Chlorine inhalation induces acute chest syndrome in humanized sickle cell mouse model and ameliorated by postexposure hemopexin.
Chlorine inhalation induces acute chest syndrome in humanized sickle cell mouse model and ameliorated by postexposure hemopexin.
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DOI：
10.1016/j.redox.2021.102009
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发表时间：
2021-08
期刊：
影响因子：
11.4
通讯作者：
Matalon S
中科院分区：
文献类型：
--
作者：
Alishlash AS;Sapkota M;Ahmad I;Maclin K;Ahmed NA;Molyvdas A;Doran S;Albert CJ;Aggarwal S;Ford DA;Ambalavanan N;Jilling T;Matalon S
急性胸部综合征（ACS）的触发因素是镰状细胞病（SCD）患者死亡的主要原因，靶向治疗有限。氯（Cl2）吸入频繁发生，但其作为ACS潜在触发因素的作用尚未确定。在这项研究中，我们假设，Cl2暴露类似于在附近的工业事故诱导急性溶血与急性肺损伤，联想到ACS在人源化SCD小鼠。当暴露于Cl2（500 ppm持续30 min）时，64%的SCD小鼠在6 h内死亡，而表达正常人血红蛋白的对照小鼠无一死亡（p<0.01）。与对照组相比，存活的SCD小鼠有急性溶血、呼吸性酸中毒、急性肺损伤以及血浆和RBC中高浓度氯化棕榈酸和硬脂酸（p<0.05）的证据。在吸入Cl2后30分钟用单次腹膜内剂量的人血红素结合蛋白治疗将死亡率降低至约15%（p<0.01），同时减少溶血（降低RBC脆性（p<0.001）和使血浆血红素恢复至正常水平（p<0.0001）），改善氧合（p<0.0001）和降低急性肺损伤评分（p<0.0001）。SCD小鼠的RBC在暴露于Cl2后6 h具有显著水平的羰基化（其使RBC易于溶血），这在用血红素结合蛋白处理的小鼠的RBC中不存在。为了理解导致羰基化的机制，我们将SCD小鼠的RBC与氯化脂质一起孵育，并与从对照小鼠获得的RBC相比鉴定出镰状化和溶血增加，并进行类似处理。我们的研究表明，吸入氯气通过诱导急性溶血在SCD小鼠中诱导ACS，并且暴露后给予血红素结合蛋白降低死亡率和肺损伤。我们的数据表明，SCD患者在Cl2暴露事件中是脆弱的，并且血红素结合蛋白是一种潜在的治疗剂。吸入氯气诱导镰状小鼠过度溶血。游离血红素导致镰状小鼠与对照小鼠的致命性急性胸部综合征。氯化脂质介导氯对红细胞的影响。血液结合素可减轻氯引起的缺氧和急性肺损伤。因此，实验后注射血红素结合蛋白可提高镰状小鼠的存活率。
Triggering factors of Acute Chest Syndrome (ACS) is a leading cause of death in patients with Sickle Cell Disease (SCD) and targeted therapies are limited. Chlorine (Cl2) inhalation happens frequently, but its role as a potential trigger of ACS has not been determined. In this study, we hypothesized that Cl2 exposure resembling that in the vicinity of industrial accidents induces acute hemolysis with acute lung injury, reminiscent of ACS in humanized SCD mice. When exposed to Cl2 (500 ppm for 30 min), 64% of SCD mice succumbed within 6 h while none of the control mice expressing normal human hemoglobin died (p<0.01). Surviving SCD mice had evidence of acute hemolysis, respiratory acidosis, acute lung injury, and high concentrations of chlorinated palmitic and stearic acids (p<0.05) in their plasmas and RBCs compared to controls. Treatment with a single intraperitoneal dose of human hemopexin 30 min after Cl2 inhalation reduced mortality to around 15% (p<0.01) with reduced hemolysis (decreased RBCs fragility (p<0.001) and returned plasma heme to normal levels (p<0.0001)), improved oxygenation (p<0.0001) and reduced acute lung injury scores (p<0.0001). RBCs from SCD mice had significant levels of carbonylation (which predisposes RBCs to hemolysis) 6 h post-Cl2 exposure which were absent in RBCs of mice treated with hemopexin. To understand the mechanisms leading to carbonylation, we incubated RBCs from SCD mice with chlorinated lipids and identified sickling and increased hemolysis compared to RBCs obtained from control mice and treated similarly. Our study indicates that Cl2 inhalation induces ACS in SCD mice via induction of acute hemolysis, and that post exposure administration of hemopexin reduces mortality and lung injury. Our data suggest that SCD patients are vulnerable in Cl2 exposure incidents and that hemopexin is a potential therapeutic agent. Chlorine inhalation induces exaggerated hemolysis in sickle mice. Free heme results in fatal acute chest syndrome in sickle versus control mice. Chlorinated lipids mediate the effects of chlorine on the red blood cells. Hemopexin alleviates chlorine induced hypoxia, and acute lung injury. Therefore, postexposure hemopexin injection improves the survival of sickle mice.
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DOI：
10.1164/rccm.200302-224oc
发表时间：
2004-03-15
影响因子：
24.7
作者：
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通讯作者：
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DOI：
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发表时间：
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DOI：
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发表时间：
2014-12-01
影响因子：
4.9
作者：
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通讯作者：
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影响因子：
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影响因子：
20.3
作者：
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