Abstract
Peritoneal dialysis (PD) is complicated by peritonitis episodes that cause loss of mesothelium and eventually sclerosing peritonitis. An improved understanding of the molecular contributors to peritoneal injury and defense may increase the therapeutic armamentarium to optimize peritoneal defenses while minimizing peritoneal injury. There is no information on the expression and function of the cytokine TWEAK and its receptor Fn14 during peritoneal injury. Fn14 expression and soluble TWEAK levels were measured in human PD peritoneal effluent cells or fluids with or without peritonitis. Fn14 expression was also analyzed in peritoneal biopsies from PD patients. Actions of intraperitoneal TWEAK were studied in mice in vivo. sTWEAK levels were increased in peritoneal effluent in PD peritonitis. Effluent sTWEAK levels correlated with the number of peritoneal macrophages (r = 0.491, p = 0.002). Potential TWEAK targets that express the receptor Fn14 include mesothelial cells and macrophages, as demonstrated by flow cytometry of peritoneal effluents and by analysis of peritoneal biopsies. Peritoneal biopsy Fn14 correlated with mesothelial injury, fibrosis and inflammation, suggesting a potential deleterious effect of TWEAK/Fn14. In this regard, intraperitoneal TWEAK administration to mice promoted peritoneal inflammation characterized by increased peritoneal effluent MCP-1, Fn14 and Gr1+ macrophages, increased mesothelial Fn14, MCP-1 and CCL21 expression and submesothelial tissue macrophage recruitment. Taken together these data suggest that the TWEAK/Fn14 system may promote inflammation and tissue injury during peritonitis and PD.
Highlights
IntroductionPeritonitis is a potentially devastating disease occurring in the context of abdominal visceral injury, cirrhosis, peritoneal dialysis (PD) and others
We report that sTWEAK levels are Peritonitis is a potentially devastating disease occurring in the context of abdominal visceral injury, cirrhosis, peritoneal dialysis (PD) and others
Results sTWEAK concentrations are increased in peritoneal effluent from PD peritonitis sTWEAK levels were measured in peritoneal effluents from PD
Summary
Peritonitis is a potentially devastating disease occurring in the context of abdominal visceral injury, cirrhosis, peritoneal dialysis (PD) and others. PD is a renal replacement therapy modality that is marred by episodes of bacterial infection, leading to localized inflammation evidenced as peritonitis [1]. PD represents an interesting human model of inflammation since the technique allows repeated non-invasive access to the peritoneal cavity, allowing both monitoring of the inflammatory process as well as therapy by local delivery of drugs [4]. Peritoneal inflammation is characterized by local upregulation of several cytokines, macrophage recruitment, and collagen synthesis by mesothelial cells and fibroblasts leading to loss of peritoneal membrane integrity and fibrosis. Both acute and chronic peritoneal inflammation may lead to PD technique failure [5]
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