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: 10457638
• 负责人: Ammar Alishlash
• 金额: $ 25.99万
• 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/10457638
• 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; Centers for Disease Control and Prevention (U.S.); 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; Pregnant Women; Public Health; Quality of life; Randomized; 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; 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 涉及氯的工业事故（CL2）在美国（美国）每2-3天发生一次，并且是 与其他毒物相比，与死亡和伤害的风险更高有关。 13个非裔美国人中有一个 具有镰状细胞性状（SCT），这是镰状细胞病（SCD）的载体状态。因此，他们有很高的 卷入CL2事故的机会。 SCT患者的猝死风险很高和多机器人 暴露于压力条件时的失败，例如高空缺氧，环境热和运动。 这些损伤是由急性溶血和横纹肌溶解介导的，释放游离血红蛋白和 肌红蛋白。因此，患有SCT的人可能更容易受到多机构伤害和死亡的攻击 暴露于CL2。我们已经表明，CL2吸入导致人性化SCD小鼠的死亡率较高，并且 CL2作用是由急性溶血介导的。 Haptoglobin是一种急性相蛋白，可中和自由 - 血红蛋白和肌红蛋白限制了它们的毒性。结果，Haptoglobin已在欧洲得到批准， 日本治疗急性溶血相关的疾病，淹没了内源性触觉球蛋白系统。 因此，我们的假设是CL2吸入诱导夸张的溶血和横纹肌溶解 人性化的SCT小鼠导致多器官损伤增加（肺，肾脏和心脏）和死亡 到人源化正常血红蛋白对照小鼠。我们进一步假设暴露后给药 Haptoglobin通过清除自由血红蛋白和肌红蛋白来改善CL2吸入的结果。测试这个 假设，我们提出（目标1）来确定人源化的SCT小鼠是否更容易受到多机构的影响 暴露于CL2吸入时失败。如果SCT发生夸张的溶血和 与对照小鼠相比，CL2暴露后的横纹肌溶解，在（AIM 1B）中，我们将研究CL2是否是否 与对照相比 老鼠。在（AIM 2）中，我们将调查CL2暴露后的治疗益处触觉球蛋白给药。 （目的 2a）将测试与载体相比，是否会降低CL2吸入对重要器官的长期影响 （肺，肾脏和心脏）通过评估CL2暴露后14天的功能和结构。而（目标 2b）将检查触觉球蛋白是否在CL2吸入后2周内降低了SCT小鼠的死亡率。工作是 创新性，因为它将1）首次显示SCT患者的死亡风险更高和多机器人失败的风险 当暴露于CL2作为有毒吸入剂的一个例子时，2）将详细介绍CL2诱导器官损伤的机制 在SCT中，3）它将为靶向疗法提供强有力的临床前证明，因为这种脆弱 人口。因此，4）可以在与急性溶血相关的其他情况下测试触觉。 SCT和SCD人群可以改善其生存和生活质量，以降低健康差异。