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

Chou-Chin Lan,Shih-En Tang,Chin-Pyng Wu,Kun-Lun Huang,Shu-Yu Wu,Chung-Kan Peng,Marie Jose Goumans

doi:10.1371/journal.pone.0159922

Abstract

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.

Highlights

Exposure of the lungs to periods of ischemia and the initiation of reperfusion causes ischemiareperfusion (IR)-induced acute lung injury (ALI)[1], which is an important issue in lung transplantation
Neutrophilic infiltration and inter-alveolar septum thickening was still prominent in B1-IR (Fig 2D) but were markedly attenuated by preconditoning anti-Vascular endothelial growth factor (VEGF) antibody 5 mg/kg (B5-IR) (Fig 2E)
The neutrophilic infiltration and inter-alveolar septum thickening were still prominent in the IR-B5 group (Fig 2F)

Summary

Introduction

Exposure of the lungs to periods of ischemia and the initiation of reperfusion causes ischemiareperfusion (IR)-induced acute lung injury (ALI)[1], which is an important issue in lung transplantation. The shortage of donor organs remains a major limiting factor in the widespread application of lung transplantation [2]. Despite advances in organ preservation and peri-operative care, IR-induced ALI remains a significant cause of post-transplantation mortality and morbidity [2]. IR-induced ALI sometimes occurs early after lung transplantation [3]. IR-induced ALI is one of the main causes of primary graft failure and contributes to early mortality after lung transplantation [2].

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Conclusion