Glucose-6-phosphate dehydrogenase inhibition attenuates acute lung injury through reduction in NADPH oxidase derived reactive oxygen species

Abstract

Acute lung injury (ALI) is a heterogeneous disease with the hallmarks of alveolar capillary membrane injury, increased pulmonary edema and pulmonary inflammation. The commonest direct etiological factor for ALI is usually parenchymal lung infection or hemorrhage. Reactive oxygen species (ROS) generated by NADPH oxidase (NOX2) are thought to play an important role in the pathophysiology of ALI. Glucose-6-phosphate dehydrogenase (G6PD) plays an important role both in production of ROS as well as their removal through supply of NADPH. However, how G6PD modulation affects NOX2-mediated ROS in the airway epithelial cells (AECs) during acute lung injury has not been explored earlier. Therefore, we investigated the effect of G6PD inhibitor, 6-aminonicotinamide on G6PD activity, NOX2 expression, ROS production and enzymatic antioxidants in AECs in a mouse model of ALI induced by lipopolysaccharide (LPS). ALI led to increased G6PD activity in the AECs with concomitant elevation of NOX2, ROS, SOD1, and nitrotyrosine. G6PD inhibitor led to reduction of LPS-induced airway inflammation, bronchoalveolar lavage fluid protein concentration as well as NOX2-derived ROS and subsequent oxidative stress. On the other hand, ALI led to decreased glutathione reductase activity in AECs which was normalized by G6PD inhibitor. These data show that activation of G6PD is associated with enhancement of oxidative inflammation in during ALI. Therefore, inhibition of G6PD might be a beneficial strategy during ALI to limit oxidative damage and ameliorate airway inflammation. This article is protected by copyright. All rights reserved.