TUMOR NECROSIS FACTOR IS NOT ASSOCIATED WITH INTESTINAL ISCHEMIA/REPERFUSION-INDUCED LUNG INFLAMMATION

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.

Fondation de la Recherche Medical (F.R.M, France)

Fondation de la Recherche Medical (F.R.M, France)

PhenoTec AG, Zug, Switzerland

PhenoTec AG, Zug, Switzerland

Immunis SA, Orleans, France

Immunis SA, Orleans, France

Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), Sao Paulo, Brazil

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

FAPESP[02/06606-3]

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

FAPESP[03/02271-0]

FAPESP[04/14128-0]

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

CNPq Conselho Nacional de Pesquisa