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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要在美国 (US) 每 2-3 天就会发生一次涉及氯 (Cl2) 的工业事故，与其他有毒物质相比，死亡和受伤的风险更高。十分之一的非洲裔美国人具有镰状细胞性状 (SCT)，这是镰状细胞病 (SCD) 的携带者状态。因此，他们有很高的发生 Cl2 事故的机会。患有 SCT 的人猝死和多器官移植的风险很高当暴露于高原缺氧、环境炎热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介导的，并释放游离血红蛋白和肌红蛋白。因此，患有 SCT 的个体在以下情况下更容易遭受多器官损伤和死亡：暴露于 Cl2。我们已经证明，吸入 Cl2 会导致人源化 SCD 小鼠的死亡率更高，并且 Cl2 作用是由急性溶血介导的。触珠蛋白是一种急性期蛋白，可中和游离血红蛋白和肌红蛋白因此限制了它们的毒性。因此，触珠蛋白已在欧洲获得批准日本治疗导致内源性触珠蛋白系统崩溃的急性溶血相关病症。因此，我们的假设是，Cl2 吸入会导致过度溶血和横纹肌溶解。人源化 SCT 小鼠导致多器官损伤（肺、肾和心脏）和死亡增加人源化正常血红蛋白对照小鼠。我们进一步假设暴露后管理触珠蛋白通过清除游离血红蛋白和肌红蛋白来改善 Cl2 吸入的结果。为了测试这个假设，我们建议（目标 1）确定人源化 SCT 小鼠是否更容易受到多器官的影响当暴露于 Cl2 吸入时失效。我们将在（目标 1A）中测试 SCT 是否出现过度溶血并且与对照小鼠相比，Cl2 暴露后横纹肌溶解症，在（目标 1B）中，我们将研究 Cl2 是否与对照组相比，吸入会导致 SCT 小鼠更严重的多器官损伤（肺、肾和心脏）老鼠。在（目标 2）中，我们将研究接触珠蛋白在 Cl2 暴露后的治疗效果。（目的 2A) 将测试触珠蛋白与赋形剂相比是否能降低吸入 Cl2 对重要器官的长期影响（肺、肾和心脏），在 Cl2 暴露 14 天后评估其功能和结构。同时（目标 2B) 将检查触珠蛋白是否能降低吸入 Cl2 两周内 SCT 小鼠的死亡率。工作是创新性在于 1) 首次显示接受 SCT 的人是否面临更高的死亡和多器官衰竭风险以接触 Cl2 作为有毒吸入剂为例，2) 将详细说明 Cl2 引起器官损伤的机制在 SCT 中，3）它将为这一弱势群体提供靶向治疗触珠蛋白的强有力的临床前证据人口。因此，4) 可以在与急性溶血相关的其他情况下测试触珠蛋白 SCT 和 SCD 人群可提高其生存率和生活质量，从而缩小健康差距。