Gomperts Edward, Belcher John D, Otterbein Leo E, Coates Thomas D, Wood John, Skolnick Brett E, Levy Howard, Vercellotti Gregory M
Hillhurst Biopharmaceuticals, Inc, 2029 Verdugo Blvd., #125, Montrose, CA, 91020, USA.
University of Minnesota, 420 Delaware Street SE, MMC 480, Minneapolis, MN, 55455, USA.
Am J Hematol. 2017 Jun;92(6):569-582. doi: 10.1002/ajh.24750. Epub 2017 Apr 29.
Sickle Cell Disease (SCD) is a painful, lifelong hemoglobinopathy inherited as a missense point mutation in the hemoglobin (Hb) beta-globin gene. This disease has significant impact on quality of life and mortality, thus a substantial medical need exists to reduce the vaso-occlusive crises which underlie the pathophysiology of the disease. The concept that a gaseous molecule may exert biological function has been well known for over one hundred years. Carbon monoxide (CO), although studied in SCD for over 50 years, has recently emerged as a powerful cytoprotective biological response modifier capable of regulating a host of physiologic and therapeutic processes that, at low concentrations, exerts key physiological functions in various models of tissue inflammation and injury. CO is physiologically generated by the metabolism of heme by the heme oxygenase enzymes and is measurable in blood. A substantial amount of preclinical and clinical data with CO have been generated, which provide compelling support for CO as a potential therapeutic in a number of pathological conditions. Data underlying the therapeutic mechanisms of CO, including in SCD, have been generated by a plethora of in vitro and preclinical studies including multiple SCD mouse models. These data show CO to have key signaling impacts on a host of metallo-enzymes as well as key modulating genes that in sum, result in significant anti-inflammatory, anti-oxidant and anti-apoptotic effects as well as vasodilation and anti-adhesion of cells to the endothelium resulting in preservation of vascular flow. CO may also have a role as an anti-polymerization HbS agent. In addition, considerable scientific data in the non-SCD literature provide evidence for a beneficial impact of CO on cerebrovascular complications, suggesting that in SCD, CO could potentially limit these highly problematic neurologic outcomes. Research is needed and hopefully forthcoming, to carefully elucidate the safety and benefits of this potential therapy across the age spectrum of patients impacted by the host of pathophysiological complications of this devastating disease.
镰状细胞病（SCD）是一种遗传性血红蛋白病，终身伴有疼痛，它由血红蛋白（Hb）β-珠蛋白基因中的错义点突变遗传而来。这种疾病对生活质量和死亡率有重大影响，因此，迫切需要医学手段来减少作为该疾病病理生理学基础的血管闭塞性危机。气态分子可能发挥生物学功能这一概念已为人所知达一百多年。一氧化碳（CO）虽然在SCD研究中已有50多年历史，但最近已成为一种强大的细胞保护生物反应调节剂，能够调节许多生理和治疗过程，在低浓度下，它在各种组织炎症和损伤模型中发挥关键生理功能。CO在生理上由血红素加氧酶对血红素的代谢产生，且可在血液中检测到。已经产生了大量关于CO的临床前和临床数据，这些数据为CO作为多种病理状况下的潜在治疗手段提供了有力支持。包括多个SCD小鼠模型在内的大量体外和临床前研究产生了CO治疗机制的数据，包括在SCD中的数据。这些数据表明，CO对许多金属酶以及关键调节基因具有关键的信号传导影响，总体而言，会产生显著的抗炎、抗氧化和抗凋亡作用，以及血管舒张和细胞与内皮的抗粘附作用，从而保持血管血流。CO还可能作为一种抗聚合HbS剂发挥作用。此外，非SCD文献中的大量科学数据为CO对脑血管并发症的有益影响提供了证据，这表明在SCD中，CO可能潜在地限制这些极具问题的神经学后果。需要并有望很快开展研究，以仔细阐明这种潜在疗法对受这种毁灭性疾病众多病理生理并发症影响的各年龄段患者的安全性和益处。
