title: Tumor necrosis factor is not associated with intestinal ischemia/reperfusion-induced lung inflammation.
abstract: Intestinal ischemia-reperfusion (I/R) injury may cause acute systemic and lung inflammation. Here, we revisited the role of TNF-alpha in an intestinal I/R model in mice, showing that this cytokine is not required for the local and remote inflammatory response upon intestinal I/R injury using neutralizing TNF-alpha antibodies and TNF ligand-deficient mice. We demonstrate increased neutrophil recruitment in the lung as assessed by myeloperoxidase activity and augmented IL-6, granulocyte colony-stimulating factor, and KC levels, whereas TNF-alpha levels in serum were not increased and only minimally elevated in intestine and lung upon intestinal I/R injury. Importantly, TNF-alpha antibody neutralization neither diminished neutrophil recruitment nor any of the cytokines and chemokines evaluated. In addition, the inflammatory response was not abrogated in TNF and TNF receptors 1 and 2-deficient mice. However, in view of the damage on the intestinal barrier upon intestinal I/R with systemic bacterial translocation, we asked whether Toll-like receptor (TLR) activation is driving the inflammatory response. In fact, the inflammatory lung response is dramatically reduced in TLR2/4-deficient mice, confirming an important role of TLR receptor signaling causing the inflammatory lung response. In conclusion, endogenous TNF-alpha is not or minimally elevated and plays no role as a mediator for the inflammatory response upon ischemic tissue injury. By contrast, TLR2/4 signaling induces an orchestrated cytokine/chemokine response leading to local and remote pulmonary inflammation, and therefore disruption of TLR signaling may represent an alternative therapeutic target.
authors.affiliation: Department of Pharmacology, University of São Paulo, São Paulo, Brazil.
authors.forename: Alexandre Learth
authors.initials: AL
authors.lastname: Soares
authors.forename: Fernando Rodrigues
authors.initials: FR
authors.lastname: Coelho
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Guabiraba
authors.forename: Mamdouh
authors.initials: M
authors.lastname: Kamal
authors.forename: B Boris
authors.initials: BB
authors.lastname: Vargaftig
authors.forename: Lily
authors.initials: L
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.forename: Wothan
authors.initials: W
authors.lastname: Tavares-de-Lima
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000097:blood; D007422:Intestines / Q000098:blood supply* / Q000201:enzymology; D008168:Lung / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology; D009195:Peroxidase / Q000032:analysis; D011014:Pneumonia / Q000209:etiology / Q000503:physiopathology*; D015427:Reperfusion Injury / Q000150:complications* / Q000503:physiopathology; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000503:physiopathology*; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*
chemical_list: D000911:Antibodies, Monoclonal; D016207:Cytokines; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase