Heme oxygenase (HO), by catabolizing heme to bile pigments, down-regulates cellular levels of heme and hemeproteins; certain of the latter, i.e. cytochrome P450s, generate pro-inflammatory products from endogenous substrates. Two HO isozymes, the products of distinct genes, have been described; HO-1 is the inducible one, whereas HO-2 is believed to be constitutively expressed. We studied the inducing effects of several metal compounds [CoCl2, SnCl2, ZnCl2, heme, and cobalt protoporphyrin (CoPP)] on HO-1 mRNA content and enzyme activity in cultures of rabbit corneal epithelial (RCE) cells; these metal compounds are known to induce HO in other tissues. Additionally, we studied HO-1 expression in an experimental model of ocular inflammation produced in rabbit corneas by extended contact lens wear, and the relation of HO expression to the induced inflammatory process. SnCl2 added to RCE cells in vitro produced marked time- and concentration-dependent increases in HO-1 mRNA and HO-1 enzyme activity; CoCl2, ZnCl2, and CoPP were inducers of HO as well, though to a lesser degree than SnCl2. Corneas treated for 6 days with contact lenses impregnated with SnCl2 displayed substantially less corneal inflammation, swelling, and new vessel invasion than did controls; attenuation of ocular inflammation was paralleled by SnCl2-induced increases in HO mRNA and HO activity in corneal epithelial cells from treated eyes. It is suggested that amelioration of the inflammatory response produced by extended contact lens wear is due, in part, to the induction of high levels of HO-1 activity by SnCl2, which results in diminished production of pro-inflammatory mediators generated through heme-dependent metabolic processes. Regulation of HO activity in this manner may have clinical applications.

译文

血红素加氧酶 (HO) 通过将血红素分解为胆汁色素,下调血红素和血红素的细胞水平; 某些后者,即细胞色素p450,从内源性底物产生促炎产物。已经描述了两个HO同工酶,即不同基因的产物; HO-1是可诱导的,而HO-2被认为是组成型表达的。我们研究了几种金属化合物 [CoCl2,SnCl2,ZnCl2,血红素和钴原卟啉 (CoPP)] 对兔角膜上皮 (RCE) 细胞培养物中HO-1 mRNA含量和酶活性的诱导作用; 这些金属化合物已知会在其他组织中诱导HO。此外,我们研究了通过长时间戴隐形眼镜在兔角膜中产生的眼部炎症的实验模型中的HO-1表达,以及HO表达与诱导的炎症过程的关系。体外添加到RCE细胞中的SnCl2会导致HO-1 mRNA和HO-1酶活性随时间和浓度的显着增加; CoCl2,ZnCl2和CoPP也是HO的诱导剂,尽管程度低于SnCl2。与对照组相比,用SnCl2浸渍的隐形眼镜治疗6天的角膜表现出明显更少的角膜炎症,肿胀和新血管浸润; 眼部炎症的减弱与治疗眼角膜上皮细胞中HO mRNA和HO活性的SnCl2-induced增加平行。建议延长隐形眼镜佩戴产生的炎症反应的改善部分是由于SnCl2诱导了高水平的HO-1活性,从而导致通过血红素产生的促炎症介质的产生减少依赖代谢过程。以这种方式调节HO活性可能具有临床应用。

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