Liu Qinlong, Rehman Hasibur, Krishnasamy Yasodha, Lemasters John J, Zhong Zhi
Department of Drug Discovery & Biomedical Sciences, Medical University of South Carolina Charleston, SC 29425, USA.
The Second Affiliated Hospital of Dalian Medical University Dalian, Liaoning Province, China.
Int J Physiol Pathophysiol Pharmacol. 2018 Apr 20;10(2):83-94. eCollection 2018.
Pulmonary complications frequently occur after liver transplantation and are often life-threatening. Thus, we investigated whether hepatic ischemic preconditioning (IP) attenuates acute lung injury (ALI) after small-for-size liver transplantation. Rat livers were explanted after 9-min ischemia plus 5-min reperfusion, reduced to 50% of original size , and implanted into recipients with approximately twice the donor body weight, resulting in quarter-size liver grafts (QSG). After QSG transplantation, hepatic Toll-like receptor 4 (TLR4) and tumor necrosis factor-α (TNFα ) expression increased markedly and high mobility group box-1 (HMGB1), an endogenous damage-associated molecular pattern molecule (DAMP), was released from QSG into the blood. IP blunted TLR4 and TNFα expression and HMGB1 release from QSG. In the lungs of QSG recipients without IP treatment, nuclear factor-κB (NF-κB) activation and intercellular adhesion molecule (ICAM)-1 expression increased; alveolar septal walls thickened with increased cellularity as neutrophils, monocytes/macrophage and T lymphocytes infiltrated into alveolar septa and alveolar spaces; and pulmonary cleaved caspase-8 and -3 and TUNEL-positive cells increased. In contrast, in the lungs of recipients of ischemic-preconditioned QSG, NF-κB activation and ICAM-1 expression were blunted; leukocyte infiltration was decreased; and alveolar septal wall thickening, caspase activation, and cell apoptosis were attenuated. IP did not increase heat-shock proteins in the lungs of QSG recipients. In conclusion, toxic cytokine and HMGB1 released from failing small-for-size grafts leads to pulmonary adhesion molecule expression, leukocyte infiltration and injury. IP prevents DAMP release and toxic cytokine formation in small-for-size grafts, thereby attenuating ALI.
肝移植后肺部并发症经常发生，且往往危及生命。因此，我们研究了肝缺血预处理（IP）是否能减轻小体积肝移植后的急性肺损伤（ALI）。大鼠肝脏在经历9分钟缺血加5分钟再灌注后被取出，体积缩小至原来的50%，然后植入体重约为供体两倍的受体体内，从而形成四分之一大小的肝移植（QSG）。QSG移植后，肝Toll样受体4（TLR4）和肿瘤坏死因子-α（TNFα）表达显著增加，高迁移率族蛋白B1（HMGB1），一种内源性损伤相关分子模式分子（DAMP），从QSG释放到血液中。IP抑制了TLR4和TNFα的表达以及HMGB1从QSG的释放。在未经IP处理的QSG受体的肺中，核因子-κB（NF-κB）激活和细胞间黏附分子（ICAM）-1表达增加；随着中性粒细胞、单核细胞/巨噬细胞和T淋巴细胞浸润到肺泡间隔和肺泡腔，肺泡间隔壁增厚且细胞增多；肺中裂解的半胱天冬酶-8和-3以及TUNEL阳性细胞增加。相比之下，在接受缺血预处理QSG的受体的肺中，NF-κB激活和ICAM-1表达受到抑制；白细胞浸润减少；肺泡间隔壁增厚、半胱天冬酶激活和细胞凋亡减轻。IP并未增加QSG受体肺中的热休克蛋白。总之，功能衰竭的小体积移植物释放的毒性细胞因子和HMGB1导致肺黏附分子表达、白细胞浸润和损伤。IP可防止小体积移植物中DAMP的释放和毒性细胞因子的形成，从而减轻ALI。
