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Endotoxin-induced endothelial fibrosis is dependent on expression of transforming growth factors beta1 and beta2 #MMPMID24935972
Echeverria C; Montorfano I; Tapia P; Riedel C; Cabello-Verrugio C; Simon F
Infect Immun 2014[Sep]; 82 (9): 3678-86 PMID24935972show ga
During endotoxemia-induced inflammatory disease, bacterial endotoxins circulate in the bloodstream and interact with endothelial cells (ECs), inducing dysfunction of the ECs. We previously reported that endotoxins induce the conversion of ECs into activated fibroblasts. Through endotoxin-induced endothelial fibrosis, ECs change their morphology and their protein expression pattern, thereby suppressing endothelial markers and upregulating fibrotic proteins. The most commonly used fibrotic inducers are transforming growth factor beta1 (TGF-beta1) and TGF-beta2. However, whether TGF-beta1 and TGF-beta2 participate in endotoxin-induced endothelial fibrosis remains unknown. We have shown that the endotoxin-induced endothelial fibrosis process is dependent on the TGF-beta receptor, ALK5, and the activation of Smad3, a protein that is activated by ALK5 activation, thus suggesting that endotoxin elicits TGF-beta production to mediate endotoxin-induced endothelial fibrosis. Therefore, we investigated the dependence of endotoxin-induced endothelial fibrosis on the expression of TGF-beta1 and TGF-beta2. Endotoxin-treated ECs induced the expression and secretion of TGF-beta1 and TGF-beta2. TGF-beta1 and TGF-beta2 downregulation inhibited the endotoxin-induced changes in the endothelial marker VE-cadherin and in the fibrotic proteins alpha-SMA and fibronectin. Thus, endotoxin induces the production of TGF-beta1 and TGF-beta2 as a mechanism to promote endotoxin-induced endothelial fibrosis. To the best of our knowledge, this is the first report showing that endotoxin induces endothelial fibrosis via TGF-beta secretion, which represents an emerging source of vascular dysfunction. These findings contribute to understanding the molecular mechanism of endotoxin-induced endothelial fibrosis, which could be useful in the treatment of inflammatory diseases.
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Infect+Immun 2014 ; 82 (9): 3678-86
