Otterbein L E, Mantell L L, Choi A M
Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven 06520, Connecticut, USA.
Am J Physiol. 1999 Apr;276(4):L688-94. doi: 10.1152/ajplung.1999.276.4.L688.
Findings in recent years strongly suggest that the stress-inducible gene heme oxygenase (HO)-1 plays an important role in protection against oxidative stress. Although the mechanism(s) by which this protection occurs is poorly understood, we hypothesized that the gaseous molecule carbon monoxide (CO), a major by-product of heme catalysis by HO-1, may provide protection against oxidative stress. We demonstrate here that animals exposed to a low concentration of CO exhibit a marked tolerance to lethal concentrations of hyperoxia in vivo. This increased survival was associated with highly significant attenuation of hyperoxia-induced lung injury as assessed by the volume of pleural effusion, protein accumulation in the airways, and histological analysis. The lungs were completely devoid of lung airway and parenchymal inflammation, fibrin deposition, and pulmonary edema in rats exposed to hyperoxia in the presence of a low concentration of CO. Furthermore, exogenous CO completely protected against hyperoxia-induced lung injury in rats in which endogenous HO enzyme activity was inhibited with tin protoporphyrin, a selective inhibitor of HO. Rats exposed to CO also exhibited a marked attenuation of hyperoxia-induced neutrophil infiltration into the airways and total lung apoptotic index. Taken together, our data demonstrate, for the first time, that CO can be therapeutic against oxidative stress such as hyperoxia and highlight possible mechanism(s) by which CO may mediate these protective effects.
近年来的研究结果有力地表明，应激诱导基因血红素加氧酶（HO）-1在抵御氧化应激中发挥着重要作用。尽管这种保护作用发生的机制尚不清楚，但我们推测气态分子一氧化碳（CO），即HO-1催化血红素的主要副产物，可能提供对氧化应激的保护。我们在此证明，暴露于低浓度CO的动物在体内对致死浓度的高氧表现出显著的耐受性。通过胸腔积液量、气道内蛋白质积聚和组织学分析评估，这种存活率的提高与高氧诱导的肺损伤的高度显著减轻有关。在低浓度CO存在的情况下暴露于高氧的大鼠中，肺完全没有气道和实质炎症、纤维蛋白沉积以及肺水肿。此外，外源性CO完全保护了内源性HO酶活性被锡原卟啉（一种HO的选择性抑制剂）抑制的大鼠免受高氧诱导的肺损伤。暴露于CO的大鼠还表现出高氧诱导的中性粒细胞向气道浸润和全肺凋亡指数的显著降低。综上所述，我们的数据首次证明，CO可以治疗诸如高氧等氧化应激，并突出了CO可能介导这些保护作用的潜在机制。
