Inhibition of focal adhesion kinase prevents experimental lung fibrosis and myofibroblast formation.

Abstract

OBJECTIVE:

Enhanced adhesive signaling, including activation of focal adhesion kinase (FAK), is a hallmark of fibroblasts from lung fibrosis patients, and FAK has therefore been hypothesized to be a key mediator of this disease. This study was undertaken to characterize the contribution of FAK to the development of pulmonary fibrosis both in vivo and in vitro.

METHODS:

FAK expression and activity were analyzed in lung tissue samples from lung fibrosis patients by immunohistochemistry. Mice orally treated with the FAK inhibitor PF-562,271, or with small interfering RNA (siRNA)-mediated silencing of FAK were exposed to intratracheally instilled bleomycin to induce lung fibrosis, and lungs were harvested for histologic and biochemical analysis. Using endothelin 1 (ET-1) as a stimulus, cell adhesion and contraction, as well as profibrotic gene expression, were studied in fibroblasts isolated from wild-type and FAK-deficient mouse embryos. ET-1-mediated FAK activation and gene expression were studied in primary mouse lung fibroblasts, as well as in wild-type and β1 integrin-deficient mouse fibroblasts.

RESULTS:

FAK expression and activity were up-regulated in fibroblast foci and remodeled vessels from lung fibrosis patients. Pharmacologic or siRNA-mediated targeting of FAK resulted in marked abrogation of bleomycin-induced lung fibrosis in mice. Loss of FAK impaired the acquisition of a profibrotic phenotype in response to ET-1. Profibrotic gene expression leading to myofibroblast differentiation required cell adhesion, and was driven by JNK activation through β1 integrin/FAK signaling.

CONCLUSION:

These results implicate FAK as a central mediator of fibrogenesis, and highlight this kinase as a potential therapeutic target in fibrotic diseases.

• Authors: David Lagares, Oscar Busnadiego, Rosa Ana García-Fernández, Mohit Kapoor, Shangxi Liu, David E Carter, David Abraham, Xu Shi-Wen, Patricia Carreira, Benjamin A Fontaine, Barry S Shea, Andrew M Tager, Andrew Leask, Santiago Lamas, Fernando Rodríguez-Pascual
• Journal: Arthritis and rheumatism (Arthritis Rheum) Vol. 64 Issue 5 Pg. 1653-64 (May 2012) ISSN: 1529-0131 [Electronic] United States
• PMID: 22492165 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 by the American College of Rheumatology.

Chemical References

• Endothelin-1
• Enzyme Inhibitors
• Indoles
• N-methyl-N-(3-((2-(2-oxo-2,3-dihydro-1H-indol-5-ylamino)-5-trifluoromethyl-pyrimidin-4-ylamino)-methyl)-pyridin-2-yl)-methanesulfonamide
• RNA, Small Interfering
• Sulfonamides
• Focal Adhesion Protein-Tyrosine Kinases

Topics

• Animals
• Cell Adhesion (drug effects)
• Cells, Cultured
• Disease Models, Animal
• Endothelin-1 (pharmacology)
• Enzyme Inhibitors (pharmacology)
• Female
• Focal Adhesion Protein-Tyrosine Kinases (antagonists & inhibitors, genetics, metabolism)
• Gene Silencing
• Humans
• Indoles (pharmacology)
• Lung (drug effects, enzymology, pathology)
• Male
• Mice
• Middle Aged
• Myofibroblasts (drug effects, metabolism, pathology)
• Pulmonary Fibrosis (enzymology, pathology, prevention & control)
• RNA, Small Interfering (genetics)
• Sulfonamides (pharmacology)
• Up-Regulation (drug effects)