Pulmonary Artery Perfusion with Anti-Tumor Necrosis Factor Alpha Antibody Reduces Cardiopulmonary Bypass-Induced Inflammatory Lung Injury in a Rabbit Model

Abstract

Inflammatory lung injury is one of the main complications associated with cardiopulmonary bypass (CPB). Tumor necrosis factor-α (TNF-α) 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-α antibody (TNF-α 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-α Ab (27 ng/kg) on lung tissue integrity and pulmonary inflammation during CPB and investigated the mechanism underlying the TNF-α Ab-mediated effects in a rabbit model of CPB. Our results from transmission electron microscopy showed that the perfusion with TNF-α Ab alleviated CPB-induced histopathological changes in lung tissue. The perfusion with TNF-α Ab also prevented CPB-induced pulmonary edema and improved oxygenation index. Parameters indicating pulmonary inflammation, including neutrophil count and plasma TNF-α and malondialdehyde (MDA) levels, were significantly reduced during CPB by pulmonary artery perfusion with TNF-α Ab, suggesting that the perfusion with TNF-α Ab reduces CPB-induced pulmonary inflammation. We further investigated the molecular mechanism underlying the protective effects of TNF-α Ab on lung. Our quantitative RT-PCR analysis revealed that pulmonary artery perfusion with TNF-α Ab significantly decreased TNF-α 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-α 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-α Ab, indicating that the perfusion with TNF-α Ab significantly reduces CPB-induced apoptosis in lung. Thus, our study suggests that pulmonary artery perfusion with TNF-α Ab might be a promising approach for attenuating CPB-induced inflammatory lung injury.

Isolated Human Pulmonary Artery Structure and Function Pre‐ and Post‐Cardiopulmonary Bypass Surgery

“…[16][17][18] Indeed, a recent study has shown that CPB carried out in rabbits caused an increase in leakage of Evans blue dye administered intravenously, which could be inhibited by an antibody against tumor necrosis factor a. 19 Therefore, macrophage and neutrophils released during CPB could cause tumor necrosis factor a-induced apoptosis in pulmonary SMCs, such as that seen in this study.…”

“…During CPB, there is minimal blood perfusion of pulmonary arteries/arteries and decreased oxygenation; these conditions are known to provoke an increased immunological response through ischemia–reperfusion injury and mechanical stress, causing atelectasis and lung dysfunction 16, 17, 18. Indeed, a recent study has shown that CPB carried out in rabbits caused an increase in leakage of Evans blue dye administered intravenously, which could be inhibited by an antibody against tumor necrosis factor α 19. Therefore, macrophage and neutrophils released during CPB could cause tumor necrosis factor α–induced apoptosis in pulmonary SMCs, such as that seen in this study.…”

Targeting the proinflammatory cytokine tumor necrosis factor-α to alleviate cardiopulmonary bypass-induced lung injury (Review)

“…In animal models of CPB in which the genetic background of the experimental animal is more uniform than in humans, including rabbit, piglet and rat models, it is consistently observed that the serum level of TNF-α is significantly increased during and following CPB (11,12,19,20). Notably, Qi et al (11) demonstrated that in a rabbit model of CPB, in addition to a significant increase of systemic levels of TNF-α, the serum level of TNF-α from the left atrium is significantly higher than that from the right atrium (Table I).…”

“…Dauber et al revealed that peak circulating TNF levels correlate with CPB-induced coronary and pulmonary vascular injury (21). Studies on a rabbit model of CPB demonstrated that endotracheal administration or pulmonary perfusion of a neutralizing antibody against TNF-α significantly reduced pulmonary edema and alleviated histological damage in the lung (11,12). In a rat model, TNF-α markedly induced pulmonary vascular barrier dysfunction with increased lung water content and impaired oxygenation (22).…”

“…Functional neutralizing antibodies against TNF-α appear to be a more specific strategy for inhibiting TNF-α activity compared with the inhibition of TNF-α transcription. Qi et al (11) and Yu et al (12) demonstrated that in a rabbit model of CPB, neutralizing antibody against TNF-α Figure 1. Mechanism underlying TNF-α mediates downregulation of TLR4 expression in monocytic cells.…”