Mancuso P, Standiford T J, Marshall T, Peters-Golden M
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0642, USA.
Infect Immun. 1998 Nov;66(11):5140-6. doi: 10.1128/IAI.66.11.5140-5146.1998.
The leukotrienes are potent lipid mediators of inflammation formed by the 5-lipoxygenase-catalyzed oxidation of arachidonic acid. Although the effects of leukotrienes on neutrophil chemotaxis and activation have been established, their role in modulating innate host defense mechanisms is poorly understood. In a previous study (M. Bailie, T. Standiford, L. Laichalk, M. Coffey, R. Strieter, and M. Peters-Golden, J. Immunol. 157:5221-5224, 1996), we used 5-lipoxygenase knockout mice to establish a critical role for endogenous leukotrienes in pulmonary clearance and alveolar macrophage phagocytosis of Klebsiella pneumoniae. In the present study, we investigated the role of specific endogenous leukotrienes in phagocytosis of K. pneumoniae and explored the possibility that exogenous leukotrienes could restore phagocytosis in alveolar macrophages with endogenous leukotriene synthesis inhibition and enhance this process in leukotriene-competent cells. Rat alveolar macrophages produced leukotriene B4 (LTB4), LTC4, and 5-hydoxyeicosatetraenoic acid (5-HETE) during the process of phagocytosis, and the inhibition of endogenous leukotriene synthesis with zileuton and MK-886 dramatically attenuated phagocytosis. We also observed a reduction in phagocytosis when we treated alveolar macrophages with antagonists to the plasma membrane receptors for either LTB4, cysteinyl-leukotrienes, or both. In leukotriene-competent cells, LTC4 augmented phagocytosis to the greatest extent, followed by 5-HETE and LTB4. These 5-lipoxygenase reaction products demonstrated similar relative abilities to reconstitute phagocytosis in zileuton-treated rat alveolar macrophages and in alveolar macrophages from 5-lipoxygenase knockout mice. We conclude that endogenous synthesis of all major 5-lipoxygenase reaction products plays an essential role in phagocytosis. The restorative and pharmacologic effects of LTC4, LTB4, and 5-HETE may provide a basis for their exogenous administration as an adjunctive treatment for patients with gram-negative bacterial pneumonia.
白三烯是由5-脂氧合酶催化花生四烯酸氧化形成的强效炎症脂质介质。虽然白三烯对中性粒细胞趋化性和活化的作用已得到证实，但其在调节先天性宿主防御机制中的作用却知之甚少。在之前的一项研究（M. 贝利、T. 斯坦迪福德、L. 莱恰尔克、M. 科菲、R. 斯特里特和M. 彼得斯-戈尔登，《免疫学杂志》157:5221 - 5224，1996年）中，我们使用5-脂氧合酶基因敲除小鼠确定了内源性白三烯在肺炎克雷伯菌的肺部清除和肺泡巨噬细胞吞噬作用中的关键作用。在本研究中，我们研究了特定内源性白三烯在肺炎克雷伯菌吞噬作用中的作用，并探讨了外源性白三烯能否在抑制内源性白三烯合成的肺泡巨噬细胞中恢复吞噬作用，以及能否在具有白三烯合成能力的细胞中增强这一过程。大鼠肺泡巨噬细胞在吞噬过程中产生白三烯B4（LTB4）、白三烯C4（LTC4）和5-羟基二十碳四烯酸（5-HETE），用齐留通和MK-886抑制内源性白三烯合成可显著减弱吞噬作用。当我们用LTB4、半胱氨酰白三烯或两者的质膜受体拮抗剂处理肺泡巨噬细胞时，我们也观察到吞噬作用降低。在具有白三烯合成能力的细胞中，LTC4对吞噬作用的增强程度最大，其次是5-HETE和LTB4。这些5-脂氧合酶反应产物在齐留通处理的大鼠肺泡巨噬细胞和5-脂氧合酶基因敲除小鼠的肺泡巨噬细胞中显示出相似的恢复吞噬作用的相对能力。我们得出结论，所有主要的5-脂氧合酶反应产物的内源性合成在吞噬作用中起重要作用。LTC4、LTB4和5-HETE的恢复和药理作用可能为它们作为革兰氏阴性细菌性肺炎患者辅助治疗的外源性给药提供依据。
