Hirsch Rhoda Elison, Sibmooh Nathawut, Fucharoen Suthat, Friedman Joel M
1 Department of Medicine (Hematology), Albert Einstein College of Medicine , Bronx, New York.
2 Department of Anatomy and Structural Biology, Albert Einstein College of Medicine , Bronx, New York.
Antioxid Redox Signal. 2017 May 10;26(14):794-813. doi: 10.1089/ars.2016.6806. Epub 2016 Nov 28.
Oxidative stress and generation of free radicals are fundamental in initiating pathophysiological mechanisms leading to an inflammatory cascade resulting in high rates of morbidity and death from many inherited point mutation-derived hemoglobinopathies. Hemoglobin (Hb)E is the most common point mutation worldwide. The β-globin gene is found in greatest frequency in Southeast Asia, including Thailand, Malaysia, Indonesia, Vietnam, Cambodia, and Laos. With the wave of worldwide migration, it is entering the gene pool of diverse populations with greater consequences than expected.
While HbE by itself presents as a mild anemia and a single gene for β-thalassemia is not serious, it remains unexplained why HbE/β-thalassemia (HbE/β-thal) is a grave disease with high morbidity and mortality. Patients often exhibit defective physical development, severe chronic anemia, and often die of cardiovascular disease and severe infections. Recent Advances: This article presents an overview of HbE/β-thal disease with an emphasis on new findings pointing to pathophysiological mechanisms derived from and initiated by the dysfunctional property of HbE as a reduced nitrite reductase concomitant with excess α-chains exacerbating unstable HbE, leading to a combination of nitric oxide imbalance, oxidative stress, and proinflammatory events.
Additionally, we present new therapeutic strategies that are based on the emerging molecular-level understanding of the pathophysiology of this and other hemoglobinopathies. These strategies are designed to short-circuit the inflammatory cascade leading to devastating chronic morbidity and fatal consequences. Antioxid. Redox Signal. 26, 794-813.
氧化应激和自由基的产生是引发病理生理机制的基础，这些机制会导致炎症级联反应，从而使许多遗传性点突变引起的血红蛋白病的发病率和死亡率居高不下。血红蛋白（Hb）E是全球最常见的点突变。β-珠蛋白基因在东南亚地区（包括泰国、马来西亚、印度尼西亚、越南、柬埔寨和老挝）的出现频率最高。随着全球移民潮的到来，它正进入不同人群的基因库，其影响比预期的更为严重。
虽然HbE本身表现为轻度贫血，单个β地中海贫血基因也并不严重，但HbE/β地中海贫血（HbE/β-thal）为何是一种具有高发病率和死亡率的严重疾病，目前仍无法解释。患者通常表现出生长发育缺陷、严重的慢性贫血，常死于心血管疾病和严重感染。最新进展：本文概述了HbE/β地中海贫血疾病，重点介绍了新发现，这些发现指出了由HbE功能失调特性引发的病理生理机制，即HbE作为一种亚硝酸盐还原酶减少，同时过量的α链加剧了不稳定的HbE，导致一氧化氮失衡、氧化应激和促炎事件的综合作用。
此外，我们还介绍了基于对这种及其他血红蛋白病病理生理学新出现的分子水平理解的新治疗策略。这些策略旨在绕过导致毁灭性慢性发病和致命后果的炎症级联反应。《抗氧化与氧化还原信号》26卷，794 - 813页。
