Toll-like receptor 4 mediates lung ischemia-reperfusion injury

Background. We have previously reported that nuclear factor (NF)-kappa B activation and inflammatory cytokine expression were involved in the development of lung ischemia-reperfusion injury (LIRI). Because Toll-like receptor 4 (TLR4) activates NF-kappa B-dependent transcription of inflammatory cytokine genes during myocardial ischemia-reperfusion injury, we examined whether absence of TLR4 in TLR4-deficient mice protects against LIRI. Methods. Left lungs of wild-type (C57BL/6J) mice or TLR4-null (TLR4(-/-)) mice were made ischemic for 60 minutes and then reperfused for 180 minutes. Response to injury was quantified by tissue myeloperoxidase activity, vascular permeability ([I-125]-bovine serum albumin extravasation), and leukocyte and inflammatory mediator accumulation in bronchoalveolar lavage expression. Lung homogenates were also analyzed for activation of mitogen-activated protein kinases and nuclear translocation of the transcription factors NF-kappa B and activator protein-1. Results. After LIRI, lungs from TLR4(-/-) mice demonstrated a 52.4% reduction in vascular permeability (p = 0.001), a 52.6% reduction in lung myeloperoxidase activity (p = 0.006), and a marked reduction in bronchoalveolar lavage leukocyte accumulation when compared with lungs from wild-type mice. The TLR4(-/-) mice lungs, subjected to LIRI, also demonstrated marked reductions in amounts of several proinflammatory cytokines/chemokines in bronchoalveolar lavage samples. Phosporylation of c-Jun NH2-terminal kinase, and activation of NF-kappa B and activator protein-1 were also significantly reduced in homogenates of lungs from TLR4(-/-) mice injured by ischemia and reperfusion (p < 0.05). Conclusions. These data suggest that TLR4 plays a role in LIRI. Thus, TLR4 may be a potential therapeutic target to minimize ischemic-reperfusion-induced tissue damage and organ dysfunction.