Cortactin loss protects against hemin-induced acute lung injury in sickle cell disease.
Cortactin loss protects against hemin-induced acute lung injury in sickle cell disease.
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Cortactin 损失可防止镰状细胞病中血红素引起的急性肺损伤。
DOI：
10.1152/ajplung.00274.2021
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Machado,RobertoF
中科院分区：
文献类型：
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作者：
Jones,NicoleM;Sysol,JustinR;Singla,Sunit;Smith,Patricia;Sandusky,GeorgeE;Wang,Huashan;Natarajan,Viswanathan;Dudek,StevenM;Machado,RobertoF
在镰状细胞病（SCD）患者中，急性胸综合征（ACS）是一种常见的急性肺损伤形式，也是发病率和死亡率的主要原因。ACS的病理生理是复杂的，血红蛋白的假体部分血红蛋白与内皮细胞（EC）激活和随后的急性肺损伤（ALI）和ACS在体外和动物研究中都有关系。在这里，我们研究了接触蛋白（CTTN），一种调节EC功能的细胞骨架蛋白，在对血红素诱导的ALI和ACS的反应中的作用。将皮质蛋白杂合子（Cttn+/ -）小鼠（n= 8）及其野生型兄弟姐妹（n= 8）照射后，随后接受从SCD小鼠（SS）股骨中提取的骨髓细胞（BMCs），生成SSCttn+/ -和sscttnw嵌合体。在BMC移植的血红蛋白电泳证明后，小鼠接受35µmol/kg血红蛋白。在24 h内对存活小鼠实施安乐死，分析支气管肺泡液（BAL）和肺样本。在体外研究中，我们使用人肺微血管内皮细胞（HLMVECs）来检测在内毒素缺乏和对照条件下血红素诱导的基因表达和活性氧（ROS）生成的变化。与野生型小鼠相比，输注血红素后SSCttn+/−小鼠的死亡率有降低的趋势，肺损伤和坏死细胞死亡程度较轻。体外研究证实，通过降低p38/HSP27的蛋白表达，改善细胞屏障功能，减少ROS的产生，接触蛋白缺乏对HMLVECs中hemin诱导的损伤具有保护作用。进一步研究CTTN在ACS中的作用是必要的，并可能为这种毁灭性疾病的潜在治疗开辟新的途径。
In patients with sickle cell disease (SCD), acute chest syndrome (ACS) is a common form of acute lung injury and a major cause of morbidity and mortality. The pathophysiology of ACS is complex, and hemin, the prosthetic moiety of hemoglobin, has been implicated in endothelial cell (EC) activation and subsequent acute lung injury (ALI) and ACS in vitro and in animal studies. Here, we examined the role of cortactin (CTTN), a cytoskeletal protein that regulates EC function, in response to hemin-induced ALI and ACS. Cortactin heterozygous (Cttn+/−) mice (n= 8) and their wild-type siblings (n= 8) were irradiated and subsequently received bone marrow cells (BMCs) extruded from the femurs of SCD mice (SS) to generate SSCttn+/−and SSCttnWTchimeras. Following hemoglobin electrophoretic proof of BMC transplantation, the mice received 35 µmol/kg of hemin. Within 24 h, surviving mice were euthanized, and bronchoalveolar fluid (BAL) and lung samples were analyzed. For in vitro studies, human lung microvascular endothelial cells (HLMVECs) were used to determine hemin-induced changes in gene expression and reactive oxygen species (ROS) generation in cortactin deficiency and control conditions. When compared with wild-type littermates, the mortality for SSCttn+/−mice trended to be lower after hemin infusion and these mice exhibited less severe lung injury and less necroptotic cell death. In vitro studies confirmed that cortactin deficiency is protective against hemin-induced injury in HMLVECs, by decreasing protein expression of p38/HSP27, improving cell barrier function, and decreasing the production of ROS. Further studies examining the role of CTTN in ACS are warranted and may open a new avenue of potential treatment for this devastating disease.