Rho GDP dissociation inhibitor α silencing attenuates silicosis by inhibiting RhoA/Rho kinase signalling

Transforming growth factor-beta 1 (TGF-beta 1) alters the fibroblast phenotype by promoting transdifferentiation into myofibroblasts, which exhibit the ability to promote collagen synthesis and extracellular matrix (ECM) deposition, thereby playing a significant role in the pathology of silicosis. In this study, we investigated the regulatory mechanisms involved in myofibroblast transdifferentiation. Two-dimensional gel electrophoresis showed that Rho GDP-dissociation inhibitor alpha (RhoGDI alpha) was upregulated following myofibroblast transdifferentiation stimulated by TGF-beta 1. We hypothesised that RhoGDIa may induce myofibroblast transdifferentiation and thus result in silicosis. Accordingly, the biological significance of RhoGDIa in cell proliferation and apoptosis was investigated by deletion of RhoGDI alpha in MRC-5 cells. In addition, a mechanistic study showed that fasudil, an inhibitor of the RhoA/Rho kinase (ROCK) signalling pathway, reduced the levels of RhoGDI alpha, RhoA, and phospho-myosin phosphatase (phospho-MYPT) in MRC-5 cells and silicosis model rats. Knockdown of RhoGDIa inhibited myofibroblast transdifferentiation and collagen deposition through RhoGDI alpha/RhoA/ROCK signalling in silicosis model mice. Overall, downregulation of RhoGDIa may significantly promote cell apoptosis and inhibit cell growth, resulting in reversal of myofibroblast transdifferentiation by RhoA/ROCK in vitro and in vivo. These data will facilitate further exploration of the potential use of RhoGDI alpha as a target for silicosis therapy.