During cardiopulmonary bypass (CPB), pulmonary ischemia/reperfusion (I/R) injury can cause acute lung injury (ALI). Our previous research confirmed that abnormal high-mobility group box 1 (HMGB1) release after CPB was closely related to ALI. However, the mechanism underlying the HMGB1-mediated induction of ALI after CPB is unclear. Our previous study found that HMGB1 binds Toll-like receptor 4 (TLR4), leading to lung injury, but direct evidence of a role for these proteins in the mechanism of CPB-induced lung injury has not been shown. We examined the effects of inhibiting HMGB1 or reducing TLR4 expression on CPB-induced lung injury in rats administered anti-HMBG1 antibody or TLR4 short-hairpin RNA (shTLR4), respectively. In these rat lungs, we studied the histologic changes and levels of interleukin- (IL-) 1β, tumour necrosis factor- (TNF-) α, HMGB1, and TLR4 after CPB. After CPB, the lung tissues from untreated rats showed histologic features of injury and significantly elevated levels of IL-1β, TNF-α, HMGB1, and TLR4. Treatment with anti-HMGB1 attenuated the CPB-induced morphological inflammatory response and protein levels of IL-1β, TNF-α, HMGB1, and TLR4 in the lung tissues and eventually alleviated the ALI after CPB. Treatment with shTLR4 attenuated the CPB-induced morphological inflammatory response and protein levels of IL-1β, TNF-α, and TLR4 in the lung tissues and eventually alleviated the ALI after CPB, but could not alleviate the HMGB1 protein levels induced by CPB. In summary, the present study demonstrated that the HMGB1/TLR4 pathway mediated the development of ALI induced by CPB.

中文翻译：

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心肺旁路通过高迁移率族框1 /收费受体4途径诱导急性肺损伤

在体外循环（CPB）期间，肺缺血/再灌注（I / R）损伤可导致急性肺损伤（ALI）。我们之前的研究证实，CPB后高迁移率族盒子1（HMGB1）的异常释放与ALI密切相关。但是，CPB后HMGB1介导的ALI诱导的潜在机制尚不清楚。我们先前的研究发现HMGB1结合Toll样受体4（TLR4），导致肺损伤，但尚未显示这些蛋白在CPB诱导的肺损伤机制中的作用的直接证据。我们在分别施用抗HMBG1抗体或TLR4短发夹RNA（shTLR4）的大鼠中研究了抑制HMGB1或降低TLR4表达对CPB诱导的肺损伤的作用。在这些大鼠的肺，我们研究了组织学变化和水平的白细胞介素（IL-）1 β，CPB后的肿瘤坏死因子-（TNF-）α，HMGB1和TLR4。CPB后，未经治疗的大鼠的肺组织显示出损伤的组织学特征，并且IL- 1β，TNF - α，HMGB1和TLR4的水平显着升高。抗HMGB1的治疗减弱了CPB诱导的形态学炎症反应和肺组织中IL- 1β，TNF - α，HMGB1和TLR4的蛋白水平，并最终减轻了CPB后的ALI。shTLR4处理减弱了CPB诱导的形态学炎症反应和IL- 1β，TNF - α的蛋白水平，肺组织中的TLR4和TLR4最终减轻了CPB后的ALI，但不能减轻CPB诱导的HMGB1蛋白水平。总而言之，本研究表明HMGB1 / TLR4途径介导了CPB诱导的ALI的发展。