Yao Hongwei, Edirisinghe Indika, Yang Se-Ran, Rajendrasozhan Saravanan, Kode Aruna, Caito Samuel, Adenuga David, Rahman Irfan
Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Box 850, 601 Elmwood Ave., Rochester, NY 14642, USA.
Am J Pathol. 2008 May;172(5):1222-37. doi: 10.2353/ajpath.2008.070765. Epub 2008 Apr 10.
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.
香烟烟雾（CS）可诱导肺部炎症细胞募集，从而导致活性氧（ROS）生成，而ROS参与肺部炎症和损伤过程。烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶是一个多聚体系统，负责哺乳动物细胞中ROS的产生。我们推测，NADPH氧化酶衍生的ROS在肺部炎症和损伤中起重要作用，并且靶向消融NADPH氧化酶的组分（p47（phox）和gp91（phox））可保护肺部免受CS的有害影响。为了验证这一假设，我们将p47（phox-/-）和gp91（phox-/-）小鼠暴露于CS，并检测肺部的炎症反应和损伤情况。令人惊讶的是，尽管与野生型小鼠相比，p47（phox-/-）和gp91（phox-/-）小鼠肺部CS诱导的ROS生成减少，但炎症反应却显著增加，并伴有远端气腔扩大和肺泡破坏的发展。这种病理异常与p47（phox-/-）和gp91（phox-/-）小鼠暴露于CS时TLR4-核因子-κB途径的激活增强有关。体外研究证实了这一现象，即用核因子-κB抑制剂处理腹膜巨噬细胞可逆转CS诱导的促炎介质释放。因此，这些数据表明，NADPH氧化酶组分的基因消融增强了对CS促炎作用的易感性，导致气腔扩大和肺泡损伤。
