Superoxide dismutase expression attenuates cigarette smoke- or elastase-generated emphysema in mice
Superoxide dismutase expression attenuates cigarette smoke- or elastase-generated emphysema in mice
复制标题
DOI：
10.1164/rccm.200506-850oc
复制
发表时间：
2006-03-15
影响因子：
24.7
通讯作者：
D'Armiento, JM
中科院分区：
文献类型：
--
作者：
Foronjy, RF;Mirochnitchenko, O;D'Armiento, JM
理由：氧化剂被认为在肺气肿的形成中起着重要作用。目的：探讨人铜锌超氧化物歧化酶（CuZnSOD）在小鼠肺内的表达是否对肺气肿的发生有保护作用。方法：将转基因CuZnSOD小鼠和同窝小鼠分别暴露于香烟烟雾中（6 h/d， 5 d/周，持续1年），并与未暴露的小鼠进行比较。第二组采用气管内弹性蛋白酶诱导肺气肿。测量方法：通过细胞计数和髓过氧化物酶水平测量肺部炎症。采用免疫荧光法检测3-硝基酪氨酸和8-羟基脱氧鸟苷的氧化损伤及脂质过氧化水平。通过测量平均线性截距（L-m）来判断肺气肿的发展。主要结果：吸烟引起嗜中性粒细胞炎症增加4倍，肺髓过氧化物酶活性增加1倍。这种炎症反应在暴露于烟雾中的CuZnSOD小鼠中没有发生。同样，CuZnSOD的表达阻止了烟雾暴露后肺脂质过氧化产物增加58%。最重要的是，CuZnSOD在烟雾诱导模型（L-m， 68暴露对照与58暴露转基因对照，p < 0.04）和弹性酶生成模型（L-m， 80暴露对照与63暴露转基因对照，p < 0.03）中均能预防肺气肿的发生。这些结果首次证明，抗氧化剂可以预防烟雾引起的炎症，并可以抵消导致肺气肿形成的蛋白水解级联反应，在两种不同的动物模型中。结论：这些发现表明，旨在增强或补充肺部抗氧化剂的策略可能有效地预防和治疗该疾病。
Rationale: Oxidants are believed to play a major role in the development of emphysema.Objectives: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.Methods: 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. Measurements: 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 (L-m).Main Results: 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 (L-m, 68 exposed control vs. 58 exposed transgenic; p < 0.04) and elastase-generated model (L-m, 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.Conclusions: These findings indicate that strategies aimed at enhancing or supplementing lung antioxidants could be effective for the prevention and treatment of this disease.