Impaired TGF-b signalling enhances peritoneal inflammation induced by E. Coli in rats

• Published in: Nephrology, dialysis, transplantation dialysis, transplantation, 2010-02, Vol.25 (2), p.399-412
• Main Authors: Wang, Xin, Nie, Jing, Jia, Zhanjun, Feng, Mingliang, Zheng, Zhihua, Chen, Wenfang, Li, Xiaoyan, Peng, Wenxing, Zhang, Shehong, Sun, Liao, Mao, Haiping, Lan, Hui Yao, Yu, Xueqing
• Format: Article
• Language: English
• Subjects: Animal models; Ascites; Cell activation; Cell culture; Dialysis; Escherichia coli; Fibrosis; Gene transfer; Inflammation; Leukocytes; NF-B protein; Peritoneum; Peritonitis; Signal transduction; Smad2 protein; Smad7 protein; Spontaneous recovery; Transforming growth factor-b; Transforming growth factor-b1; Tumor necrosis factor-a
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfp480

Background. Peritonitis is a common and severe complication of peritoneal dialysis (PD). Although TGF-b is a key mediator in peritoneal fibrosis with chronic PD, its role in acute peritoneal inflammation remains unclear.Methods. Potential role of TGF-b signalling in acute peritonitis was investigated in a rat model by infecting peritoneum with E.coli and in primary culture of peritoneal mesothelial cells (PMC) by LPS.Results. We found that a single infection of E.coli caused an acute, but transient peritonitis by a significant increase in ascites white blood cells (WBC), peritoneal CD45+ leukocytes, upregulation of TNFa, activation of NF-B/p65 and impaired peritoneal function (all P < 0.01). Interestingly, spontaneous recovery of acute peritonitis occurred with upregulation of TGF-b1 and activation of Smad2/3, suggesting a protective role of TGF-b signalling in acute peritonitis. This was demonstrated by the finding that blockade of the TGF-b signalling pathway with gene transfer of Smad7 inactivated peritoneal Smad2/3 but worsened E.coli-induced, NF-B-dependent peritoneal inflammation and peritoneal dysfunction (all P < 0.01). Furthermore, studies in vitro also found that impaired TGF-b signalling by overexpressing Smad7 in PMC were able to overcome the inhibitory effect of TGF-b on LPS-induced, NF-B-mediated peritoneal inflammation.Conclusion. Results from this study demonstrate that TGF-b signalling is essential in protection against acute peritoneal inflammation induced by bacterial infection.