دانلود رایگان مقاله GYY4137 ameliorates آسیب مانع روده ای در مدل موش اندوتوکسمیا

abstract

Intestinal barrier injury has been reported to play a vital role in the pathogenesis of endotoxemia. This study aimed to investigate the protective effect of GYY4137, a newly synthesized H2S donor, on the intestinal barrier function in the context of endotoxemia both in vitro and in vivo. Caco-2 (a widely used human colon cancer cell line in the study of intestinal epithelial barrier function) monolayers incubated with lipopolysaccharide (LPS) or TNF-a/IFN-c and a mouse model of endotoxemia were used in this study. The results suggested that GYY4137 significantly attenuated LPS or TNF-a/IFN-c induced increased Caco-2 monolayer permeability. The decreased expression of TJ (tight junction) proteins induced by LPS and the altered localization of TJs induced by TNF-a/IFN-c was significantly inhibited by GYY4137; similar results were obtained in vivo. Besides, GYY4137 promoted the clinical score and histological score of mice with endotoxemia. Increased level of TNF-a/IFN-c in the plasma and increased apoptosis in colon epithelial cells was also attenuated by GYY4137 in mice with endotoxemia. This study indicates that GYY4137 preserves the intestinal barrier function in the context of endotoxemia via multipathways and throws light on the development of potential therapeutic approaches for endotoxemia.

4. Discussion

The intact function of intestinal barrier is mainly determined by TJs, which function as a physical barrier between the lumen and the internal milieu. The ‘‘leaky gut”, resulting from the decreased intestinal barrier function, played a pivotal role in the pathogenesis of multiple kinds of diseases including endotoxemia by allowing increased flux of noxious antigens into the internal milieu, leading to unremitting inflammatory responses. The increased level of LPS in the plasma, commonly seen in the context of endotoxemia, has been reported to induce intestinal barrier injury through multiple mechanisms, including decreasing expression of TJ proteins and altering localization of TJs via NF-kB signaling. Upon activation, NF-kB p65 binds to the MLCK promoter region and increases the expression of MLCK mRNA [31,32]. The increased phosphorylation of MLC2 mediated by MLCK leads to contraction of actin-myosin filaments, resulting in altered localization of TJ proteins and consequently, the functional opening of TJs [33,34]. These studies imply the existence of a vicious cycle in the intestinal epithelium consisting of the inflammatory response and the injured intestinal barrier function in the context of endotoxemia. Thus, it remains a promising method for seeking potential therapeutic reagents for endotoxemia by verifying novel regents that may have protective effect on the intestinal barrier function.