NLRP3 Inflammasome Activates Endothelial-to-Mesenchymal Transition via Focal Adhesion Kinase Pathway in Bleomycin-Induced Pulmonary Fibrosis

Author:

Chen Wei-Chih123ORCID,Yu Wen-Kuang234,Su Vincent Yi-Fong25,Hsu Han-Shui126,Yang Kuang-Yao1237ORCID

Affiliation:

1. Institute of Emergency and Critical Care Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan

2. School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan

3. Department of Chest Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan

4. Institute of Physiology, College of Medicine, National Yang-Ming University, Taipei 112, Taiwan

5. Department of Internal Medicine, Taipei City Hospital, Taipei 110, Taiwan

6. Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112, Taiwan

7. Cancer Progression Research Center, National Yang-Ming University, Taipei 112, Taiwan

Abstract

Idiopathic pulmonary fibrosis has poor clinical outcomes despite antifibrotic treatment. The nucleotide-binding domain leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3) inflammasome and endothelial-to-mesenchymal transition (EndoMT) were shown to be involved in the pathogenesis of pulmonary fibrosis. However, the detailed mechanism is unknown. Our study aimed to investigate the role of the NLRP3 inflammasome in the regulation of EndoMT in pulmonary fibrosis. The inhibition of the NLRP3 inflammasome via a caspase-1 inhibitor, Ac-YVAD-cmk (YVAD), was intraperitoneally administered to male C57BL/6 mice (8–12 weeks old) one hour before bleomycin intratracheal injection (1.5 U/kg). Immunohistochemical staining, Masson’s trichrome staining, enzyme-linked immunosorbent assay, immunofluorescence, and Western blotting were used to assess the activity of the NLRP3 inflammasome and EndoMT in lung samples from mice. Human pulmonary microvascular endothelial cells (HPMECs) were used as a model of EndoMT in vitro with YVAD and bleomycin stimulation. We observed the activation of the NLRP3 inflammasome and EndoMT (decreased vascular endothelial cadherin with increased alpha-smooth muscle actin and vimentin) in the lung samples after bleomycin. However, inhibition of the NLRP3 inflammasome significantly reduces EndoMT via inhibiting focal adhesion kinase (FAK). In vitro studies also confirmed these findings. In conclusion, NLRP3 inflammasome inhibition could reduce lung inflammation and fibrosis via the regulation of EndoMT by the FAK pathway.

Funder

National Science and Technology Council

Taipei Veterans General Hospital

Yin Shu-Tien Foundation Taipei Veterans General Hospital-National Yang-Ming University Excellent Physician Scientists Cultivation Program

Ministry of Education, Higher Education SPROUT Project for Cancer Progression Research Center

Cancer and Immunology Research Center

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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