Vacchiano C A, Osborne G R, Tempel G E
Department of Physiology, Medical University of South Carolina, Charleston 29425, USA.
Shock. 1998 Apr;9(4):266-73. doi: 10.1097/00024382-199804000-00006.
Oxygen exposure for a sufficient duration at high partial pressure results in pulmonary edema in humans and animals. Although the specific mediators of oxygen toxicity are unknown, evidence suggests that oxygen-based radicals such as superoxide anion (O2.) are increased in the lungs in the presence of hyperoxia and contribute to this injury. A series of isomeric prostanoid compounds, the isoprostanes, are formed by the free radical-initiated lipid peroxidation of arachidonic acid (AA). One of these isomers, 8-iso-PGF2alpha, is elevated in the bronchial alveolar lavage fluid of rats exposed to 90% oxygen for 48 h and is associated with a significant increase in protein accumulation in the pulmonary extravascular space. Alveolar macrophages (AMs) are capable of producing large quantities of (O2.), suggesting a role in pulmonary oxygen toxicity. We hypothesized that isolated rat AMs exposed to hyperoxia generate increased amount of 8-iso-PGF2alpha. AMs were exposed to air or 90% oxygen for 6, 12, 24, 48, 72, 96, and 120 h in the absence and presence of AA and/or calcium ionophore (A23187) and 8-iso-PGF2alpha was measured in the culture media. Exposure of primary cultures of AMs to 90% oxygen resulted in a significant increase in 8-iso-PGF2alpha in the media (25 +/- 2 pg/mL) compared with air-exposed controls (14 +/- 1 pg/mL). The addition of 10 microM AA and 2 microM A23187 to the culture media resulted in a marked increase in 8-iso-PGF2alpha production by AMs exposed to air and 90% oxygen. However, treatment of AMs with the combination of AA and A23187, followed by exposure to 90% oxygen for 72 h, resulted in a 27-fold increase in 8-iso-PGF2alpha compared with media alone and 90% oxygen. AMs metabolized free and phospholipid-bound AA to 8-iso-PGF2alpha, an activity enhanced in the 90% oxygen environment. Finally, acetylsalicylic acid, a cyclooxygenase inhibitor and free radical scavenger, reduced but did not abolish production of 8-iso-PGF2alpha. This study provides evidence that AMs produce a free radical-mediated isomeric prostaglandin compound that may be involved in pulmonary oxygen toxicity.
在高分压下暴露于氧气足够长的时间会导致人和动物出现肺水肿。尽管氧中毒的具体介质尚不清楚，但有证据表明，在高氧环境下，肺中诸如超氧阴离子（O₂⁻）等氧自由基会增加，并导致这种损伤。一系列异构前列腺素化合物，即异前列腺素，是由自由基引发的花生四烯酸（AA）脂质过氧化形成的。其中一种异构体，8-异前列腺素F2α（8-iso-PGF2α），在暴露于90%氧气48小时的大鼠支气管肺泡灌洗液中升高，并且与肺血管外间隙中蛋白质积聚的显著增加有关。肺泡巨噬细胞（AMs）能够产生大量的（O₂⁻），提示其在肺氧中毒中起作用。我们假设，暴露于高氧环境的离体大鼠AMs会产生增加量的8-iso-PGF2α。在有和没有AA和/或钙离子载体（A23187）的情况下，将AMs暴露于空气或90%氧气中6、12、24、48、72、96和120小时，并测定培养基中的8-iso-PGF2α。与暴露于空气的对照（14±1 pg/mL）相比，将AMs原代培养物暴露于90%氧气会导致培养基中8-iso-PGF2α显著增加（25±2 pg/mL）。向培养基中添加10μM AA和2μM A23187会导致暴露于空气和90%氧气的AMs产生的8-iso-PGF2α显著增加。然而，用AA和A23187联合处理AMs，随后暴露于90%氧气72小时，与单独培养基和90%氧气相比，8-iso-PGF2α增加了27倍。AMs将游离的和磷脂结合的AA代谢为8-iso-PGF2α，这种活性在90%氧气环境中增强。最后，环氧化酶抑制剂和自由基清除剂乙酰水杨酸减少但并未消除8-iso-PGF2α的产生。本研究提供了证据表明AMs产生一种自由基介导的异构前列腺素化合物，其可能参与肺氧中毒。
