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
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.