title: Proinflammatory chemokines in the intestinal lumen contribute to intestinal dysfunction during endotoxemia.
abstract: Intestinal failure is common in patients with septic shock, with dysfunction of the gut often manifesting as both a cause and consequence of their critical illness. Most studies investigating the pathogenesis of intestinal failure focus on the systemic aspect, although few data examine the inflammatory signaling in the intestinal lumen. Having previously demonstrated apical/luminal chemokine secretion in an in vitro model of intestinal inflammation, we hypothesized that endotoxemia would induce secretion of proinflammatory chemokines into the intestinal lumen. In addition, we examined the contribution of these mediators to intestinal dysmotility. C57/BL6 male mice were injected intraperitoneally with LPS. Serum, intestinal tissue, and intestinal luminal contents were harvested for cytokine analysis. For intestinal motility studies, a transit assay was performed after oral gavage of chemokines. Caco-2 cells grown on Transwell culture inserts were used to examine the role of the intestinal epithelium in chemokine secretion. Monocyte chemoattractant protein 1 (MCP-1/CCL2) and macrophage-derived chemokine (MDC/CCL22) were secreted into the lumen of multiple segments of the gut during endotoxemia in mice. In vitro work showed that the intestinal epithelium participates in monocyte chemoattractant protein 1 and MDC secretion and expresses the CCR2 and CCR4 receptors for these chemokines. Intestinal transit studies show that oral gavage of MDC results in impaired gut motility. This study demonstrates that the intestinal lumen is an active compartment in the gut's inflammatory response. Proinflammatory chemokines are secreted into the intestinal lumen during endotoxemia. These intraluminal chemokines contribute to intestinal dysmotility, complicating intestinal failure.
authors.affiliation: Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
authors.forename: Dennis I
authors.initials: DI
authors.lastname: Sonnier
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Bailey
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Schuster
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Gangidine
authors.forename: Alex B
authors.initials: AB
authors.lastname: Lentsch
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Pritts
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000276:immunology; D054422:Chemokine CCL22 / Q000096:biosynthesis* / Q000276:immunology; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007410:Intestinal Diseases / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D054390:Receptors, CCR2 / Q000096:biosynthesis / Q000276:immunology; D054398:Receptors, CCR4 / Q000096:biosynthesis / Q000276:immunology
chemical_list: C491768:Ccl2 protein, mouse; C515483:Ccl22 protein, mouse; C515335:Ccr2 protein, mouse; C515355:Ccr4 protein, mouse; D018932:Chemokine CCL2; D054422:Chemokine CCL22; D008070:Lipopolysaccharides; D054390:Receptors, CCR2; D054398:Receptors, CCR4; C440499:lipopolysaccharide, Escherichia coli O111 B4
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