CIMETIDINE REDUCES HYPEROXIC LUNG INJURY IN LAMBS
CIMETIDINE REDUCES HYPEROXIC LUNG INJURY IN LAMBS
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DOI：
10.1152/jappl.1989.67.6.2586
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发表时间：
1989-12-01
影响因子：
3.3
通讯作者：
HANSEN, TN
中科院分区：
文献类型：
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作者：
HAZINSKI, TA;FRANCE, M;HANSEN, TN
我们之前曾报道，内毒素治疗前显著减少了羔羊的急性肺氧中毒(J.Appl。物理。65：1579-1585,1988)。S说，内毒素的诸多作用之一是抑制细胞色素P-450的单加氧反应，据信这些反应会产生有毒的O2物种。因此，内毒素对S有益作用的一个可能解释是，它抑制了高氧时P-450介导的氧自由基的产生。为了验证这一假设，我们在持续暴露于95%O2之前，给9只羔羊注射了单剂量的西咪替丁，这是一种非竞争性的P-450活性抑制剂。与6只对照羔羊相比，西咪替丁处理组羔羊氧气暴露72 h后维持正常气体交换的时间较长(P<；0.01)，肺水蓄积速度较慢(P<；0.01)，微血管通透性正常。西咪替丁处理的羔羊死后无血肺匀浆中抗氧化酶水平没有增加。然而，服用非米替丁的羔羊体内氧化谷胱甘肽水平显著降低，还原型谷胱甘肽与氧化型谷胱甘肽的比率(谷胱甘肽/谷胱甘肽比值)是对照组的7倍(P<；0.001)。在4只羔羊中，雷尼替丁(一种化学上与西咪替丁有关但没有P-450抑制活性的药物)对O2损伤的时间进程和死后抗氧化剂都没有影响。从所有研究动物的无血肺中分离出微粒体，并测定其形式2同工酶的P-450活性。氧暴露显著增加P-450活性，内毒素和西咪替丁(但不是雷尼替丁)预处理可显著抑制这种增加。我们的结论是，与内毒素一样，西咪替丁通过一种不涉及抗氧化酶增强的机制来减轻O2诱导的羔羊肺损伤。低水平的氧化谷胱甘肽和对细胞色素P-450活性的抑制表明，西咪替丁处理的羔羊在氧气暴露期间可能产生了较少的P-450衍生氧化剂。
We previously reported that pretreamtent with endotoxin significantly reduced acute pulmonary O2 toxicity in lambs (J. Appl. Physiol. 65: 1579-1585, 1988). One of endotoxin''s many effects is to inhibit cytochrome P-450 monooxygenation reactions, which are believed to produce toxic O2 species. Therefore, one possible explanation for endotoxin''s beneficial effect is that it inhibited P-450-mediated O2 radical production during hyperoxia. To test this hypothesis, we administered a single dose of cimetidine, a noncompetitive inhibitor of P-450 activity, to nine lambs before continuous exposure to > 95% O2. Compared with six control O2-exposed lambs, the cimetidine-treated O2-exposed lambs maintained normal gas exchange for a longer period of time (P < 0.01), accumulated lung water at a slower rate (P < 0.01), and had normal microvascular permeability after 72 h of O2 exposure. Postmortem levels of antioxidant enzymes in blood-free lung homogenate were not increased in cimetidine-treated lambs. However, the levels of oxidized glutathione were significantly lower in fimetidine-treated lambs, and the ratio of reduced to oxidized glutathione concentrations (GSH/GSSG ratio) was sevenfold higher than the ratio measured in control O2-exposed lambs (P < 0.001). In four lambs, pretreatment with ranitidine (a drug chemically related to cimetidine but without P-450 inhibitory activity) had no effect either on the time course of O2 injury or on postmortem antioxidants. Microsomes were isolated from blood-free lung of all study animals and P-450 activity of the form 2 isozyme was measured. O2 exposure significantly increased P-450 activity, and pretreatment with both endotoxin and cimetidine (but not ranitidine) significantly blunted this increase. We conclude that, like endotoxin, cimetidine reduces O2-induced lung injury in lambs by a mechanism that does not involve antioxidant enzyme augmentation. The low levels of oxidized glutathione and the inhibition of cytochrome P-450 activity suggest that the cimetidine-treated lambs may have produced less P-450-derived oxidants during O2 exposure.