Proteomics in idiopathic pulmonary fibrosis: the quest for biomarkers

2021 ◽  
Author(s):  
Tila Khan ◽  
Sanjukta Dasgupta ◽  
Nilanjana Ghosh ◽  
Koel Chaudhury
Keyword(s):  
Animal Models ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Lines ◽  
Proteomics Analysis

This review focuses on proteomics analysis of biofluids derived from IPF patients, animal models of pulmonary fibrosis and cell lines.

scholarly journals Pathologic Proteolytic Processing of N-Cadherin as a Marker of Human Fibrotic Disease

Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 156
Author(s):  
Paul Durham Ferrell ◽  
Kristianne Michelle Oristian ◽  
Everett Cockrell ◽  
Salvatore Vincent Pizzo
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Surface ◽  
Cell Lines ◽  
Cell Adhesion Molecule ◽  
Protein Processing ◽  
Proteolytic Processing ◽  
Fibrotic Disease ◽  
Nonalcoholic Fatty Liver ◽  
Murine Antibody

Prior research has implicated the involvement of cell adhesion molecule N-cadherin in tissue fibrosis and remodeling. We hypothesize that anomalies in N-cadherin protein processing are involved in pathological fibrosis. Diseased tissues associated with fibrosis of the heart, lung, and liver were probed for the precursor form of N-cadherin, pro-N-cadherin (PNC), by immunohistochemistry and compared to healthy tissues. Myofibroblast cell lines were analyzed for cell surface pro-N-cadherin by flow cytometry and immunofluorescent microscopy. Soluble PNC products were immunoprecipitated from patient plasmas and an enzyme-linked immunoassay was developed for quantification. All fibrotic tissues examined show aberrant PNC localization. Cell surface PNC is expressed in myofibroblast cell lines isolated from cardiomyopathy and idiopathic pulmonary fibrosis but not on myofibroblasts isolated from healthy tissues. PNC is elevated in the plasma of patients with cardiomyopathy (p ≤ 0.0001), idiopathic pulmonary fibrosis (p ≤ 0.05), and nonalcoholic fatty liver disease with cirrhosis (p ≤ 0.05). Finally, we have humanized a murine antibody and demonstrate that it significantly inhibits migration of PNC expressing myofibroblasts. Collectively, the aberrant localization of PNC is observed in all fibrotic tissues examined in our study and our data suggest a role for cell surface PNC in the pathogenesis of fibrosis.

scholarly journals The contribution of animal models to understanding the role of the immune system in human idiopathic pulmonary fibrosis

2020 ◽  
Vol 9 (7) ◽  
Author(s):  
Tylah Miles ◽  
Gerard F Hoyne ◽  
Darryl A Knight ◽  
Mark W Fear ◽  
Steven E Mutsaers ◽  
...  
Keyword(s):  
Immune System ◽  
Animal Models ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis

scholarly journals Upregulation of ACE2 and TMPRSS2 by particulate matter and idiopathic pulmonary fibrosis: a potential role in severe COVID-19

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Hsin-Hsien Li ◽  
Chen-Chi Liu ◽  
Tien-Wei Hsu ◽  
Jiun-Han Lin ◽  
Jyuan-Wei Hsu ◽  
...  
Keyword(s):  
Air Pollution ◽  
Particulate Matter ◽  
Animal Models ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Specific Protein ◽  
Lung Fibroblasts ◽  
Alveolar Cells ◽  
Air Pollution Exposure ◽  
Pollution Exposure

Abstract Background Air pollution exposure and idiopathic pulmonary fibrosis (IPF) cause a poor prognosis after SARS-CoV-2 infection, but the underlying mechanisms are not well explored. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the keys to the entry of SARS-CoV-2. We therefore hypothesized that air pollution exposure and IPF may increase the expression of ACE2 and TMPRSS2 in the lung alveolar region. We measured their expression levels in lung tissues of control non-IPF and IPF patients, and used murine animal models to study the deterioration of IPF caused by particulate matter (PM) and the molecular pathways involved in the expression of ACE2 and TMPRSS2. Results In non-IPF patients, cells expressing ACE2 and TMPRSS2 were limited to human alveolar cells. ACE2 and TMPRSS2 were largely upregulated in IPF patients, and were co-expressed by fibroblast specific protein 1 (FSP-1) + lung fibroblasts in human pulmonary fibrotic tissue. In animal models, PM exposure increased the severity of bleomycin-induced pulmonary fibrosis. ACE2 and TMPRSS2 were also expressed in FSP-1+ lung fibroblasts in bleomycin-induced pulmonary fibrosis, and when combined with PM exposure, they were further upregulated. The severity of pulmonary fibrosis and the expression of ACE2 and TMPRSS2 caused by PM exposure were blocked by deletion of KC, a murine homologue of IL-8, or treatment with reparixin, an inhibitor of IL-8 receptors CXCR1/2. Conclusions These data suggested that risk of SARS-CoV-2 infection and COVID-19 disease severity increased by air pollution exposure and underlying IPF. It can be mediated through upregulating ACE2 and TMPRSS2 in pulmonary fibroblasts, and prevented by blocking the IL-8/CXCR1/2 pathway.

scholarly journals The role of tyrosine kinases in the pathogenesis of idiopathic pulmonary fibrosis

2015 ◽  
Vol 45 (5) ◽  
pp. 1426-1433 ◽  
Author(s):  
Friedrich Grimminger ◽  
Andreas Günther ◽  
Carlo Vancheri
Keyword(s):  
Growth Factor ◽  
Animal Models ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Phase Iii

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a median survival time from diagnosis of 2–3 years. Although the pathogenic pathways have not been fully elucidated, IPF is believed to be caused by persistent epithelial injury in genetically susceptible individuals. Tyrosine kinases are involved in a range of signalling pathways that are essential for cellular homeostasis. However, there is substantial evidence from in vitro studies and animal models that receptor tyrosine kinases, such as the platelet-derived growth factor receptor, vascular endothelial growth factor receptor and fibroblast growth factor receptor, and non-receptor tyrosine kinases, such as the Src family, play critical roles in the pathogenesis of pulmonary fibrosis. For example, the expression and release of tyrosine kinases are altered in patients with IPF, while specific tyrosine kinases stimulate the proliferation of lung fibroblasts in vitro. Agents that inhibit tyrosine kinases have shown anti-fibrotic and anti-inflammatory effects in animal models of pulmonary fibrosis. Recently, the tyrosine kinase inhibitor nintedanib has shown positive results in two phase III trials in patients with IPF. Here, we summarise the evidence for involvement of specific tyrosine kinases in the pathogenesis of IPF and the development of tyrosine kinase inhibitors as treatments for IPF.

scholarly journals Upregulation of ACE2 and TMPRSS2 by particulate matter and idiopathic pulmonary fibrosis: A potential role in severe COVID-19

2020 ◽  
Author(s):  
Hsin-Hsien Li ◽  
Chen-Chi Liu ◽  
Tien-Wei Hsu ◽  
Jiun-Han Lin ◽  
Jyuan-Wei Hsu ◽  
...  
Keyword(s):  
Air Pollution ◽  
Particulate Matter ◽  
Animal Models ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Poor Prognosis ◽  
Specific Protein ◽  
Lung Fibroblasts ◽  
Alveolar Cells ◽  
Transmembrane Serine Protease

Abstract Background: Air pollution and idiopathic pulmonary fibrosis (IPF) cause a poor prognosis after COVID-19 infection, but the underlying mechanisms are not well exploited. Angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) are the keys to the entry of SARS-CoV-2. We measured their expression levels in lung tissues of control non-IPF and IPF patients, and used murine animal models to study the deterioration of IPF caused by particulate matter (PM) and the molecular pathways involved in the expression of ACE2 and TMPRSS2.Results: In non-IPF patients, cells expressing ACE2 and TMPRSS2 were limited to human alveolar cells. ACE2 and TMPRSS2 were largely upregulated in IPF patients, and were co-expressed by fibroblast specific protein 1 (FSP-1)+ lung fibroblasts in human pulmonary fibrotic tissue. In animal models, PM exposure increased the severity of bleomycin-induced pulmonary fibrosis. ACE2 and TMPRSS2 were also expressed in FSP-1+ lung fibroblasts in bleomycin-inuced pulmonary fibrosis, and when combined with PM exposure, they were further upregulated. The severity of pulmonary fibrosis and the expression of ACE2 and TMPRSS2 caused by PM exposure were blocked by deletion of KC, a murine homologue of IL‐8, or treatment with reparixin, an inhibitor of IL‐8 receptors CXCR1/2.Conclusions: These data suggest that poor prognosis after COVID-19 infection caused by air pollution and IPF is mediated through upregulation of ACE2 and TMPRSS2 in pulmonary fibroblasts, which can be prevented by blocking the IL-8/CXCR1/2 pathway.

scholarly journals Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis

2017 ◽  
Vol 4 ◽  
Author(s):  
Jun Tashiro ◽  
Gustavo A. Rubio ◽  
Andrew H. Limper ◽  
Kurt Williams ◽  
Sharon J. Elliot ◽  
...  
Keyword(s):  
Animal Models ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis

scholarly journals Proteomic Analysis Reveals Key Proteins in Extracellular Vesicles Cargo Associated with Idiopathic Pulmonary Fibrosis In Vitro

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 1058
Author(s):  
Juan Manuel Velázquez-Enríquez ◽  
Jovito Cesar Santos-Álvarez ◽  
Alma Aurora Ramírez-Hernández ◽  
Edilburga Reyes-Jiménez ◽  
Armando López-Martínez ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Cell Lines ◽  
Extracellular Vesicles ◽  
Proteomic Analysis ◽  
Fibroblast Cell ◽  
Differentially Expressed ◽  
Differentially Expressed Proteins ◽  
Collagen Chain ◽  
Fibroblast Cell Lines

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, and highly fatal disease. It is characterized by the increased activation of both fibroblast and myofibroblast that results in excessive extracellular matrix (ECM) deposition. Extracellular vesicles (EVs) have been described as key mediators of intercellular communication in various pathologies. However, the role of EVs in the development of IPF remains poorly understood. This study aimed to characterize the differentially expressed proteins contained within EVs cargo derived from the fibroblast cell lines LL97A (IPF-1) and LL29 (IPF-2) isolated from lungs bearing IPF as compared to those derived from the fibroblast cell lines CCD8Lu (NL-1) and CCD19Lu (NL-2) isolated from healthy donors. Isolated EVs were subjected to label-free quantitative proteomic analysis by LC-MS/MS, and as a result, 331 proteins were identified. Differentially expressed proteins were obtained after the pairwise comparison, including all experimental groups. A total of 86 differentially expressed proteins were identified in either one or more comparison groups. Of note, proteins involved in fibrogenic processes, such as tenascin-c (TNC), insulin-like-growth-factor-binding protein 7 (IGFBP7), fibrillin-1 (FBN1), alpha-2 collagen chain (I) (COL1A2), alpha-1 collagen chain (I) (COL1A1), and lysyl oxidase homolog 1 (LOXL1), were identified in EVs cargo isolated from IPF cell lines. Additionally, KEGG pathway enrichment analysis revealed that differentially expressed proteins participate in focal adhesion, PI3K-Akt, and ECM–receptor interaction signaling pathways. In conclusion, our findings reveal that proteins contained within EVs cargo might play key roles during IPF pathogenesis.

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