Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation.
Targeting heme oxygenase-1 and carbon monoxide for therapeutic modulation of inflammation.
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DOI：
10.1016/j.trsl.2015.06.011
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Choi AM
中科院分区：
文献类型：
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作者：
Ryter SW;Choi AM
血红素氧合酶-1(HO-1)酶系统仍然是治疗炎症性疾病的一个有吸引力的靶点。HO-1是一种细胞应激蛋白，在血红素降解生成一氧化碳(CO)、铁和胆绿素-IXα(BV)的过程中起着重要的代谢作用，BV转化为胆红素-IXα(BR)。HO-1可能通过产生其生物活性的最终产物，即CO和BV/BR，发挥炎症信号程序的多效性调节作用。当外源性应用时，一氧化碳可以影响细胞的凋亡、增殖和炎症程序。具体地说，一氧化碳可以调节促炎或抗炎细胞因子和介质的产生。HO-1/CO还可能在调节抗原提呈细胞、树突状细胞和调节性T细胞的功能方面具有免疫调节作用。在疾病中调节HO-1的治疗策略包括应用天然诱导化合物，以及靶向基因过度表达或敲除HO-1的基因治疗方法。几种化合物已被用于治疗抑制HO活性，包括金属卟啉系列的竞争性抑制剂，或咪唑-二氧杂环戊烷的非竞争性异构体选择性衍生物。HO活性的最终产物BV/BR和CO可用于药物治疗。可以通过吸入或使用CO释放分子(球茎)来应用CO。本文将讨论HO-1作为炎症相关疾病的治疗靶点，包括肺和血管损伤、脓毒症、缺血/再灌注损伤和移植排斥反应。
The heme oxygenase-1 (HO-1) enzyme system remains an attractive therapeutic target for the treatment of inflammatory conditions. HO-1, a cellular stress protein, serves a vital metabolic function as the rate-limiting step in the degradation of heme to generate carbon monoxide (CO), iron, and biliverdin-IXα (BV) which is converted to bilirubin-IXα (BR). HO-1 may function as a pleiotropic regulator of inflammatory signaling programs, through the generation of its biologically active end-products, namely CO and BV/BR. CO, when applied exogenously, can affect apoptotic, proliferative, and inflammatory cellular programs. Specifically, CO can modulate the production of pro- or anti-inflammatory cytokines and mediators. HO-1/CO may also have immunomodulatory effects with respect to regulating the functions of antigen-presenting cells, dendritic cells, and regulatory T-cells. Therapeutic strategies to modulate HO-1 in disease include the application of natural inducing compounds, as well as gene therapy approaches for the targeted genetic overexpression or knockdown of HO-1. Several compounds have been used therapeutically to inhibit HO activity, including competitive inhibitors of the metalloporphyrin series, or non-competitive isoform-selective derivatives of imidazole-dioxolanes. The end-products of HO activity, BV/BR and CO may be used therapeutically as pharmacological treatments. CO may be applied by inhalation, or through the use of CO releasing molecules (CORMs). This review will discuss HO-1 as a therapeutic target in diseases involving inflammation, including lung and vascular injury, sepsis, ischemia/reperfusion injury and transplant rejection.