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

点击翻译按钮获取中文摘要

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.