Sporn P H, Murphy T M, Peters-Golden M
Department of Internal Medicine, University of Michigan, Ann Arbor.
Am J Respir Cell Mol Biol. 1990 Jan;2(1):81-90. doi: 10.1165/ajrcmb/2.1.81.
Metabolites of arachidonic acid (AA) released into bronchoalveolar lavage fluid of animals exposed to hyperoxia have previously been implicated as mediators of pulmonary oxygen toxicity. The alveolar macrophage (AM) represents an important potential source of these eicosanoids. We have therefore investigated the effects of in vitro hyperoxia (95% O2/5% CO2) versus normoxia (95% air/5% CO2) on the metabolism of AA in the AM of the rat. Exposure to 95% O2 for up to 72 h did not impair the viability or affect the protein content of cultured AMs. Hyperoxia for 24 to 72 h increased the accumulation of free AA liberated from endogenous stores in cultures of resting AMs. Despite this increase in free AA, no changes in synthesis of thromboxane B2, prostaglandin (PG) E2, PGF2 alpha, leukotriene (LT) B4, or LTC4 were observed in resting AMs exposed to hyperoxia for up to 72 h. This was not due to degradation of eicosanoids in hyperoxia. However, formation of cyclooxygenase metabolites from exogenously supplied AA was reduced in hyperoxia-incubated AMs, suggesting that hyperoxia inhibited the cyclooxygenase enzyme. In AMs stimulated with calcium ionophore A23187, both AA release and synthesis of cyclooxygenase and lipoxygenase eicosanoids were augmented after incubation in hyperoxia for 24 to 72 h. The increase in A23187-stimulated LTB4 synthesis caused by hyperoxia was inhibited by the antioxidants catalase, superoxide dismutase, and the intracellular cysteine loading agent L-2-oxothiazolidine-4-carboxylic acid, suggesting that the augmentation by hyperoxia of A23187-induced AA metabolism was mediated by reactive oxygen metabolites. Thus, hyperoxia has complex effects on AA metabolism in the AM, which include the ability to augment the release of AA and formation of bioactive eicosanoids. These findings support a possible role for eicosanoid synthesis by the AM in the pathogenesis of oxygen toxicity of the lung.
花生四烯酸（AA）的代谢产物释放到暴露于高氧环境的动物支气管肺泡灌洗液中，此前一直被认为是肺氧中毒的介质。肺泡巨噬细胞（AM）是这些类二十烷酸的一个重要潜在来源。因此，我们研究了体外高氧（95% O₂/5% CO₂）与常氧（95%空气/5% CO₂）对大鼠AM中AA代谢的影响。暴露于95% O₂长达72小时并未损害培养的AM的活力，也未影响其蛋白质含量。24至72小时的高氧暴露增加了静息AM培养物中从内源性储存释放的游离AA的积累。尽管游离AA有所增加，但在暴露于高氧长达72小时的静息AM中，未观察到血栓素B₂、前列腺素（PG）E₂、PGF₂α、白三烯（LT）B₄或LTC₄合成的变化。这并非由于高氧环境中类二十烷酸的降解。然而，在高氧孵育的AM中，外源性提供的AA生成环氧化酶代谢产物的过程减少，这表明高氧抑制了环氧化酶。在用钙离子载体A23187刺激的AM中，在高氧孵育24至72小时后，AA释放以及环氧化酶和脂氧化酶类二十烷酸的合成均增加。高氧引起的A23187刺激的LTB₄合成增加被抗氧化剂过氧化氢酶、超氧化物歧化酶以及细胞内半胱氨酸加载剂L-2-氧代噻唑烷-4-羧酸抑制，这表明高氧对A23187诱导的AA代谢的增强作用是由活性氧代谢产物介导的。因此，高氧对AM中的AA代谢具有复杂的影响，包括增加AA的释放和生物活性类二十烷酸的形成。这些发现支持了AM合成类二十烷酸在肺氧中毒发病机制中可能发挥的作用。
