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

ABSTRACT 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, Sep 26, 2015
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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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    ABSTRACT: Rel/NF-κB transcription factors play a key role in modulating the response of immunoregulatory genes including cytokines and chemokines, cell adhesion molecules, acute phase proteins, and anti-microbial peptides. Furthermore, an array of genes important for angiogenesis, tumor invasion and metastasis is also regulated by nuclear factor-κB (NF-κB). Close association of NF-κB with inflammation and tumorigenesis makes it an attractive target for basic research as well as for pharmaceutical industries. Studies involving various animal and cellular models have revealed the importance of NF-κB in pathobiology of lung diseases. This review (a) describes structures, activities, and regulation of NF-κB family members; (b) provides information which implicates NF-κB in pathogenesis of pulmonary inflammation and cancer; and (c) discusses information about available synthetic and natural compounds which target NF-κB or specific components of NF-κB signal transduction pathway and which may provide the foundation for development of effective therapy for lung inflammation and bronchogenic carcinomas.
    Archivum Immunologiae et Therapiae Experimentalis 07/2011; 59(5):335-51. DOI:10.1007/s00005-011-0136-z · 3.18 Impact Factor
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    • "CS-induced reactive oxygen species production via NADPH oxidase activation is involved in the positive regulation of the Nrf2/ARE pathway. NADPH oxidase, as a critical regulator of innate immunity, also limits lung inflammation by attenuating NF-κB and by activating Nrf2 [28,29]. On the other hand, CS activates the NF-κB pathway, which participates in the negative regulation of Nrf2/ARE signaling [30,31]. "
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    ABSTRACT: An Nrf2-dependent response is a central protective mechanism against oxidative stress. We propose that particular genetic variants of the Nrf2 gene may be associated with a rapid forced expiratory volume in one second (FEV1) decline induced by cigarette smoking. We conducted a retrospective cohort study of 915 Japanese from a general population. Values of annual decline in FEV1 were computed for each individual using a linear mixed-effect model. Multiple clinical characteristics were assessed to identify associations with annual FEV1 decline. Tag single-nucleotide polymorphisms (SNPs) in the Nrf2 gene (rs2001350, rs6726395, rs1962142, rs2364722) and one functional SNP (rs6721961) in the Nrf2 promoter region were genotyped to assess interactions between the Nrf2 polymorphisms and smoking status on annual FEV1 decline. Annual FEV1 decline was associated with smoking behavior and inversely correlated with FEV1/FVC and FEV1 % predicted. The mean annual FEV1 declines in individuals with rs6726395 G/G, G/A, or A/A were 26.2, 22.3, and 20.8 mL/year, respectively, and differences in these means were statistically significant (pcorr = 0.016). We also found a significant interaction between rs6726395 genotype and smoking status on the FEV1 decline (p for interaction = 0.011). The haplotype rs2001350T/rs6726395A/rs1962142A/rs2364722A/rs6721961T was associated with lower annual decline in FEV1 (p = 0.004). This study indicated that an Nrf2-dependent response to exogenous stimuli may affect annual FEV1 decline in the general population. It appears that the genetic influence of Nrf2 is modified by smoking status, suggesting the presence of a gene-environment interaction in accelerated decline in FEV1.
    BMC Medical Genetics 07/2011; 12(1):97. DOI:10.1186/1471-2350-12-97 · 2.08 Impact Factor
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    • "Med. (2011), doi:10.1016/j.freeradbiomed.2011.02.027 exposure [19]. Consistent with these data, we have recently shown that genetic deficiency of NADPH oxidase does not diminish, but rather enhances, LPS-induced acute lung inflammatory responses [21]. "
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    ABSTRACT: In vitro and limited in vivo evidence suggests that reactive oxygen species derived from NADPH oxidases (NOX-ROS) play an important role in inflammatory responses by enhancing the activity of redox-sensitive cell signaling pathways and transcription factors. Here, we investigated the role of NOX-ROS in TNFα-induced acute inflammatory responses in vivo, using mice deficient in the gp91(phox) (NOX2) or p47(phox) subunits of NADPH oxidase. Age- and body weight-matched C57BL/6J wild-type (WT) and gp91(phox) or p47(phox) knockout mice were injected intraperitoneally with 50 μg TNFα/kg bw or saline vehicle control and sacrificed at various time points up to 24 h. Compared to WT mice, gp91(phox -/-) mice exhibited significantly diminished (P<0.05) TNFα-induced acute inflammatory responses in the lungs but not other tissues, including heart, liver, and kidney, as evidenced by decreased activation of the redox-sensitive transcription factor NF-κB, and decreased gene expression of interleukin (IL)-1β, IL-6, TNFα, E-selectin, and other cellular adhesion molecules. Similar results were observed in p47(phox -/-) mice. Interestingly, decreased lung inflammation in knockout mice was accompanied by increased leukocyte infiltration into the lungs compared to other tissues. Our data suggest that phagocytic NOX-ROS signaling plays a critical role in promoting TNFα-induced, NF-κB-dependent acute inflammatory responses and tissue injury specifically in the lungs, which is effected by preferential leukocyte infiltration.
    Free Radical Biology and Medicine 03/2011; 50(11):1517-25. DOI:10.1016/j.freeradbiomed.2011.02.027 · 5.74 Impact Factor
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