Inflammatory lung injury is one of the main complications associated with cardiopulmonary bypass (CPB). Tumor necrosis factor-a (TNF-alpha) is one of the key factors mediating the CPB-induced inflammatory reactions. Our previous studies have shown that endotracheal administration of anti-tumor necrosis factor-alpha antibody (TNF-alpha Ab) produces some beneficial effects on lung in a rabbit CPB model. In this study, we further examined the effects of pulmonary artery perfusion with TNF-alpha Ab (27 ng/ kg) on lung tissue integrity and pulmonary inflammation during CPB and investigated the mechanism underlying the TNF-alpha Ab-mediated effects in a rabbit model of CPB. Our results from transmission electron microscopy showed that the perfusion with TNF-alpha Ab alleviated CPB-induced histopathological changes in lung tissue. The perfusion with TNF-alpha Ab also prevented CPB-induced pulmonary edema and improved oxygenation index. Parameters indicating pulmonary inflammation, including neutrophil count and plasma TNF-alpha and malondialdehyde (MDA) levels, were significantly reduced during CPB by pulmonary artery perfusion with TNF-alpha Ab, suggesting that the perfusion with TNF-alpha Ab reduces CPB-induced pulmonary inflammation. We further investigated the molecular mechanism underlying the protective effects of TNF-alpha Ab on lung. Our quantitative RT-PCR analysis revealed that pulmonary artery perfusion with TNFa Ab significantly decreased TNF-alpha expression in lung tissue during CPB. The apoptotic index in lung tissue and the expression of proteins that play stimulatory roles in apoptosis pathways including the fas ligand (FasL) and Bax were markedly reduced during CPB by the perfusion with TNF-alpha Ab. In contrast, the expression of Bcl-2, which plays an inhibitory role in apoptosis pathways, was significantly increased during CPB by the perfusion with TNF-alpha Ab, indicating that the perfusion with TNF-alpha Ab significantly reduces CPB-induced apoptosis in lung. Thus, our study suggests that pulmonary artery perfusion with TNF-alpha Ab might be a promising approach for attenuating CPB-induced inflammatory lung injury.