title: Local and remote tissue injury upon intestinal ischemia and reperfusion depends on the TLR/MyD88 signaling pathway.
abstract: Innate immune responses against microorganisms may be mediated by Toll-like receptors (TLRs). Intestinal ischemia-reperfusion (i-I/R) leads to the translocation of bacteria and/or bacterial products such as endotoxin, which activate TLRs leading to acute intestinal and lung injury and inflammation observed upon gut trauma. Here, we investigated the role of TLR activation by using mice deficient for the common TLR adaptor protein myeloid differentiation factor 88 (MyD88) on local and remote inflammation following intestinal ischemia. Balb/c and MyD88(-/-) mice were subjected to occlusion of the superior mesenteric artery (45 min) followed by intestinal reperfusion (4 h). Acute neutrophil recruitment into the intestinal wall and the lung was significantly diminished in MyD88(-/-) after i-I/R, which was confirmed microscopically. Diminished neutrophil recruitment was accompanied with reduced concentration of TNF-alpha and IL-1beta level. Furthermore, diminished microvascular leak and bacteremia were associated with enhanced survival of MyD88(-/-) mice. However, neither TNF-alpha nor IL-1beta neutralization prevented neutrophil recruitment into the lung but attenuated intestinal inflammation upon i-I/R. In conclusion, our data demonstrate that disruption of the TLR/MyD88 pathway in mice attenuates acute intestinal and lung injury, inflammation, and endothelial damage allowing enhanced survival.
authors: Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors: Tatiana
authors: T
authors: Victoni
authors: Fernando Rodrigues
authors: FR
authors: Coelho
authors: Alexandre Learth
authors: AL
authors: Soares
authors: Andressa
authors: A
authors: de Freitas
authors: Thomas
authors: T
authors: Secher
authors: Rodrigo
authors: R
authors: Guabiraba
authors: François
authors: F
authors: Erard
authors: Ricardo Martins
authors: RM
authors: de Oliveira-Filho
authors: B Boris
authors: BB
authors: Vargaftig
authors: Gregoire
authors: G
authors: Lauvaux
authors: Mamdouh A
authors: MA
authors: Kamal
authors: Bernhard
authors: B
authors: Ryffel
authors: René
authors: R
authors: Moser
authors: Wothan
authors: W
authors: Tavares-de-Lima
mesh_terms: D000818:Animals; D016470:Bacteremia; D001419:Bacteria / Q000276:immunology; D001427:Bacterial Toxins / Q000276:immunology; D002199:Capillary Permeability; D006651:Histocytochemistry; D053583:Interleukin-1beta / Q000032:analysis; D007410:Intestinal Diseases / Q000150:complications* / Q000473:pathology*; D007422:Intestines / Q000473:pathology; D007511:Ischemia / Q000150:complications* / Q000473:pathology; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008853:Microscopy; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D015427:Reperfusion Injury / Q000150:complications* / Q000473:pathology; D016019:Survival Analysis; D051193:Toll-Like Receptors / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D001427:Bacterial Toxins; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha