TGF-beta(1) gene. It is essential to know which transcription pathways are activated because of the wide distribution of TNF-alpha and TGF-beta(1), the general lack of effective treatments for fibroproliferative disease and the possibility that targeting the correct transcription factors could be palliative.
Collapse
Affiliation(s)
- Deborah E Sullivan
- Department of Microbiology and Immunology, Biomedical Sciences Graduate Program, Tulane University School of Medicine, New Orleans, LA, USA
| | | | | | | | | |
Collapse
|
|
42
|
Srisuma S, Bhattacharya S, Simon DM, Solleti SK, Tyagi S, Starcher B, Mariani TJ. Fibroblast growth factor receptors control epithelial-mesenchymal interactions necessary for alveolar elastogenesis. Am J Respir Crit Care Med 2010; 181:838-50. [PMID: 20093646 DOI: 10.1164/rccm.200904-0544oc] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
RATIONALE The mechanisms contributing to alveolar formation are poorly understood. A better understanding of these processes will improve efforts to ameliorate lung disease of the newborn and promote alveolar repair in the adult. Previous studies have identified impaired alveogenesis in mice bearing compound mutations of fibroblast growth factor (FGF) receptors (FGFRs) 3 and 4, indicating that these receptors cooperatively promote postnatal alveolar formation. OBJECTIVES To determine the molecular and cellular mechanisms of FGF-mediated alveolar formation. METHODS Compound FGFR3/FGFR4-deficient mice were assessed for temporal changes in lung growth, airspace morphometry, and genome-wide expression. Observed gene expression changes were validated using quantitative real-time RT-PCR, tissue biochemistry, histochemistry, and ELISA. Autocrine and paracrine regulatory mechanisms were investigated using isolated lung mesenchymal cells and type II pneumocytes. MEASUREMENTS AND MAIN RESULTS Quantitative analysis of airspace ontogeny confirmed a failure of secondary crest elongation in compound mutant mice. Genome-wide expression profiling identified molecular alterations in these mice involving aberrant expression of numerous extracellular matrix molecules. Biochemical and histochemical analysis confirmed changes in elastic fiber gene expression resulted in temporal increases in elastin deposition with the loss of typical spatial restriction. No abnormalities in elastic fiber gene expression were observed in isolated mesenchymal cells, indicating that abnormal elastogenesis in compound mutant mice is not cell autonomous. Increased expression of paracrine factors, including insulin-like growth factor-1, in freshly-isolated type II pneumocytes indicated that these cells contribute to the observed pathology. CONCLUSIONS Epithelial/mesenchymal signaling mechanisms appear to contribute to FGFR-dependent alveolar elastogenesis and proper airspace formation.
Collapse
Affiliation(s)
- Sorachai Srisuma
- Division of Neonatology and Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, New York 14642, USA
| | | | | | | | | | | | | |
Collapse
|
|
43
|
Lai TC, Pociask DA, Ferris M, Nguyen HT, Miller CA, Brody A, Sullivan D. Small interfering RNAs (siRNAs) targeting TGF-beta1 mRNA suppress asbestos-induced expression of TGF-beta1 and CTGF in fibroblasts. J Environ Pathol Toxicol Oncol 2009; 28:109-19. [PMID: 19817698 DOI: 10.1615/jenvironpatholtoxicoloncol.v28.i2.30] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Interstitial lung disease (ILD) afflicts millions of people worldwide. ILD can be caused by a number of agents, including inhaled asbestos, and may ultimately result in respiratory failure and death. Currently, there are no effective treatments for ILD. Transforming growth factor-beta1 (TGF-beta1) is thought to play an important role in the development of pulmonary fibrosis, and asbestos has been shown to induce TGF-beta1 expression in a murine model of ILD. To better define the role of TGF-beta1 in ILD, we developed several small interfering RNAs (siRNAs) that target TGF-beta1 mRNA for degradation. To assess the efficacy of each siRNA in reducing asbestos-induced TGF-beta1 expression, Swiss 3T3 fibroblasts were transfected with TGF-beta1 siRNAs and then treated with chrysotile asbestos for 48 h. Two independent siRNAs targeting TGF-beta1 mRNA knocked-down asbestos-induced expression of TGF-beta1 mRNA by 72-89% and protein by 70-84%. Interestingly, siRNA knockdown of TGF-beta1 also reduced asbestos-induced expression of connective tissue growth factor (CTGF). CTGF can be upregulated by TGF-beta1 and appears to play an important role in the development of pulmonary fibrosis. These results suggest that siRNAs could be effective in preventing or possibly arresting the progression of pulmonary fibrosis. Studies are underway in vivo to test this postulate.
Collapse
Affiliation(s)
- Tai-Cheng Lai
- Department of Environmental Health Sciences, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
| | | | | | | | | | | | | |
Collapse
|
|
44
|
Raoust E, Balloy V, Garcia-Verdugo I, Touqui L, Ramphal R, Chignard M. Pseudomonas aeruginosa LPS or flagellin are sufficient to activate TLR-dependent signaling in murine alveolar macrophages and airway epithelial cells. PLoS One 2009; 4:e7259. [PMID: 19806220 PMCID: PMC2752798 DOI: 10.1371/journal.pone.0007259] [Citation(s) in RCA: 121] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2009] [Accepted: 09/02/2009] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The human lung is exposed to a large number of airborne pathogens as a result of the daily inhalation of 10,000 liters of air. Innate immunity is thus essential to defend the lungs against these pathogens. This defense is mediated in part through the recognition of specific microbial ligands by Toll-like receptors (TLR) of which there are at least 10 in humans. Pseudomonas aeruginosa is the main pathogen that infects the lungs of cystic fibrosis patients. Based on whole animal experiments, using TLR knockout mice, the control of this bacterium is believed to occur by the recognition of LPS and flagellin by TLRs 2,4 and 5, respectively. METHODOLOGY/PRINCIPAL FINDINGS In the present study, we investigated in vitro the role of these same TLR and ligands, in alveolar macrophage (AM) and epithelial cell (EC) activation. Cellular responses to P. aeruginosa was evaluated by measuring KC, TNF-alpha, IL-6 and G-CSF secretion, four different markers of the innate immune response. AM and EC from WT and TLR2, 4, 5 and MyD88 knockout mice for were stimulated with the wild-type P. aeruginosa or with a mutant devoid of flagellin production. CONCLUSIONS/SIGNIFICANCE The results clearly demonstrate that only two ligand/receptor pairs are necessary for the induction of KC, TNF-alpha, and IL-6 synthesis by P. aeruginosa-activated cells, i.e. TLR2,4/LPS and TLR5/flagellin. Either ligand/receptor pair is sufficient to sense the bacterium and to trigger cell activation, and when both are missing lung EC and AM are unable to produce such a response as were cells from MyD88(-/-) mice.
Collapse
Affiliation(s)
- Eloïse Raoust
- Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France
- INSERM U874, Paris, France
| | - Viviane Balloy
- Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France
- INSERM U874, Paris, France
| | - Ignacio Garcia-Verdugo
- Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France
- INSERM U874, Paris, France
| | - Lhousseine Touqui
- Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France
- INSERM U874, Paris, France
| | - Reuben Ramphal
- Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France
- INSERM U874, Paris, France
- Department of Medicine, University of Florida, Gainesville, Florida, United States of America
| | - Michel Chignard
- Unité de Défense Innée et Inflammation, Institut Pasteur, Paris, France
- INSERM U874, Paris, France
| |
Collapse
|
|
45
|
Salazar KD, Lankford SM, Brody AR. Mesenchymal stem cells produce Wnt isoforms and TGF-beta1 that mediate proliferation and procollagen expression by lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2009; 297:L1002-11. [PMID: 19734317 DOI: 10.1152/ajplung.90347.2008] [Citation(s) in RCA: 103] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Studies have been carried out previously to determine whether mesenchymal stem cells (MSC) influence the progression of pulmonary fibrosis. Here, we asked whether MSC (derived from mouse bone marrow and human umbilical cord blood) produce factors that mediate lung fibroblast (LF) growth and matrix production. MSC-conditioned media (CM) were found by ELISA to contain significant amounts of PDGF-AA and transforming growth factor-beta1 (TGF-beta1). Proliferation was increased in a concentration-dependent manner in LF cell lines and primary cells cultured in MSC-CM, but neither anti-PDGF antibodies nor PDGF receptor-specific antibodies affected proliferation, nor did a number of other antibodies to well-known mitogenic factors. However, proliferation was significantly inhibited by the Wnt signaling antagonist, secreted frizzled related protein-1 (sFRP-1). In addition, anti-Wnt1 and anti-Wnt2 antibodies attenuated MSC-CM-induced proliferation, and increased expression of Wnt7b was identified. As would be expected in cells activated by Wnt, nuclear beta-catenin was increased. The amount of TGF-beta1 in MSC-CM and its biological activity were revealed by activation at acidic pH. The stem cells synthesized and released TGF-beta1 that increased alpha1-procollagen gene expression by LF target cells. Addition of anti-TGF-beta to the MSC-CM blocked upregulation of collagen gene expression. These data demonstrate that MSC from mice and humans produce Wnt proteins and TGF-beta1 that respectively stimulate LF proliferation and matrix production, two hallmarks of fibroproliferative lung disease. It will be essential to determine whether these factors can play a role in attempts to use MSC for therapeutic approaches.
Collapse
Affiliation(s)
- Keith D Salazar
- Department of Molecular Biomedical Sciences, North Carolina State University, 4700 Hillsborough St., Raleigh, NC 27606, USA
| | | | | |
Collapse
|
|
46
|
Abdulamir AS, Hafidh RR, Abubakar F. Different inflammatory mechanisms in lungs of severe and mild asthma: crosstalk of NF-kappa-B, TGFbeta1, Bax, Bcl-2, IL-4 and IgE. Scandinavian Journal of Clinical and Laboratory Investigation 2009; 69:487-95. [PMID: 19347746 DOI: 10.1080/00365510902749131] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE To examine differences in the apoptotic, inflammatory, allergic and immunological features in the lungs of adults with asthma. MATERIAL AND METHODS Thirty-six patients with mild asthma (MA), 16 with severe asthma (SA) and 20 healthy volunteers (HVs) were enrolled. Bronchoalveolar lavage fluid (BALF) was processed into cell-free fluid for enzyme-linked immunosorbent assay detecting soluble TGFbeta1, IL-4 and IgE and BALF lymphocytes for immunocytochemical staining of cellular Bax, Bcl-2 and nuclear factor-Kappa-B (NFkappaB). RESULTS Cellular NFkappaB expression was higher in SA than in MA and HVs, while extracellular TGFbeta1 was high in both the SA and MA groups but low in the HVs. Bcl-2/Bax ratio was higher in SA than in MA and in MA than in HV groups and correlated significantly with NFkappaB level. Interestingly, the levels of IgE and, to a lesser extent, IL-4 were higher in MA than in SA and both were much higher than in HVs, and were inversely correlated with NFkappaB level in the SA group and with TGFbeta1 level in the MA group. CONCLUSIONS NFkappaB has a central role in the perpetuation of persistent inflammation in SA and might induce apoptosis via Bcl-2. The SA group appears not associated much with allergen-based IgE and IL-4 reactions as efficiently as in MA. This was supported by the lower levels of IgE and IL-4 in SA compared to MA. TGFbeta1 appears to be associated with asthma pathogenesis, especially allergen-based MA.
Collapse
Affiliation(s)
- A S Abdulamir
- Microbiology Research Department, University Putra Malaysia, UPM, Serdang, Malaysia
| | | | | |
Collapse
|
|
47
|
Di Giuseppe M, Gambelli F, Hoyle GW, Lungarella G, Studer SM, Richards T, Yousem S, McCurry K, Dauber J, Kaminski N, Leikauf G, Ortiz LA. Systemic inhibition of NF-kappaB activation protects from silicosis. PLoS One 2009; 4:e5689. [PMID: 19479048 PMCID: PMC2682759 DOI: 10.1371/journal.pone.0005689] [Citation(s) in RCA: 51] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2007] [Accepted: 04/07/2009] [Indexed: 11/29/2022] Open
Abstract
Background Silicosis is a complex lung disease for which no successful treatment is available and therefore lung transplantation is a potential alternative. Tumor necrosis factor alpha (TNFα) plays a central role in the pathogenesis of silicosis. TNFα signaling is mediated by the transcription factor, Nuclear Factor (NF)-κB, which regulates genes controlling several physiological processes including the innate immune responses, cell death, and inflammation. Therefore, inhibition of NF-κB activation represents a potential therapeutic strategy for silicosis. Methods/Findings In the present work we evaluated the lung transplant database (May 1986–July 2007) at the University of Pittsburgh to study the efficacy of lung transplantation in patients with silicosis (n = 11). We contrasted the overall survival and rate of graft rejection in these patients to that of patients with idiopathic pulmonary fibrosis (IPF, n = 79) that was selected as a control group because survival benefit of lung transplantation has been identified for these patients. At the time of lung transplantation, we found the lungs of silica-exposed subjects to contain multiple foci of inflammatory cells and silicotic nodules with proximal TNFα expressing macrophage and NF-κB activation in epithelial cells. Patients with silicosis had poor survival (median survival 2.4 yr; confidence interval (CI): 0.16–7.88 yr) compared to IPF patients (5.3 yr; CI: 2.8–15 yr; p = 0.07), and experienced early rejection of their lung grafts (0.9 yr; CI: 0.22–0.9 yr) following lung transplantation (2.4 yr; CI:1.5–3.6 yr; p<0.05). Using a mouse experimental model in which the endotracheal instillation of silica reproduces the silica-induced lung injury observed in humans we found that systemic inhibition of NF-κB activation with a pharmacologic inhibitor (BAY 11-7085) of IκBα phosphorylation decreased silica-induced inflammation and collagen deposition. In contrast, transgenic mice expressing a dominant negative IκBα mutant protein under the control of epithelial cell specific promoters demonstrate enhanced apoptosis and collagen deposition in their lungs in response to silica. Conclusions Although limited by its size, our data support that patients with silicosis appear to have poor outcome following lung transplantation. Experimental data indicate that while the systemic inhibition of NF-κB protects from silica-induced lung injury, epithelial cell specific NF-κB inhibition appears to aggravate the outcome of experimental silicosis.
Collapse
Affiliation(s)
- Michelangelo Di Giuseppe
- Division of Occupational and Environmental Medicine, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Federica Gambelli
- Division of Occupational and Environmental Medicine, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Gary W. Hoyle
- Department of Environmental and Occupational Health Sciences, School of Public Health and Informational Sciences, University of Louisville, Louisville, Kentucky, United States of America
| | | | - Sean M. Studer
- Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America
| | - Thomas Richards
- Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America
| | - Sam Yousem
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America
| | - Ken McCurry
- Department of Thoracic Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America
| | - James Dauber
- Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America
| | - Naftali Kaminski
- Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America
| | - George Leikauf
- Division of Occupational and Environmental Medicine, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
| | - Luis A. Ortiz
- Division of Occupational and Environmental Medicine, Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America
- Simmons Center for Interstitial Lung Disease, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America
- * E-mail:
| |
Collapse
|
|
48
|
Bhandary YP, Velusamy T, Shetty P, Shetty RS, Idell S, Cines DB, Jain D, Bdeir K, Abraham E, Tsuruta Y, Shetty S. Post-transcriptional regulation of urokinase-type plasminogen activator receptor expression in lipopolysaccharide-induced acute lung injury. Am J Respir Crit Care Med 2009; 179:288-98. [PMID: 19029002 PMCID: PMC2643078 DOI: 10.1164/rccm.200712-1787oc] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2007] [Accepted: 11/20/2008] [Indexed: 11/16/2022] Open
Abstract
RATIONALE Urokinase-type plasminogen activator (uPA) receptor (uPAR) is required for the recruitment of neutrophils in response to infection. uPA induces its own expression in lung epithelial cells, which involves its interaction with cell surface uPAR. Regulation of uPAR expression is therefore crucial for uPA-mediated signaling in infectious acute lung injury (ALI). OBJECTIVES To determine the role of uPA in uPAR expression during ALI caused by sepsis. METHODS We used Western blot, Northern blot, Northwestern assay, and immunohistochemistry. Phosphate-buffered saline- and lipopolysaccharide (LPS)-treated wild-type and uPA(-/-) mice were used. MEASUREMENTS AND MAIN RESULTS Biological activities of uPA, including proteolysis, cell adhesion, migration, proliferation, and differentiation, are dependent on its association with uPAR. Bacterial endotoxin (LPS) is a major cause of pulmonary dysfunction and infection-associated mortality. The present study shows that LPS induces uPAR expression both in vitro and in vivo, and that the mechanism involves post-transcriptional stabilization of uPAR mRNA by reciprocal interaction of phosphoglycerate kinase (PGK) and heterogeneous nuclear ribonucleoprotein C (hnRNPC) with uPAR mRNA coding region and 3' untranslated region determinants, respectively. The process involves tyrosine phosphorylation of PGK and hnRNPC. uPA(-/-) mice failed to induce uPAR expression after LPS treatment. In these mice, LPS treatment failed to alter the binding of PGK and hnRNPC protein with uPAR mRNA due to lack of tyrosine phosphorylation. CONCLUSIONS Our study shows that induction of LPS-mediated uPAR expression is mediated through tyrosine phosphorylation of PGK and hnRNPC. This involves expression of uPA as an obligate intermediary.
Collapse
Affiliation(s)
- Yashodhar P Bhandary
- The Texas Lung Injury Institute, The University of Texas Health Center at Tyler, Tyler, TX 75708, USA
| | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Bhalla DK, Hirata F, Rishi AK, Gairola CG. Cigarette smoke, inflammation, and lung injury: a mechanistic perspective. JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH. PART B, CRITICAL REVIEWS 2009; 12:45-64. [PMID: 19117209 DOI: 10.1080/10937400802545094] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/27/2023]
Abstract
Inflammation is a common feature in the pathogenesis of cigarette smoke-associated diseases. The recruitment of inflammatory cells into the lung following cigarette smoke exposure presents a risk of tissue damage through the release of toxic mediators, including proteolytic enzymes and reactive oxygen species. This review represents a toxicological approach to investigation of cigarette smoke-induced lung injury, with a focus on laboratory studies and an emphasis on inflammatory mechanisms. The studies discussed in this review analyze the role of inflammation and inflammatory mediators in the development of injury. In cases where information relating to cigarette smoke is limited, examples are taken from other models of lung injury applicable to cigarette smoke. The primary aim of the review is to summarize published work so as to permit (1) an evaluation of chronic lung injury and inflammatory responses in animal models, (2) a discussion of inflammatory mediators in the development of chronic injury, and (3) identification of immunological mechanisms of injury. These studies discuss the currently understood roles of cytokines, cell adhesion molecules, and oxidative stress in inflammatory reactions and lung injury. A role for lipocortin 1 (annexin 1), a naturally occurring defense factor against inflammation, is discussed because of the possibility that impaired synthesis and degradation of lipocortin 1 will influence immune responses in animals exposed to cigarette smoke either by augmenting T helper cell Th1 response or by shifting Th1 to Th2 response. While Th1 augmentation will increase the risk for development of emphysema, Th1 to Th2 shift will favor development of asthma.
Collapse
Affiliation(s)
- Deepak K Bhalla
- Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, Michigan 48202, USA.
| | | | | | | |
Collapse
|
|
50
|
Effect of infliximab on the levels of TNF-alpha and TGF-beta in the whole blood cultures of irradiated patients. Folia Histochem Cytobiol 2008; 46:291-7. [PMID: 19056532 DOI: 10.2478/v10042-008-0050-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
TGF-beta is supposed to be the major cytokine responsible for post-radiation fibrosis of healthy tissues and actively modifies post-radiation changes. The growth of TGF-beta level induces the expression of collagen synthesis gene which triggers off the production of fibrosis of hyaline membranes. The main purpose of this study was to discover the way and methods of reducing post-radiation damage of normal tissues and provide an adequate scientific justification for using Infliximab as an effective radio protector in the neoplasm radiotherapy. A group of 97 patients were subjected to the experiment. Randomly selected patients were assigned to 3 groups according to the radiation exposure. The samples of whole blood were suspended in RPMI 1640 growth medium standardized according to the number of leukocytes. Two milliliters of whole blood was taken from each patient immediately before irradiation and 100 microl sample of the blood was placed in wells with 0.8 mg/ml of Infliximab or without the preparation. TGF-beta levels in blood culture without cA2 before irradiation showed continuous rise from 3978 to 8950 pg/ml at the 96th h. In the post irradiated group without cA2, a continuous growth was recorded till the 48th h (from 4758 to 13324 pg/ml at the 24th h) and then a slight decline to 11950 pg/ml at 96th h, respectively. In the cultures with cA2, TGF-beta levels before irradiation showed also the peak value at the 48th h (from 4050 to 7340 pg/ml at the 48th h) and then started to go down (6500 pg/ml at the 72nd h and 5720 pg/ml at the 96th h). In the post-irradiated group, during the first 6 hours, there was a growth from 4717 pg/ml to 7462 pg/ml, and then a paradoxical increase to 16885 pg/ml at the 12th h. From the 12th h the values started to decrease to 6895 pg/ml at the 96th h. The obtained results confirmed the hypothesis of decreasing the TGF-beta expression by inactivating TNF-alpha with a monoclonal antibody (Infliximab) in the patients' whole blood culture in vitro. These observations are a good starting point for further experiments in vitro and in vivo, whose main objective is to reduce post radiation fibrosis.
Collapse
|