Genetic Ablation of NADPH Oxidase Enhances Susceptibility to Cigarette Smoke-Induced Lung Inflammation and Emphysema in Mice

Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Box 850, 601 Elmwood Ave., Rochester, NY 14642, USA.
American Journal Of Pathology (Impact Factor: 4.59). 06/2008; 172(5):1222-37. DOI: 10.2353/ajpath.2008.070765
Source: PubMed


Cigarette smoke (CS) induces recruitment of inflammatory cells in the lungs leading to the generation of reactive oxygen species (ROS), which are involved in lung inflammation and injury. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is a multimeric system that is responsible for ROS production in mammalian cells. We hypothesized that NADPH oxidase-derived ROS play an important role in lung inflammation and injury and that targeted ablation of components of NADPH oxidase (p47(phox) and gp91(phox)) would protect lungs against the detrimental effects of CS. To test this hypothesis, we exposed p47(phox-/-) and gp91(phox-/-) mice to CS and examined inflammatory response and injury in the lung. Surprisingly, although CS-induced ROS production was decreased in the lungs of p47(phox-/-) and gp91(phox-/-) mice compared with wild-type mice, the inflammatory response was significantly increased and was accompanied by development of distal airspace enlargement and alveolar destruction. This pathological abnormality was associated with enhanced activation of the TLR4-nuclear factor-kappaB pathway in response to CS exposure in p47(phox-/-) and gp91(phox-/-) mice. This phenomenon was confirmed by in vitro studies in which treatment of peritoneal macrophages with a nuclear factor-kappaB inhibitor reversed the CS-induced release of proinflammatory mediators. Thus, these data suggest that genetic ablation of components of NADPH oxidase enhances susceptibility to the proinflammatory effects of CS leading to airspace enlargement and alveolar damage.

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Available from: Saravanan Rajendrasozhan
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    • "Mice deficient in p47phox or NOX-2 exhibit increased cigarette smoke-induced lung inflammation and emphysema despite decreased ROS production compared with control mice (Yao et al., 2008). The lung responses in p47phox-and NOX2-null mice were associated with increased production of pro-inflammatory cytokines and chemokines via a TLR4–NF-kB pathway, indicating that NOX-2 may mediate anti-inflammatory functions by restraining TLR4 activation (Yao et al., 2008). However, another group reported that p47phox-null mice have less inflammation, IL-6, keratinocyte-derived chemokine, and monocyte chemoattractant protein-1 in lung-lavage specimens after cigarette-smoke exposure compared with WT mice (Gicquel et al., 2008). "
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    • "Furthermore, a low i.p. dose of LPS [5 lg/g body weight (bw)], equally induced pulmonary NF-jB activation in p47 phox-/-and WT mice, however, 20 lg/g bw, i.p. dose of LPS-mediated NF-jB activation was lower in p47 phox-/mice (Koay et al. 2001). In support of these observations, another report showed that susceptibility to cigarette smokeinduced lung inflammation and emphysema was significantly enhanced in mice genetically ablated of NADPH oxidase (p47 phox and gp91 phox ) (Yao et al. 2008). These contradictory findings clearly state that low dose of LPS does not induce NF-jB activation via ROS, or that mice deficient in NADPH oxidase components can compensate this defect by either xanthine oxidase (Faggioni et al. 1994; Nakai et al. 2006) or mitochondria-mediated ROS production (Boczkowski et al. 1999; Ritter et al. 2003). "
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