Sickle Cell Trait Mice are More Susceptible to Chlorine Exposure and Haptoglobin Improves the Outcomes

镰状细胞性状小鼠对氯暴露更敏感，触珠蛋白改善了结果

• 批准号: 10599327
• 负责人: Ammar Alishlash
• 金额: $ 18.56万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599327
• 关键词: Accidents; Accounting; Acute; Acute Renal Failure with Renal Papillary Necrosis; Acute-Phase Proteins; Adverse effects; Affect; African American population; Altitude; Attenuated; Binding; Carrier State; Cessation of life; Child; Chlorine; Chronic; Data; Death Rate; Development; Disease; Dose; Elderly woman; Erythrocytes; Europe; Exercise; Exhibits; Exposure to; Haptoglobins; Heart; Heart Injuries; Heme; Hemoglobin; Hemolysis; Hemopexin; Hour; Hypoxia; Individual; Industrial Accidents; Inhalant dose form; Inhalation; Injections; Injury; Injury to Kidney; Japan; Kidney; Long-Term Effects; Lung; Mediating; Medical Device; Multiple Organ Failure; Mus; Myoglobin; Organ; Persons; Population; Predisposition; Pregnant Women; Public Health; Quality of life; Randomized; Recommendation; Reduce health disparities; Reporting; Research; Rhabdomyolysis; Risk; Risk Factors; Sickle Cell Anemia; Sickle Cell Trait; Strenuous Exercise; Structure; Sudden Death; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Toxicant exposure; Transfusion; United States; Vulnerable Populations; Work; comparison control; hemoglobin AA; high risk; improved; improved outcome; innovation; intraperitoneal; lung injury; mass casualty; mortality; mortality risk; multiorgan injury; organ injury; pre-clinical; stressor; targeted treatment; therapeutic evaluation; toxicant

PROJECT SUMMARY/ABSTRACT Industrial accidents involving chlorine (Cl2) occur once every 2-3 days in the United States (US) and are associated with higher risk of death and injuries compared to other toxicants. One out of 13 African Americans have Sickle Cell Trait (SCT) which is the carrier state of Sickle Cell Disease (SCD). Therefore, they have a high chance of being involved in Cl2 accidents. People with SCT are at high risk of sudden death and multiorgan failure when exposed to stressful conditions such as high-altitude hypoxia, environmental heat, and exercise. These injuries are mediated by acute hemolysis and rhabdomyolysis with the release of free hemoglobin and myoglobin. Consequently, individuals with SCT can be more vulnerable to multiorgan injury and death when exposed to Cl2. We have shown that Cl2 inhalation results in higher death rate in humanized SCD mice and that Cl2 action is mediated by acute hemolysis. Haptoglobin is an acute phase protein that neutralizes free- hemoglobin and myoglobin thus limiting their toxicity. As a result, haptoglobin has been approved in Europe and Japan to treat acute hemolysis associated conditions that overwhelm the endogenous haptoglobin system. Therefore, our hypothesis is that Cl2 inhalation induces exaggerated hemolysis and rhabdomyolysis in humanized SCT mice resulting in increased multiorgan injury (lungs, kidneys, and heart) and death compared to humanized normal hemoglobin control mice. We further hypothesize that postexposure administration of haptoglobin improves the outcomes of Cl2 inhalation by scavenging free hemoglobin and myoglobin. To test this hypothesis, we are proposing (Aim 1) to determine if humanized SCT mice are more susceptible to multiorgan failure when exposed to Cl2 inhalation. We will test in (Aim 1A) if SCT develop exaggerated hemolysis and rhabdomyolysis after Cl2 exposure compared to control mice, and in (Aim 1B) we will investigate whether Cl2 inhalation induces more severe multiorgan injury (lungs, kidneys, and heart) in the SCT mice compared to control mice. In (Aim 2) we will investigate the therapeutic benefits haptoglobin administration after Cl2 exposure. (Aim 2A) will test if haptoglobin compared to vehicle reduces the long-term effects of Cl2 inhalation on the vital organs (lungs, kidneys, and heart) by evaluating their functions and structures 14 days after Cl2 exposure. While (Aim 2B) will examine if haptoglobin reduces the death rate of SCT mice within 2 weeks of Cl2 inhalation. The work is innovative as it will 1) show for the first time if people with SCT are at higher risk of death and multiorgan failure when exposed to Cl2 as an example of toxic inhalants, 2) it will detail the mechanism of Cl2 induced organ injury in SCT, and 3) it will provide a strong preclinical proof of targeted therapy, haptoglobin, for this vulnerable population. Consequently, 4) haptoglobin can be tested in other conditions associated with acute hemolysis in SCT and SCD population to improve their survival and quality of life towards decreasing the health disparity.

项目摘要/摘要 在美国，涉及氯(Cl2)的工业事故每2-3天发生一次， 与其他毒物相比，具有更高的死亡和受伤风险。每13名非洲裔美国人中就有一人 具有镰刀细胞性状(SCT)，这是镰刀细胞病(SCD)的携带者状态。因此，他们有很高的 涉及Cl2事故的几率。SCT患者猝死和多器官的风险很高 暴露在高海拔低氧、环境高温和运动等压力条件下时会失败。 这些损伤是由急性溶血和横纹肌溶解引起的，释放出游离的血红蛋白和 肌红蛋白。因此，SCT患者在以下情况下更容易受到多器官损伤和死亡的影响 暴露在Cl2中。我们已经证明，吸入Cl2会导致人源化SCD小鼠更高的死亡率，而且 Cl2的作用是通过急性溶血来调节的。结合珠蛋白是一种急性期蛋白，能中和游离态 血红蛋白和肌红蛋白因此限制其毒性。因此，结合珠蛋白已在欧洲和 日本将治疗压倒内源性结合珠蛋白系统的急性溶血相关疾病。 因此，我们的假设是，吸入Cl2会导致大鼠过度的溶血和横纹肌溶解。 人源化SCT小鼠导致多器官损伤(肺、肾和心脏)增加和死亡比较 人源化的正常血红蛋白对照组小鼠。我们进一步假设，暴露后给药 结合珠蛋白通过清除游离血红蛋白和肌红蛋白改善吸入Cl2的结果。为了测试这一点 假设，我们建议(目标1)确定人源化的SCT小鼠是否更容易患多器官移植 当接触到Cl2吸入时失败。我们将在(目标1A)中测试SCT是否出现夸大的溶血和 与对照组小鼠的横纹肌溶解反应的比较，以及在(Aim 1B)中，我们将调查Cl2是否 吸入导致SCT小鼠比对照组更严重的多器官损伤(肺、肾和心脏) 老鼠。在(目标2)中，我们将研究接触Cl2后使用结合珠蛋白的治疗效果。(目标 将测试结合珠蛋白与赋形剂相比是否降低了吸入Cl2对重要器官的长期影响 (肺、肾和心脏)，在接触Cl2 14天后评估它们的功能和结构。While(瞄准 2b)将在吸入Cl2的2周内检查结合珠蛋白是否降低SCT小鼠的死亡率。这项工作是 创新之处在于它将首次展示SCT患者的死亡风险和多器官衰竭风险是否更高 当接触到Cl2作为有毒吸入剂的例子时，2)它将详细说明Cl2引起的器官损伤的机制 在SCT中，以及3)它将为这种脆弱的患者提供靶向治疗的强有力的临床前证据，结合珠蛋白。 人口。因此，结合珠蛋白可以在其他与急性溶血有关的条件下进行检测。 旨在改善SCT和SCD人群的生存和生活质量，以缩小健康差距。