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.

Links

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Publisher Full Text

Authors

Lagares D, Busnadiego O, García-Fernández RA, Kapoor M, Liu S, Carter DE, Abraham D, Shi-Wen X, Carreira P, Fontaine BA, Shea BS, Tager AM, Leask A, Lamas S, Rodríguez-Pascual F

Institution

Centro de Biología Molecular Severo Ochoa, CSIC and Fundación Renal Iñigo Alvarez de Toledo, Madrid, Spain.

Source

Arthritis and rheumatism 64:5 2012 May pg 1653-64

MeSH

Animals
Cell Adhesion
Cells, Cultured
Disease Models, Animal
Endothelin-1
Enzyme Inhibitors
Female
Focal Adhesion Protein-Tyrosine Kinases
Gene Silencing
Humans
Indoles
Lung
Male
Mice
Middle Aged
Myofibroblasts
Pulmonary Fibrosis
RNA, Small Interfering
Sulfonamides
Up-Regulation

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22492165