Division of Endocrinology, Department of Medicine, College of Medicine, University of Arizona, Tucson, AZ.
Blood. 2020 Aug 6;136(6):749-754. doi: 10.1182/blood.2019003986.
Several studies demonstrate that hemolysis and free heme in circulation cause endothelial barrier dysfunction and are associated with severe pathological conditions such as acute respiratory distress syndrome, acute chest syndrome, and sepsis. However, the precise molecular mechanisms involved in the pathology of heme-induced barrier disruption remain to be elucidated. In this study, we investigated the role of free heme in the endothelial barrier integrity and mechanisms of heme-mediated intracellular signaling of human lung microvascular endothelial cells (HLMVECs). Heme, in a dose-dependent manner, induced a rapid drop in the endothelial barrier integrity of HLMVECs. An investigation into barrier proteins revealed that heme primarily affected the tight junction proteins zona occludens-1, claudin-1, and claudin-5, which were significantly reduced after heme exposure. The p38MAPK/HSP27 pathway, involved in the regulation of endothelial cytoskeleton remodeling, was also significantly altered after heme treatment, both in HLMVECs and mice. By using a knockout (KO) mouse for MKK3, a key regulator of the p38MAPK pathway, we showed that this KO effectively decreased heme-induced endothelial barrier dysfunction. Taken together, our results indicate that targeting the p38MAPK pathway may represent a crucial treatment strategy in alleviating hemolytic diseases.
多项研究表明，血液中的溶血和游离血红素会导致内皮屏障功能障碍，并与急性呼吸窘迫综合征、急性胸部综合征和败血症等严重病理状况相关。然而，血红素诱导的屏障破坏的病理机制仍有待阐明。在这项研究中，我们研究了游离血红素在人肺微血管内皮细胞（HLMVEC）内皮屏障完整性中的作用及其介导的血红素细胞内信号转导的机制。血红素以剂量依赖的方式诱导 HLMVEC 内皮屏障完整性的快速下降。对屏障蛋白的研究表明，血红素主要影响紧密连接蛋白 zonula occludens-1、claudin-1 和 claudin-5，血红素暴露后这些蛋白显著减少。参与内皮细胞骨架重塑调节的 p38MAPK/HSP27 通路在血红素处理后，无论是在 HLMVEC 还是在小鼠中，都发生了显著改变。通过使用 MKK3 的敲除（KO）小鼠，该基因是 p38MAPK 通路的关键调节因子，我们表明这种 KO 可有效降低血红素诱导的内皮屏障功能障碍。综上所述，我们的结果表明，靶向 p38MAPK 通路可能是缓解溶血性疾病的重要治疗策略。
