NAD(P)H quinone oxidoreductase 1 regulates neutrophil elastase-induced mucous cell metaplasia.
Mucous cell metaplasia (MCM) and neutrophil-predominant airway inflammation are pathological features of chronic inflammatory airway diseases. A signature feature of MCM is increased expression of a major respiratory tract mucin, MUC5AC. Neutrophil elastase (NE) upregulates MUC5AC in primary airway epithelial cells by generating reactive oxygen species, and this response is due in part to upregulation of NADPH quinone oxidoreductase 1 (NQO1) activity. Delivery of NE directly to the airway triggers inflammation and MCM and increases synthesis and secretion of MUC5AC protein from airway epithelial cells. We hypothesized that NE-induced MCM is mediated in vivo by NQO1. Male wild-type and Nqo1-null mice (C57BL/6 background) were exposed to human NE (50 μg) or vehicle via oropharyngeal aspiration on days 1, 4, and 7. On days 8 and 11, lung tissues and bronchoalveolar lavage (BAL) samples were obtained and evaluated for MCM, inflammation, and oxidative stress. MCM, inflammation, and production of specific cytokines, granulocyte-macrophage colony-stimulating factor, macrophage inflammatory protein-2, interleukin-4, and interleukin-5 were diminished in NE-treated Nqo1-null mice compared with NE-treated wild-type mice. However, in contrast to the role of NQO1 in vitro, we demonstrate that NE-treated Nqo1-null mice had greater levels of BAL and lung tissue lipid carbonyls and greater BAL iron on day 11, all consistent with increased oxidative stress. NQO1 is required for NE-induced inflammation and MCM. This model system demonstrates that NE-induced MCM directly correlates with inflammation, but not with oxidative stress.
Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA.
Marisa L
ML
Meyer
Erin N
EN
Potts-Kant
Andrew J
AJ
Ghio
Bernard M
BM
Fischer
W Michael
WM
Foster
Judith A
JA
Voynow
D000818:Animals; D018893:Bronchoalveolar Lavage; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007501:Iron / Q000378:metabolism; D019272:Leukocyte Elastase / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D008679:Metaplasia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055271:Mucin 5AC / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology*
D016207:Cytokines; D055271:Mucin 5AC; D017382:Reactive Oxygen Species; D007501:Iron; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D019272:Leukocyte Elastase