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Superoxide dismutase expression attenuates cigarette smoke- or elastase-generated emphysema in mice.

ABSTRACT: Oxidants are believed to play a major role in the development of emphysema.This study aimed to determine if the expression of human copper-zinc superoxide dismutase (CuZnSOD) within the lungs of mice protects against the development of emphysema.Transgenic CuZnSOD and littermate mice were exposed to cigarette smoke (6 h/d, 5 d/wk, for 1 yr) and compared with nonexposed mice. A second group was treated with intratracheal elastase to induce emphysema.Lung inflammation was measured by cell counts and myeloperoxidase levels. Oxidative damage was assessed by immunofluorescence for 3-nitrotyrosine and 8-hydroxydeoxyguanosine and lipid peroxidation levels. The development of emphysema was determined by measuring the mean linear intercept (Lm).Smoke exposure caused a fourfold increase in neutrophilic inflammation and doubled lung myeloperoxidase activity. This inflammatory response did not occur in the smoke-exposed CuZnSOD mice. Similarly, CuZnSOD expression prevented the 58% increase in lung lipid peroxidation products that occurred after smoke exposure. Most important, CuZnSOD prevented the onset of emphysema in both the smoke-induced model (Lm, 68 exposed control vs. 58 exposed transgenic; p < 0.04) and elastase-generated model (Lm, 80 exposed control vs. 63 exposed transgenic; p < 0.03). These results demonstrate for the first time that antioxidants can prevent smoke-induced inflammation and can counteract the proteolytic cascade that leads to emphysema formation in two separate animal models of the disease.These findings indicate that strategies aimed at enhancing or supplementing lung antioxidants could be effective for the prevention and treatment of this disease.

SUBMITTER: Foronjy RF

PROVIDER: S-EPMC3982860 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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Superoxide dismutase expression attenuates cigarette smoke- or elastase-generated emphysema in mice.

Foronjy Robert F RF Mirochnitchenko Oleg O Propokenko Olga O Lemaitre Vincent V Jia Yuxia Y Inouye Masayori M Okada Yasunori Y D'Armiento Jeanine M JM

American journal of respiratory and critical care medicine 20051230 6

<h4>Rationale</h4>Oxidants are believed to play a major role in the development of emphysema.<h4>Objectives</h4>This study aimed to determine if the expression of human copper-zinc superoxide dismutase (CuZnSOD) within the lungs of mice protects against the development of emphysema.<h4>Methods</h4>Transgenic CuZnSOD and littermate mice were exposed to cigarette smoke (6 h/d, 5 d/wk, for 1 yr) and compared with nonexposed mice. A second group was treated with intratracheal elastase to induce emph ...[more]

PMID: 16387805

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Project description:BackgroundThere is a need for agents that suppress inflammation and progression of chronic obstructive pulmonary disease. p38 mitogen-activated protein kinase (p38 MAPK) has been associated with this disorder, and several inhibitors of this cascade are in clinical trials for its treatment, but their efficacy and utility are unknown. This study evaluated the relationship between p38 MAPK activation and susceptibility to cigarette smoke (CS)-induced emphysema, and whether its inhibition ameliorated the lung inflammation and injury in murine models of cigarette smoke exposure.MethodsIn acute and chronic CS exposure, the activation and expression of p38 MAPK in the lungs, as well as lung inflammation and injury (proteinase production, apoptosis, and oxidative DNA damage), were compared between two mouse strains: C57BL/6 (emphysema-susceptible) and NZW (emphysema-resistant). The selective p38 MAPK inhibitor SB203580 (45 mg/kg) was administrated intra-peritoneally to C57BL/6 mice, to examine whether it ameliorated cigarette smoke-induced lung inflammation and injury.ResultsAcute CS-induced lung inflammation (neutrophil infiltration, mRNA expressions of TNF-? and MIP-2), proteinase expression (MMP-12 mRNA), apoptosis, and oxidative DNA damage were significantly lower in NZW than C57BL/6 mice. p38 MAPK was significantly activated and up-regulated by both acute and chronic CS exposure in C57BL/6 but not NZW mice. mRNA expression of p38 MAPK was also upregulated in C57BL/6 by chronic CS exposure and tended to be constitutively suppressed in NZW mice. SB203580 significantly attenuated lung inflammation (neutrophil infiltration, mRNA expressions of TNF-? and MIP-2, protein levels of KC, MIP-1?, IL-1?, and IL-6), proteinase expression (MMP-12 mRNA), oxidative DNA damage, and apoptosis caused by acute CS exposure.ConclusionsCigarette smoke activated p38 MAPK only in mice that were susceptible to cigarette smoke-induced emphysema. Its selective inhibition ameliorated lung inflammation and injury in a murine model of cigarette smoke exposure. p38 MAPK pathways are a possible molecular target for the treatment of chronic obstructive pulmonary disease.

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Superoxide dismutase expression attenuates cigarette smoke- or elastase-generated emphysema in mice.

Publications

Superoxide dismutase expression attenuates cigarette smoke- or elastase-generated emphysema in mice.

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