Pendino K J, Laskin J D, Shuler R L, Punjabi C J, Laskin D L
Department of Pharmacology, Rutgers University, Piscataway, NJ.
J Immunol. 1993 Dec 15;151(12):7196-205.
Alveolar macrophages represent the first line of defense of the lung against inhaled environmental agents. These cells release a variety of inflammatory mediators including reactive oxygen and nitrogen intermediates that have been implicated in host defense and in tissue injury. In the present studies we characterized production of these mediators by lung phagocytes after exposure of rats to an inhaled pulmonary irritant. Freshly isolated alveolar macrophages from control rats were found to produce nitric oxide as well as hydrogen peroxide and superoxide anion in response to in vitro treatment with inflammatory mediators such as IFN-gamma or LPS and phorbol esters, respectively. Production of nitric oxide by lung phagocytes was enhanced in the presence of superoxide dismutase. Western blot analysis revealed that production of nitric oxide after treatment of the cells with IFN-gamma and LPS was a result of increased expression of inducible nitric oxide synthase. After brief exposure of rats to ozone (O3, 1 to 2 ppm, 3 h), a pulmonary irritant and inflammatory agent that is rapidly converted to molecular oxygen, lung phagocytes produced significantly increased amounts of nitric oxide when compared with control animals. These cells were also sensitized to produce more nitric oxide in response to in vitro treatment with IFN-gamma and LPS. This was due, at least in part, to increased expression of inducible nitric oxide synthase by the cells, which was evident in protein blots and in immunohistochemically stained sections of lung tissue. In further studies we found that O3 inhalation also caused enhanced production of hydrogen peroxide, but an apparent decrease in release of superoxide anion by lung phagocytes. Taken together, these data demonstrate that acute irritant exposure modifies production of reactive oxygen and nitrogen intermediates by lung phagocytes. These alterations may be important in the pathophysiologic response of the lungs to irritants.
肺泡巨噬细胞是肺抵御吸入环境因子的第一道防线。这些细胞释放多种炎症介质，包括活性氧和氮中间体，它们与宿主防御和组织损伤有关。在本研究中，我们对大鼠吸入肺部刺激物后肺吞噬细胞产生这些介质的情况进行了表征。发现从对照大鼠新鲜分离的肺泡巨噬细胞在分别用炎症介质如干扰素-γ或脂多糖以及佛波酯进行体外处理后，会产生一氧化氮、过氧化氢和超氧阴离子。在超氧化物歧化酶存在的情况下，肺吞噬细胞产生一氧化氮的能力增强。蛋白质印迹分析表明，用干扰素-γ和脂多糖处理细胞后一氧化氮的产生是诱导型一氧化氮合酶表达增加的结果。大鼠短暂暴露于臭氧（O3，1至2 ppm，3小时）后，臭氧是一种肺部刺激物和炎症介质，会迅速转化为分子氧，与对照动物相比，肺吞噬细胞产生的一氧化氮量显著增加。这些细胞在用干扰素-γ和脂多糖进行体外处理时也更易产生更多的一氧化氮。这至少部分是由于细胞中诱导型一氧化氮合酶的表达增加，这在蛋白质印迹和肺组织免疫组化染色切片中都很明显。在进一步的研究中，我们发现吸入臭氧还会导致过氧化氢产生增加，但肺吞噬细胞释放的超氧阴离子明显减少。综上所述，这些数据表明急性刺激物暴露会改变肺吞噬细胞产生活性氧和氮中间体的情况。这些改变可能在肺对刺激物的病理生理反应中起重要作用。
