Exploring Animal Models That Resemble Idiopathic Pulmonary Fibrosis

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.

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

European Respiratory Journal ◽

10.1183/09031936.00149614 ◽

2015 ◽

Vol 45 (5) ◽

pp. 1426-1433 ◽

Cited By ~ 56

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.

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

10.21203/rs.3.rs-112349/v1 ◽

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.

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