Bromine inhalation mimics ischemia-reperfusion cardiomyocyte injury and calpain activation in rats
Bromine inhalation mimics ischemia-reperfusion cardiomyocyte injury and calpain activation in rats
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DOI：
10.1152/ajpheart.00652.2017
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发表时间：
2019-01-01
影响因子：
4.8
通讯作者：
Dell'Italia, Louis J.
中科院分区：
文献类型：
--
作者：
Ahmad, Shama;Juncos, Juan Xavier Masjoan;Dell'Italia, Louis J.
卤素是一种被广泛使用的剧毒化学物质，由于其含量丰富，对人类构成潜在威胁。卤素如溴（Br-2）造成严重的肺部和全身损伤；然而，它们的毒性机制在很大程度上是未知的。在这里，我们证明了Br-2和反应性溴化物质在肺中产生并通过血液释放到达心脏并引起大鼠急性心脏超微结构损伤和功能障碍。br -2诱导的心脏损伤表现为循环肌钙蛋白I、心脏型脂肪酸结合蛋白和nh2末端前脑利钠肽的急性（3-24小时）升高。透射电镜显示急性（3-24小时）心脏收缩带坏死，z盘破裂，线粒体肿胀和紊乱。超声心动图和血流动力学分析显示左室（LV）收缩和舒张功能障碍7天。血浆和左室组织中溴化脂肪酸水平升高。正常大鼠左室腔内注射2-溴十六进醛（Br-HDA）可引起急性左室增大，并伴有广泛的肌体结构破坏和线粒体损伤。暴露于Br2或Br-2反应物的大鼠心脏中存在广泛的中性粒细胞浸润和髓过氧化物酶水平升高。吸入Br-2后，sarco（内）质网Ca2+- atp酶（SERCA）溴化增加和磷蛋白增加使心脏SERCA活性降低70%。SERCA失活伴随着Ca2+敏感左室钙蛋白酶活性的增加。暴露后1小时内给予calpain特异性抑制剂MDL28170显著降低calpain活性和急性死亡率。溴的吸入和反应性溴化物的形成可引起急性心脏损伤和心肌损伤，可导致心力衰竭。新的和值得注意的是，本研究定义了溴（Br-2）吸入后心脏损伤引起的左心室收缩和舒张功能障碍。钙蛋白酶依赖机制被确定为心脏超微结构损伤的潜在介质。这项研究不仅强调了监测Br-2暴露受害者急性心脏症状的重要性，而且还确定了钙痛作为治疗Br-2诱导毒性的潜在靶点。
Halogens are widely used, highly toxic chemicals that pose a potential threat to humans because of their abundance. Halogens such as bromine (Br-2) cause severe pulmonary and systemic injuries; however, the mechanisms of their toxicity are largely unknown. Here, we demonstrated that Br-2 and reactive brominated species produced in the lung and released in blood reach the heart and cause acute cardiac ultrastructural damage and dysfunction in rats. Br-2-induced cardiac damage was demonstrated by acute (3-24 h) increases in circulating troponin I, heart-type fatty acid-binding protein, and NH2-terminal pro-brain natriuretic peptide. Transmission electron microscopy demonstrated acute (3-24 h) cardiac contraction band necrosis, disruption of z-disks, and mitochondrial swelling and disorganization. Echocardiography and hemodynamic analysis revealed left ventricular (LV) systolic and diastolic dysfunction at 7 days. Plasma and LV tissue had increased levels of brominated fatty acids. 2-Bromohexadecanal (Br-HDA) injected into the LV cavity of a normal rat caused acute LV enlargement with extensive disruption of the sarcomeric architecture and mitochondrial damage. There was extensive infiltration of neutrophils and increased myeloperoxidase levels in the hearts of Br2- or Br-2 reactant-exposed rats. Increased bromination of sarco(endo) plasmic reticulum Ca2+-ATPase (SERCA) and increased phosphalamban after Br-2 inhalation decreased cardiac SERCA activity by 70%. SERCA inactivation was accompanied by increased Ca2+-sensitive LV calpain activity. The calpain-specific inhibitor MDL28170 administered within 1 h after exposure significantly decreased calpain activity and acute mortality. Bromine inhalation and formation of reactive brominated species caused acute cardiac injury and myocardial damage that can lead to heart failure.NEW & NOTEWORTHY The present study defines left ventricular systolic and diastolic dysfunction due to cardiac injury after bromine (Br-2) inhalation. A calpain-dependent mechanism was identified as a potential mediator of cardiac ultrastructure damage. This study not only highlights the importance of monitoring acute cardiac symptoms in victims of Br-2 exposure but also defines calpains as a potential target to treat Br-2-induced toxicity.