Mononuclear Phagocyte-Derived Microparticulate Caspase-1 Induces Pulmonary Vascular Endothelial Cell Injury.
Mononuclear Phagocyte-Derived Microparticulate Caspase-1 Induces Pulmonary Vascular Endothelial Cell Injury.
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DOI：
10.1371/journal.pone.0145607
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sarkar A
中科院分区：
文献类型：
--
作者：
Mitra S;Wewers MD;Sarkar A
肺内皮细胞凋亡和损伤发生在急性肺损伤（ALI/ARDS）的各个阶段，并影响疾病的进展。肺内皮损伤传统上集中于由促炎细胞因子表达诱导的中性粒细胞运输至肺血管整合素受体的作用。尽管我们对ALI/ARDS中细胞损伤和死亡的发病机制了解很多，但我们的知识仍存在差距;因此，目前还没有有效的药物治疗方法。称为半胱天冬酶的酶对于完成凋亡程序和促炎细胞因子的分泌是必不可少的。我们推测caspase-1可能是ALI/ARDS中人肺微血管内皮细胞（HPMVEC）凋亡的关键调节因子。我们最近的实验证实，从刺激的单核细胞（THP 1）释放的微粒诱导肺内皮细胞凋亡。用半胱天冬酶-1抑制剂YVAD或泛半胱天冬酶抑制剂ZVAD预处理的微粒不能诱导HPMVEC的细胞死亡，表明半胱天冬酶-1或其底物在诱导HPMVEC细胞死亡中的作用。未诱导的微粒（对照）和用LPS直接处理均不诱导HPMVEC的凋亡。进一步的实验表明，caspase-1的摄取到HPMVEC和诱导HPMVEC凋亡的caspase-1促进与微粒囊泡的相互作用。改变囊泡的完整性完全废除了HPMVEC的凋亡，这表明靶细胞摄取活性半胱天冬酶-1需要封装。综上所述，我们证实了微粒中心的caspase-1可以在内皮细胞损伤中发挥调节作用。
Lung endothelial cell apoptosis and injury occurs throughout all stages of acute lung injury (ALI/ARDS) and impacts disease progression. Lung endothelial injury has traditionally been focused on the role of neutrophil trafficking to lung vascular integrin receptors induced by proinflammatory cytokine expression. Although much is known about the pathogenesis of cell injury and death in ALI/ARDS, gaps remain in our knowledge; as a result of which there is currently no effective pharmacologic therapy. Enzymes known as caspases are essential for completion of the apoptotic program and secretion of pro-inflammatory cytokines. We hypothesized that caspase-1 may serve as a key regulator of human pulmonary microvascular endothelial cell (HPMVEC) apoptosis in ALI/ARDS. Our recent experiments confirm that microparticles released from stimulated monocytic cells (THP1) induce lung endothelial cell apoptosis. Microparticles pretreated with the caspase-1 inhibitor, YVAD, or pan-caspase inhibitor, ZVAD, were unable to induce cell death of HPMVEC, suggesting the role of caspase-1 or its substrate in the induction of HPMVEC cell death. Neither un-induced microparticles (control) nor direct treatment with LPS induced apoptosis of HPMVEC. Further experiments showed that caspase-1 uptake into HPMVEC and the induction of HPMVEC apoptosis was facilitated by caspase-1 interactions with microparticulate vesicles. Altering vesicle integrity completely abrogated apoptosis of HPMVEC suggesting an encapsulation requirement for target cell uptake of active caspase-1. Taken together, we confirm that microparticle centered caspase-1 can play a regulator role in endothelial cell injury.