Am. J. Respir. Crit. Care Med., Volume 163, Number 1, January 2001, 210-217

Contribution of Small GTPase Rho and Its Target Protein ROCK in a Murine Model of Lung Fibrosis

YASUO SHIMIZU, KUNIO DOBASHI, KUNIHIKO IIZUKA, TAKEO HORIE, KOUKI SUZUKI, HIDEO TUKAGOSHI, TUGIO NAKAZAWA, YOICHI NAKAZATO, and MASATOMO MORI

First Department of Internal Medicine, Gunma University Faculty of Medicine, School of Medicine, Gunma University School of Health Sciences, and First Department of Pathology, Gunma University School of Medicine, Gunma, Japan

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 mediated by reorganization of the actin cytoskelton. Activated ROCK inhibits myosin phosphatase, and this in turn induces phosphorylation of the myosin light chain (MLC). To determine the mechanisms underlying the deterioration process of IPF, we investigated the effect of Y-27632, a selective ROCK inhibitor, in a murine model of bleomycin (BLM)-induced lung fibrosis. The Aschcroft score and hydroxyproline content of the BLM-treated mouse lung decreased in response to Y-27632 treatment. The number of broncoalveolar cells was decreased by Y-27632, and migration of macrophages, neutrophils, and fibroblasts in vitro was inhibited by Y-27632 regardless of various stimuli. Although expression of ROCK-II mRNA in the lung homogenates of the BLM-treated mice was increased approximately 9-fold, expression of ROCK-II protein showed only a slight tendency to increase. BLM elevated MLC phosphorylation levels, and Y-27632 inhibited BLM response. These findings indicate that the Rho/ROCK-mediated pathway plays an important role in IPF, and that blocking of this pathway leads to inhibition of IPF development.

This article has been cited by other articles:

				A. Navarro, M. Rezaiekhaligh, J. A. Keightley, S. M. Mabry, R. E. Perez, and I. I. Ekekezie Higher TRIP-1 level explains diminished collagen contraction ability of fetal versus adult fibroblasts Am J Physiol Lung Cell Mol Physiol, June 1, 2009; 296(6): L928 - L935. [Abstract] [Full Text] [PDF]

				M. Utsugi, K. Dobashi, A. Ono, T. Ishizuka, S.-i. Matsuzaki, T. Hisada, Y. Shimizu, T. Kawata, H. Aoki, Y. Kamide, et al. PI3K p110{beta} Positively Regulates Lipopolysaccharide-Induced IL-12 Production in Human Macrophages and Dendritic Cells and JNK1 Plays a Novel Role J. Immunol., May 1, 2009; 182(9): 5225 - 5231. [Abstract] [Full Text] [PDF]

				M. R. Quinlan, N. G. Docherty, R. W. G. Watson, and J. M. Fitzpatrick Exploring mechanisms involved in renal tubular sensing of mechanical stretch following ureteric obstruction Am J Physiol Renal Physiol, July 1, 2008; 295(1): F1 - F11. [Abstract] [Full Text] [PDF]

				D. Schaafsma, I. S. T. Bos, A. B. Zuidhof, J. Zaagsma, and H. Meurs The inhaled Rho kinase inhibitor Y-27632 protects against allergen-induced acute bronchoconstriction, airway hyperresponsiveness, and inflammation Am J Physiol Lung Cell Mol Physiol, July 1, 2008; 295(1): L214 - L219. [Abstract] [Full Text] [PDF]

				Y. Koike, T. Hisada, M. Utsugi, T. Ishizuka, Y. Shimizu, A. Ono, Y. Murata, J. Hamuro, M. Mori, and K. Dobashi Glutathione Redox Regulates Airway Hyperresponsiveness and Airway Inflammation in Mice Am. J. Respir. Cell Mol. Biol., September 1, 2007; 37(3): 322 - 329. [Abstract] [Full Text] [PDF]

				M. Utsugi, K. Dobashi, T. Ishizuka, T. Kawata, T. Hisada, Y. Shimizu, A. Ono, and M. Mori Rac1 Negatively Regulates Lipopolysaccharide-Induced IL-23 p19 Expression in Human Macrophages and Dendritic Cells and NF-{kappa}B p65 trans Activation Plays a Novel Role J. Immunol., October 1, 2006; 177(7): 4550 - 4557. [Abstract] [Full Text] [PDF]

				M. Sawafuji, A. Ishizaka, M. Kohno, H. Koh, S. Tasaka, Y. Ishii, and K. Kobayashi Role of Rho-kinase in reexpansion pulmonary edema in rabbits Am J Physiol Lung Cell Mol Physiol, December 1, 2005; 289(6): L946 - L953. [Abstract] [Full Text] [PDF]

				J. U. Gutterman, H. T. Lai, P. Yang, V. Haridas, A. Gaikwad, and S. Marcus Effects of the tumor inhibitory triterpenoid avicin G on cell integrity, cytokinesis, and protein ubiquitination in fission yeast PNAS, September 6, 2005; 102(36): 12771 - 12776. [Abstract] [Full Text] [PDF]

				H. CEULEMANS and M. BOLLEN Functional Diversity of Protein Phosphatase-1, a Cellular Economizer and Reset Button Physiol Rev, January 1, 2004; 84(1): 1 - 39. [Abstract] [Full Text] [PDF]

				M. Utsugi, K. Dobashi, T. Ishizuka, K. Endou, J. Hamuro, Y. Murata, T. Nakazawa, and M. Mori c-Jun N-Terminal Kinase Negatively Regulates Lipopolysaccharide-Induced IL-12 Production in Human Macrophages: Role of Mitogen-Activated Protein Kinase in Glutathione Redox Regulation of IL-12 Production J. Immunol., July 15, 2003; 171(2): 628 - 635. [Abstract] [Full Text] [PDF]

				P.-L. Tharaux, R. C. Bukoski, P. N. Rocha, S. D. Crowley, P. Ruiz, C. Nataraj, D. N. Howell, K. Kaibuchi, R. F. Spurney, and T. M. Coffman Rho Kinase Promotes Alloimmune Responses by Regulating the Proliferation and Structure of T Cells J. Immunol., July 1, 2003; 171(1): 96 - 105. [Abstract] [Full Text] [PDF]

				K. Suga, Y. Yuan, N. Ogasawara, T. Tsukuda, and N. Matsunaga Altered Clearance of Gadolinium Diethylenetriaminepentaacetic Acid Aerosol from Bleomycin-injured Dog Lungs: Initial Observations Am. J. Respir. Crit. Care Med., June 15, 2003; 167(12): 1704 - 1710. [Abstract] [Full Text] [PDF]

				M. Utsugi, K. Dobashi, T. Ishizuka, K. Masubuchi, Y. Shimizu, T. Nakazawa, and M. Mori C-Jun-NH2-Terminal Kinase Mediates Expression of Connective Tissue Growth Factor Induced by Transforming Growth Factor-{beta}1 in Human Lung Fibroblasts Am. J. Respir. Cell Mol. Biol., June 1, 2003; 28(6): 754 - 761. [Abstract] [Full Text] [PDF]

				J. N. Rao, X. Guo, L. Liu, T. Zou, K. S. Murthy, J. X.-J. Yuan, and J.-Y. Wang Polyamines regulate Rho-kinase and myosin phosphorylation during intestinal epithelial restitution Am J Physiol Cell Physiol, April 1, 2003; 284(4): C848 - C859. [Abstract] [Full Text] [PDF]

				M. J. TOBIN Tuberculosis, Lung Infections, Interstitial Lung Disease, and Socioeconomic Issues in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 631 - 641. [Full Text] [PDF]