rac inhibition reverses the phenotype of fibrotic fibroblastsrac抑制逆转纤维化的成纤维细胞的表型.pdfVIP

Rac Inhibition Reverses the Phenotype of Fibrotic Fibroblasts 1 2 3 4 1 Xu Shi-wen , Shangxi Liu , Mark Eastwood , Sonali Sonnylal , Christopher P. Denton , David J Abraham1., Andrew Leask2.* 1 Centre for Rheumatology, Department of Medicine, University College London (Royal Free Campus), London, United Kingdom, 2 The Canadian Institute of Health Research Group in Skeletal Development and Remodeling, Division of Oral Biology and Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada, 3 School of Biosciences, University of Westminster, London, United Kingdom, 4 University of Texas, M. D. Anderson Cancer Center, Houston, Texas, United States of America Abstract Background: Fibrosis, the excessive deposition of scar tissue by fibroblasts, is one of the largest groups of diseases for which there is no therapy. Fibroblasts from lesional areas of scleroderma patients possess elevated abilities to contract matrix and produce a 2smooth muscle actin (a-SMA), type I collagen and CCN2 (connective tissue growth factor, CTGF). The basis for this phenomenon is poorly understood, and is a necessary prerequisite for developing novel, rational anti-fibrotic strategies. Methods and Findings: Compared to healthy skin fibroblasts, dermal fibroblasts cultured from lesional areas of scleroderma (SSc) patients possess elevated Rac activity. NSC23766, a Rac inhibitor, suppressed the persistent fibrotic phenotype of lesional SSc fibroblasts. NSC23766 caused a decrease in migration on and contraction of matrix, and a 2SMA, type I collagen and CCN2 mRNA and protein expression. SSc fibroblasts possessed elevated Akt phosphorylation, which was