Targeting Src attenuates peritoneal fibrosis and inhibits the epithelial to mesenchymal transition

Abstract

Src has been reported to mediate tissue fibrosis in several organs, but its role in peritoneal fibrosis remains unknown. In this study, we evaluated the therapeutic effect of KX2-391, a highly selective inhibitor of Src, on the development of peritoneal fibrosis in a rat model. Daily intraperitoneal injections of chlorhexidine gluconate induced peritoneal fibrosis, as indicated by thickening of the submesothelial area with an accumulation of collagen fibrils and activation of myofibroblasts. This was accompanied by time-dependent phosphorylation of Src at tyrosine 416. Administration of KX2-391 attenuated peritoneal fibrosis and abrogated increased phosphorylation of Src and multiple signaling molecules associated with tissue fibrosis, including epidermal growth factor receptor, Akt, Signal transducer and activator of transcription 3 and nuclear factor-κB in the injured peritoneum. KX2-391 also inhibited the production of proinflammatory cytokines and the infiltration of macrophages into the injured peritoneum. In cultured human peritoneal mesothelial cells, inhibition of Src by KX2-391 or siRNA resulted in decreased expression of α-smooth muscle actin (α-SMA), fibronectin and collagen I, the hallmarks of epithelial to mesenchymal transition. These results suggest that Src is a critical mediator of peritoneal fibrosis and the epithelial to mesenchymal transition. Thus, Src could be a potential therapeutic target in the treatment of peritoneal fibrosis.

Nintedanib inhibits the development and progression of peritoneal fibrosis

“…In the present study, we found that nintedanib was effective in reducing the number of CD31-positive cells and increased thickened peritoneum area in CG-injured mice. In addition to VEGF, inhibition of Src also reduced CD31 expression and CD31-positive cells population induced by CG injury as shown in our previous study [28]. These suggest that nintedanib may inhibit peritoneal angiogenesis through at least targeting VEGF receptor and Src.…”

Direct and Indirect Roles of Macrophages in Hypertrophic Scar Formation

“…Moreover, myofibroblasts are characterized by contractility and distorting structural organs, which are due to the expression of alpha-smooth muscle actin (α-SMA) (Rao et al, 2014). Other studies have also confirmed that M2 macrophages predominantly undergo macrophage-myofibroblast transition in chronic renal allograft injury (Wang et al, 2017). The majority of macrophage-to-myofibroblast transition cells were a major source of collagen-producing fibroblasts in the fibrosing kidney, accounting for more than 60% of α-SMA cells originating from macrophages (Wang et al, 2016).…”

Airway Basal Cells show a dedifferentiated KRT17highPhenotype and promote Fibrosis in Idiopathic Pulmonary Fibrosis

“…SRC signaling is closely linked to epithelial injury [55][56][57][58][59][60][61][62] induced by various noxious agents including cigarette smoking 63 . A role for SRC has been proposed in fibrosis in multiple organs but most of this work focused on the role of SRC in fibroblasts [64][65][66][67][68][69] . We found abundant SRC expression in ABCs covering the fibroblast foci in IPF lungs.…”