Ethanol ingestion increases activation of matrix metalloproteinases in rat lungs during acute endotoxemia
Ethanol ingestion increases activation of matrix metalloproteinases in rat lungs during acute endotoxemia
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DOI：
10.1164/ajrccm.160.4.9811060
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发表时间：
1999-10-01
影响因子：
24.7
通讯作者：
Guidot, DM
中科院分区：
文献类型：
--
作者：
Lois, M;Brown, LAS;Guidot, DM
以前我们曾报道过酒精滥用会增加脓毒症患者急性呼吸窘迫综合征（ARDS）的发病率，大鼠长期摄入乙醇会耗尽肺泡上皮谷胱甘肽并增加内毒素介导的肺水肿。在这项研究中，我们研究了乙醇诱导的谷胱甘肽耗竭可能导致急性肺损伤的潜在机制。我们假设谷胱甘肽耗竭激活基质金属蛋白酶（MMPs），从而增加脓毒症期间肺泡细胞外基质（ECM）的降解。用乙醇喂养大鼠（20%vol/vol的水溶液，持续6周），给予内毒素（2 mg/kg，腹膜内），2 h后进行肺分离，并用n-甲酰-甲硫氨酰-亮氨酰-苯丙氨酸（fMLP）（10（-7）M）离体灌注。与对照组大鼠相比，乙醇摄入增加了（p < 0.05）MMP-9和MMP-2活性（通过酶谱法测定），在肺组织和灌洗液中，并增加了（p < 0.05）肺灌洗液中IV型胶原7S片段的水平。乙醇摄入增加激活，但不生产，MMP-9和MMP-2酶原。最后，虽然同时摄入N-乙酰半胱氨酸对MMP的产生没有影响（p > 0.05），但它增加了（p > 0.05）肺谷胱甘肽水平，阻断了（p < 0.05）MMP-9和MMP-2的活化，并降低了（p < 0.05）IV型胶原7S片段的水平。我们的结论是，慢性乙醇摄入，通过谷胱甘肽耗竭，激活基质金属蛋白酶在脓毒症，从而增加肺泡上皮细胞外基质的降解。
Previously we reported that alcohol abuse increases the incidence of the acute respiratory distress syndrome (ARDS) in septic patients, and that chronic ethanol ingestion in rats depletes alveolar epithelial glutathione and increases endotoxin-mediated lung edema. In this study we examined a potential mechanism by which ethanol-induced glutathione depletion could predispose to acute lung injury. We hypothesized that glutathione depletion activates matrix metalloproteinases (MMPs), thereby increasing degradation of the alveolar extracellular matrix (ECM) during sepsis. Ethanol-fed rats (20% vol/vol in water for 6 wk) were given endotoxin (2 mg/kg, intraperitoneally) followed 2 h later by lung isolation and ex vivo perfusion with n-formyl-methionyl-leucyl-phenylalanine (fMLP) (10(-7) M). Ethanol ingestion increased (p < 0.05) MMP-9 and MMP-2 activity, as determined by zymography, in the lung tissue and lavage fluid compared with control-fed rats, and increased (p < 0.05) levels of the 7S fragment of type IV collagen in the lung lavage fluid. Ethanol ingestion increased activation, but not production, of the MMP-9 and MMP-2 zymogens. Finally, although concomitant ingestion of N-acetylcysteine had no effect (p > 0.05) on MMP production, it increased (p > 0.05) lung glutathione levels, blocked (p < 0.05) MMP-9 and MMP-2 activation, and decreased (p < 0.05) levels of the 7S fragment of type IV collagen. We conclude that chronic ethanol ingestion, via glutathione depletion, activates MMPs during sepsis, thereby increasing degradation of the alveolar epithelial ECM.