NADPH Oxidase and Nrf2 Regulate Gastric Aspiration–Induced Inflammation and Acute Lung Injury

Abstract

Recruitment of neutrophils and release of reactive oxygen species are considered to be major pathogenic components driving acute lung injury (ALI). However, NADPH oxidase, the major source of reactive oxygen species in activated phagocytes, can paradoxically limit inflammation and injury. We hypothesized that NADPH oxidase protects against ALI by limiting neutrophilic inflammation and by activating Nrf2, a transcriptional factor that induces anti-oxidative and cytoprotective pathways. Our objective was to delineate the roles of NADPH oxidase and Nrf2 in modulating acute lung inflammation and injury in clinically relevant models of acute gastric aspiration injury, a major cause of ALI. Acid aspiration caused increased ALI (as assessed by bronchoalveolar lavage fluid albumin concentration) in both NADPH oxidase-deficient (p47phox−/−) mice and in Nrf2−/− mice compared to wild-type mice. NADPH oxidase reduced airway neutrophil accumulation, but Nrf2 decreased ALI without affecting neutrophil recovery. Acid injury resulted in a 120-fold increase in mitochondrial DNA, a pro-inflammatory and injurious product of cellular necrosis, in cell-free bronchoalveolar lavage fluid. Pharmacologic activation of Nrf2 by the triterpenoid, CDDO-Im, limited aspiration-induced ALI in wild-type mice and reduced endothelial cell injury caused by mitochondrial extract-primed human neutrophils, leading to the conclusion that NADPH oxidase and Nrf2 have coordinated, but distinct, functions in modulating inflammation and injury. These results also point to Nrf2 as a therapeutic target to limit ALI by attenuating neutrophil-induced cellular injury.

NADPH Oxidase Promotes Neutrophil Extracellular Trap Formation in Pulmonary Aspergillosis

“…Further studies are required to delineate the relative importance of ROI-mediated fungal damage versus NETosis in promoting Aspergillus clearance. In addition to its host defense function, we and others have found that NADPH oxidase can modulate oxidant-sensitive pathways that limit lung inflammation and injury following challenge with both microbial products and direct caustic insult (14,15,30,(65)(66)(67)(68). Delineating…”

Mitochondria in lung biology and pathology: more than just a powerhouse

“…Immunogenic DNA, such as is present in bacteria and mitochondria, is sufficient to promote ALI in animal models (46,87), and mtDNA has been specifically linked to the pathogenesis of ALI in setting of sterile inflammation induced experimentally by acid aspiration (17), surgical trauma (100), and acute liver necrosis (55). PMNs, through activation of TLR9, appear to play a major role in initiating ALI under these conditions.…”

Danger in the Intensive Care Unit

“…Concerning the S100 protein family, both S100A9 and S100A12 (EN-RAGE) are increased in BALF of patients with acute respiratory distress syndrome (ARDS) compared with healthy controls (27,28), although no studies have been undertaken to investigate the effects of neutralization of HSPs or S100 proteins in VILI. Concerning nucleic acids, previous studies have shown that acid aspiration results in profoundly increased mtDNA level in BALF of mice (29), and that exogenous administration of mtDNA in the lungs or circulation of rats and mice elicits inflammatory lung injury in a TLR9-dependent manner (30,31). However, the effect of endogenous mtDNA release or neutralization during mechanical ventilation and its role in ventilator-induced inflammation has not yet been investigated.…”