Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways.
Inhibition of IP3R/Ca2+ Dysregulation Protects Mice From Ventilator-Induced Lung Injury via Endoplasmic Reticulum and Mitochondrial Pathways.
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DOI：
10.3389/fimmu.2021.729094
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发表时间：
2021
影响因子：
7.3
通讯作者：
Pan L
中科院分区：
文献类型：
--
作者：
Ye L;Zeng Q;Ling M;Ma R;Chen H;Lin F;Li Z;Pan L
细胞内钙（Ca 2+）稳态的破坏与炎症反应有关。在这里，我们研究了内质网（ER）Ca 2+流出通过肌醇1，4，5-三磷酸受体（IP 3R）作为一个潜在的机制，在呼吸机诱导的肺损伤（VILI）小鼠模型的炎症病理生理。将C57 BL/6小鼠暴露于使用大潮气量（HTV）的机械通气。用IP 3R激动剂卡巴胆碱、IP 3R抑制剂2-氨基乙氧基二苯基硼酸酯（2-APB）或Ca 2+螯合剂BAPTA-AM预处理小鼠。收集肺组织和支气管肺泡灌洗液（BALF）以测量Ca 2+浓度、炎症反应和与ER应激、NLRP 3炎性体活化和炎症相关的mRNA/蛋白表达。与培养的鼠肺细胞系一起进行分析。HIV感染小鼠的肺显示ER和MAMs的IP 3R表达上调，MAMs的形成增强。此外，HTV破坏了Ca 2+的稳态，增加了从ER到细胞质和线粒体的流量。卡巴胆碱的管理加重了HTV诱导的肺损伤和炎症，而2-APB或BAPTA-AM预处理在很大程度上防止了这些影响。HTV激活ER应激信号反应的IRE 1 α和PERK臂，并以IP 3R依赖的方式诱导线粒体功能障碍-NLRP 3炎性小体激活。类似地，使用卡巴胆碱破坏MLE 12和RAW264.7细胞中的IP 3R/Ca 2+导致炎症反应，并刺激ER应激和线粒体功能障碍。IP 3R介导的Ca 2+释放增加通过ER应激和线粒体功能障碍参与VILI的炎症病理生理学。拮抗IP 3R/Ca 2+和/或维持肺组织中的Ca 2+稳态代表了VILI的前瞻性治疗方法。
Disruption of intracellular calcium (Ca2+) homeostasis is implicated in inflammatory responses. Here we investigated endoplasmic reticulum (ER) Ca2+ efflux through the Inositol 1,4,5-trisphosphate receptor (IP3R) as a potential mechanism of inflammatory pathophysiology in a ventilator-induced lung injury (VILI) mouse model. C57BL/6 mice were exposed to mechanical ventilation using high tidal volume (HTV). Mice were pretreated with the IP3R agonist carbachol, IP3R inhibitor 2-aminoethoxydiphenyl borate (2-APB) or the Ca2+ chelator BAPTA-AM. Lung tissues and bronchoalveolar lavage fluid (BALF) were collected to measure Ca2+ concentrations, inflammatory responses and mRNA/protein expression associated with ER stress, NLRP3 inflammasome activation and inflammation. Analyses were conducted in concert with cultured murine lung cell lines. Lungs from mice subjected to HTV displayed upregulated IP3R expression in ER and mitochondrial-associated-membranes (MAMs), with enhanced formation of MAMs. Moreover, HTV disrupted Ca2+ homeostasis, with increased flux from the ER to the cytoplasm and mitochondria. Administration of carbachol aggravated HTV-induced lung injury and inflammation while pretreatment with 2-APB or BAPTA-AM largely prevented these effects. HTV activated the IRE1α and PERK arms of the ER stress signaling response and induced mitochondrial dysfunction-NLRP3 inflammasome activation in an IP3R-dependent manner. Similarly, disruption of IP3R/Ca2+ in MLE12 and RAW264.7 cells using carbachol lead to inflammatory responses, and stimulated ER stress and mitochondrial dysfunction. Increase in IP3R-mediated Ca2+ release is involved in the inflammatory pathophysiology of VILI via ER stress and mitochondrial dysfunction. Antagonizing IP3R/Ca2+ and/or maintaining Ca2+ homeostasis in lung tissue represents a prospective treatment approach for VILI.
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影响因子：
82.9
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64.5
作者：
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通讯作者：
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