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

Background. Peritonitis is a common and severe complication of peritoneal dialysis (PD). Although TGF-β is a key mediator in peritoneal fibrosis with chronic PD, its role in acute peritoneal inflammation remains unclear. Methods. Potential role of TGF-β 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 TNFα, activation of NF- K B/p65 and impaired peritoneal function (all P < 0.01). Interestingly, spontaneous recovery of acute peritonitis occurred with up-regulation of TGF-β1 and activation of Smad2/3, suggesting a protective role of TGF-β signalling in acute peritonitis. This was demonstrated by the finding that blockade of the TGF-β signalling pathway with gene transfer of Smad7 inactivated peritoneal Smad2/3 but worsened E. coli-induced, NF-κB-dependent peritoneal inflammation and peritoneal dysfunction (all P < 0.01). Furthermore, studies in vitro also found that impaired TGF-β signalling by overexpressing Smad7 in PMC were able to overcome the inhibitory effect of TGF-β on LPS-induced, NF-κB-mediated peritoneal inflammation. Conclusion. Results from this study demonstrate that TGF-β signalling is essential in protection against acute peritoneal inflammation induced by bacterial infection.