Inhibition of SOCs Attenuates Acute Lung Injury Induced by Severe Acute Pancreatitis in Rats and PMVECs Injury Induced by Lipopolysaccharide
Inhibition of SOCs Attenuates Acute Lung Injury Induced by Severe Acute Pancreatitis in Rats and PMVECs Injury Induced by Lipopolysaccharide
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抑制 SOC 可减轻大鼠重症急性胰腺炎引起的急性肺损伤和脂多糖引起的 PMVEC 损伤
DOI：
10.1007/s10753-016-0335-1
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发表时间：
2016-03
期刊：
影响因子：
5.1
通讯作者：
Chen Hailong
中科院分区：
文献类型：
--
作者：
Wang Guanyu;Zhang Jingwen;Xu Caiming;Han Xiao;Gao Yanyan;Chen Hailong
急性肺损伤（acute lung injury，ALI）是重症急性胰腺炎（severe acute pancreatitis，SAP）的重要并发症，以肺通透性增加为特征，病死率高。肺微血管内皮细胞（PMVECs）损伤和凋亡在ALI中起重要作用。以往的研究表明，钙库操纵的钙内流（SOCE）可以调节多种细胞过程。本研究旨在探讨SOCE抑制剂对SAP诱导的SD大鼠急性肺损伤及脂多糖（LPS）诱导的PMVECs损伤的影响。采用逆行注射脱氧胆酸钠建立SAP相关性ALI大鼠模型。观察ALI大鼠血清淀粉酶、肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）水平、肺组织学改变、肺含水量、氧合指数和PMVECs超微结构的变化。在体外研究中，用针对钙释放激活的钙通道蛋白1（Orai 1）和基质相互作用分子1（STIM 1）的小干扰RNA（siRNA）瞬时转染或不转染PMVEC，然后暴露于LPS。测定PMVEC的活力。实时定量PCR和Western blot检测肺组织和PMVEC中STIM 1、Orai 1、Bax和caspase 3的表达。给药脱氧胆酸钠可上调肺组织SOC蛋白的表达。LPS诱导的PMVECs中SOC蛋白表达增加。2-APB可降低血清淀粉酶、TNF-α和IL-6水平，减轻肺组织含水量和组织学改变。此外，2-APB可改善SAP相关的肺微血管内皮细胞氧合指数下降和超微结构损伤。STIM 1和Orai 1的敲低抑制LPS诱导的PMVEC死亡。此外，阻断SOCE可显著抑制Orai 1、STIM 1、Bax和caspase 3在体内和体外的表达。这些结果表明，SOCE可能在SAP相关的ALI中发挥关键作用，抑制SOCs的保护作用可能是通过抑制PMVEC线粒体相关的凋亡来介导的。
Acute lung injury (ALI) is a critical complication of the severe acute pancreatitis (SAP), characterized by increased pulmonary permeability with high mortality. Pulmonary microvascular endothelial cells (PMVECs) injury and apoptosis play a key role in ALI. Previous studies indicated that store-operated calcium entry (SOCE) could regulate a variety of cellular processes. The present study was to investigate the effects of SOCE inhibition on ALI induced by SAP in Sprague-Dawley rats, and PMVECs injury induced by lipopolysaccharide (LPS). Rat model of SAP-associated ALI were established by the retrograde infusion of sodium deoxycholate. Serum levels of amylase, TNF-α, and IL-6, histological changes, water content of the lung, oxygenation index, and ultrastructural changes of PMVECs were examined in ALI rats with or without store-operated Ca2+channels (SOCs) pharmacological inhibitor (2-aminoethoxydiphenyl borate, 2-APB) pretreatment. Forin vitrostudies, PMVECs were transiently transfected with or without small interfering RNA (siRNA) against calcium release-activated calcium channel protein1 (Orai1) and stromal interaction molecule1 (STIM1), the two main molecular constituents of SOCs, then exposed to LPS. The viability of PMVECs was determined. The expression of STIM1, Orai1, Bax, and caspase3, both in lung tissue and in PMVECs, were assessed by quantitative real-time PCR and western blot. Administration of sodium deoxycholate upregulated the expression of SOCs proteins in lung tissue. Similarly, the SOCs proteins were increased in PMVECs induced by LPS. 2-APB reduced the serum levels of amylase, TNF-α, and IL-6, and attenuated lung water content and histological findings. In addition, the decreased oxygenation index and ultrastructural damage in PMVECs associated with SAP were ameliorated after administration of 2-APB. Knockdown of STIM1 and Orai1 inhibited LPS-induced PMVECs death. Furthermore, blockade of SOCE significantly suppressed Orai1, STIM1, Bax, and caspase3 expression bothin vivoandin vitro. These results suggest that SOCE may play a critical role in SAP-associated ALI and the protective effects of inhibition of SOCs could be mediated, at least partially, by restraining mitochondrial associated apoptosis of PMVECs.
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影响因子：
3.6
作者：
Aoun, Elie;Chen, Joy;Papachristou, Georgios I.
通讯作者：
Papachristou, Georgios I.
影响因子：
64.8
作者：
Prakriya, Murali;Feske, Stefan;Hogan, Patrick G.
通讯作者：
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影响因子：
4.3
作者：
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影响因子：
2.8
作者：
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通讯作者：
Chan Yanyan;Qi Guoxian;Guo Yang;Wang Leting
影响因子：
56.9
作者：
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通讯作者：
Kroemer, G