Synergistic protection against hyperoxia-induced lung injury by neutrophils blockade and EC-SOD overexpression

Jae H Min,Edmund J Miller,Champa N Codipilly,Sonya Nasim,Mohamed N Ahmed

doi:10.1186/1465-9921-13-58

Abstract

BackgroundOxygen may damage the lung directly via generation of reactive oxygen species (ROS) or indirectly via the recruitment of inflammatory cells, especially neutrophils. Overexpression of extracellular superoxide dismutase (EC-SOD) has been shown to protect the lung against hyperoxia in the newborn mouse model. The CXC-chemokine receptor antagonist (Antileukinate) successfully inhibits neutrophil influx into the lung following a variety of pulmonary insults. In this study, we tested the hypothesis that the combined strategy of overexpression of EC-SOD and inhibiting neutrophil influx would reduce the inflammatory response and oxidative stress in the lung after acute hyperoxic exposure more efficiently than either single intervention.MethodsNeonate transgenic (Tg) (with an extra copy of hEC-SOD) and wild type (WT) were exposed to acute hyperoxia (95% FiO2 for 7 days) and compared to matched room air groups. Inflammatory markers (myeloperoxidase, albumin, number of inflammatory cells), oxidative markers (8-isoprostane, ratio of reduced/oxidized glutathione), and histopathology were examined in groups exposed to room air or hyperoxia. During the exposure, some mice received a daily intraperitoneal injection of Antileukinate.ResultsAntileukinate-treated Tg mice had significantly decreased pulmonary inflammation and oxidative stress compared to Antileukinate-treated WT mice (p < 0.05) or Antileukinate-non-treated Tg mice (p < 0.05).ConclusionCombined strategy of EC-SOD and neutrophil influx blockade may have a therapeutic benefit in protecting the lung against acute hyperoxic injury.

Highlights

Oxygen may damage the lung directly via generation of reactive oxygen species (ROS) or indirectly via the recruitment of inflammatory cells, especially neutrophils
In wild type (WT) mice, Antileukinate significantly reduced neutrophil counts and MPO activity (p < 0.05) (Figure 1A&B)
There were significantly less neutrophils and MPO in the bronchoalveolar lavage (BAL) of Antileukinate-treated Tg compared to Antileukinate treated WT group after acute hyperoxic exposure (p < 0.05)

Summary

Introduction

Oxygen may damage the lung directly via generation of reactive oxygen species (ROS) or indirectly via the recruitment of inflammatory cells, especially neutrophils. Overexpression of extracellular superoxide dismutase (EC-SOD) has been shown to protect the lung against hyperoxia in the newborn mouse model. We tested the hypothesis that the combined strategy of overexpression of EC-SOD and inhibiting neutrophil influx would reduce the inflammatory response and oxidative stress in the lung after acute hyperoxic exposure more efficiently than either single intervention. Preterm infants are vulnerable to oxygen toxicity as a consequence of an immature antioxidant system [9,10]. Overexpression or administration of EC-SOD has been shown to protect against a variety of pulmonary insults, including exposure to hyperoxia [17,18,19], lipopolysaccaride (LPS) [20], and influenzainduced lung injury [21]. EC-SOD is known to inhibit neutrophil influx in response to hyperoxia [18], LPS [20], bleomycin and bacteria [22]

Methods

Results

Conclusion