Anti-Vascular Endothelial Growth Factor Antibody Suppresses ERK and NF-κB Activation in Ischemia-Reperfusion Lung Injury

Ischemia-reperfusion (IR)-induced acute lung injury (ALI) is implicated in several clinical conditions like lung transplantation, acute pulmonary embolism after thrombolytic therapy, re-expansion of collapsed lung from pneumothorax or pleural effusion, cardiopulmonary bypass and etc. Because mortality remains high despite advanced medical care, prevention and treatment are important clinical issues for IR-induced ALI. Vascular endothelial growth factor (VEGF) has a controversial role in ALI. We therefore conducted this study to determine the effects of anti-VEGF antibody in IR-induced ALI. In the current study, the IR-induced ALI was conducted in a rat model of isolated-perfused lung in situ in the chest. The animals were divided into the control, control + preconditioning anti-VEGF antibody (bevacizumab, 5mg/kg), IR, IR + preconditioning anti-VEGF antibody (1mg/kg), IR+ preconditioning anti-VEGF antibody (5mg/kg) and IR+ post-IR anti-VEGF antibody (5mg/kg) group. There were eight adult male Sprague-Dawley rats in each group. The IR caused significant pulmonary micro-vascular hyper-permeability, pulmonary edema, neutrophilic infiltration in lung tissues, increased tumor necrosis factor-α, and total protein concentrations in bronchoalveolar lavage fluid. VEGF and extracellular signal-regulated kinase (ERK) were increased in IR-induced ALI. Administration of preconditioning anti-VEGF antibody significantly suppressed the VEGF and ERK expressions and attenuated the IR-induced lung injury. This study demonstrates the important role of VEGF in early IR-induced ALI. The beneficial effects of preconditioning anti-VEGF antibody in IR-induced ALI include the attenuation of lung injury, pro-inflammatory cytokines, and neutrophilic infiltration into the lung tissues.缺血再灌注（Ischemia-reperfusion, IR）诱导的急性肺损伤（acute lung injury, ALI）可累及多种临床场景，包括肺移植、溶栓治疗后急性肺栓塞、气胸或胸腔积液所致萎陷肺复张、体外循环等。尽管当前已采用先进的临床诊疗手段，此类损伤的病死率仍居高不下，因此缺血再灌注性急性肺损伤的预防与治疗已成为重要的临床议题。血管内皮生长因子（Vascular endothelial growth factor, VEGF）在急性肺损伤中的作用尚存争议，为此本研究旨在探讨抗VEGF抗体在缺血再灌注性急性肺损伤中的干预效果。本研究采用原位胸腔内离体灌注肺的大鼠模型构建缺血再灌注性急性肺损伤模型，将实验动物随机分为6组：对照组、对照组+抗VEGF抗体预处理组（贝伐珠单抗，5mg/kg）、缺血再灌注组、缺血再灌注+抗VEGF抗体预处理组（1mg/kg）、缺血再灌注+抗VEGF抗体预处理组（5mg/kg）以及缺血再灌注+抗VEGF抗体后处理组（5mg/kg），每组各纳入8只成年雄性Sprague-Dawley大鼠。实验结果显示，缺血再灌注可引发显著的肺微血管高通透性、肺水肿、肺组织中性粒细胞浸润，同时可升高肿瘤坏死因子-α（tumor necrosis factor-α）水平以及支气管肺泡灌洗液中的总蛋白浓度；在缺血再灌注性急性肺损伤模型中，VEGF与细胞外调节蛋白激酶（extracellular signal-regulated kinase, ERK）的表达均显著上调，给予抗VEGF抗体预处理可显著抑制VEGF与ERK的表达，并减轻缺血再灌注诱导的肺损伤。本研究证实VEGF在早期缺血再灌注性急性肺损伤中发挥关键调控作用，抗VEGF抗体预处理对缺血再灌注性急性肺损伤的保护效应包括减轻肺损伤、降低促炎细胞因子水平以及抑制肺组织中性粒细胞浸润。