Contribution of Toll-Like Receptor Activation to Lung Damage After Donor Brain Death

Abstract

Donor brain death is the first injurious event that can produce inflammatory dysfunction after pulmonary transplantation. This study was designed to determine whether stimulation of the toll-like receptor (TLR) system contributes to the changes produced by brain death. Rats were repeatedly treated with specific agonists for TLR4 or TLR2/6 to desensitize these receptors. Brain death was then induced by inflation of a balloon catheter within the extradural space. Mean arterial pressure changes and inflammatory markers were measured serially by protein and mRNA analysis. Both desensitizing pretreatments prevented the neurogenic hypotension (P<0.001) and metabolic acidosis (P<0.001) observed in control animals after brain death. These treatments also reduced the levels of tumor necrosis factor-α and CXCL1 in serum and bronchoalveolar lavage fluid, although desensitization of TLR4 produced a greater inhibition than desensitization of TLR2. Desensitization of TLR4 also reduced (P<0.05) expression of the adhesive integrin CD11b on blood neutrophils after brain death. Examination of mRNA levels in lung tissue 5 hr after brain death showed that desensitization of TLR4 limited the expression of interferon (IFN)-γ, IFNβ, and CXCL10, whereas desensitization of TLR2/6 reduced only the expression of IFNγ. These results indicate that activation of TLR signaling pathways can contribute to the lung damage produced by brain death; this may increase subsequent graft injury after transplantation.