Contribution of small GTPase Rho and its target protein ROCK in a murine model of lung fibrosis

Citation
Y. Shimizu et al., Contribution of small GTPase Rho and its target protein ROCK in a murine model of lung fibrosis, AM J R CRIT, 163(1), 2001, pp. 210-217
Citations number
30
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cardiovascular & Respiratory Systems","da verificare
Journal title
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
ISSN journal
1073-449X → ACNP
Volume
163
Issue
1
Year of publication
2001
Pages
210 - 217
Database
ISI
SICI code
1073-449X(200101)163:1<210:COSGRA>2.0.ZU;2-X
Abstract
Excess fibroblasts and inflammatory cells may play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The small GTPase, Rho , and its target protein, Rho-associated coiled-coil-forming protein kinase (ROCK), have been recognized to be major regulators of cell locomotion med iated by reorganization of the actin cytoskelton. Activated ROCK inhibits m yosin phosphatase, and this in turn induces phosphorylation of the myosin l ight chain (MLC). To determine the mechanisms underlying the deterioration process of IPF, we investigated the effect of Y-27632, a selective ROCK inh ibitor, in a murine model of bleomycin (BLM)-induced lung fibrosis. The Asc hcroft score and hydroxyproline content of the BLM-treated mouse lung decre ased in response to Y-27632 treatment. The number of broncoalveolar cells w as decreased by Y-27632, and migration of macrophages, neutrophils, and fib roblasts in vitro was inhibited by Y-27632 regardless of various stimuli. A lthough expression of ROCK-II mRNA in the lung homogenates of the BLM-treat ed mice was increased approximately 9-fold, expression of ROCK-II protein s howed only a slight tendency to increase. BLM elevated MLC phosphorylation levels, and Y-27632 inhibited BLM response. These findings indicate that th e Rho/ROCK-mediated pathway plays an important role in IPF, and that blocki ng of this pathway leads to inhibition of IPF development.