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

项目总结/摘要 在美国，涉及氯（Cl 2）的工业事故每2-3天发生一次， 与其他毒物相比，死亡和受伤的风险更高。每13个非洲裔美国人中就有一个 具有镰状细胞特征（SCT），这是镰状细胞病（SCD）的携带状态。因此，他们有很高的 发生氯气事故的可能性SCT患者猝死和多器官功能衰竭的风险很高。 当暴露在高海拔缺氧、环境高温和运动等压力条件下时，会出现衰竭。 这些损伤由急性溶血和横纹肌溶解介导，伴随游离血红蛋白的释放， 肌红蛋白因此，SCT患者在以下情况下更容易发生多器官损伤和死亡： 暴露于Cl 2。我们已经表明，吸入Cl 2导致人源化SCD小鼠的死亡率较高， Cl 2的作用是由急性溶血介导的。触珠蛋白是一种急性时相蛋白， 血红蛋白和肌红蛋白，从而限制了它们的毒性。因此，触珠蛋白已在欧洲获得批准， 日本治疗急性溶血相关的条件，压倒内源性触珠蛋白系统。 因此，我们的假设是，Cl 2吸入诱导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， 触珠蛋白通过清除游离血红蛋白和肌红蛋白改善Cl 2吸入的结果。为了验证这一 假设，我们提出（目的1），以确定是否人源化SCT小鼠更容易受到多器官移植， 当暴露于Cl 2吸入时失效。我们将在（目标1A）中测试SCT是否发生过度溶血， 与对照组小鼠相比，暴露于Cl 2后横纹肌溶解，在（目的1B）中，我们将研究Cl 2是否 与对照组相比，吸入在SCT小鼠中诱导更严重的多器官损伤（肺、肾和心脏 小鼠在（目的2）中，我们将研究在Cl 2暴露后施用触珠蛋白的治疗益处。（目标 2A）将测试触珠蛋白与媒介物相比是否减少Cl 2吸入对重要器官的长期影响 （肺，肾和心脏），通过评估其功能和结构14天后，氯暴露。目标（Aim） 图2B）将检查触珠蛋白是否降低吸入Cl 2的2周内SCT小鼠的死亡率。这项工作是 创新，因为它将1）首次显示SCT患者死亡和多器官衰竭的风险是否更高 当暴露于Cl 2作为有毒吸入剂的例子时，2）它将详细描述Cl 2诱导的器官损伤的机制 在SCT，和3）它将提供一个强有力的临床前证据的靶向治疗，触珠蛋白，为这个脆弱的 人口因此，4）触珠蛋白可以在与急性溶血相关的其他条件下测试， SCT和SCD人群，以改善他们的生存和生活质量，减少健康差距。

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.