LPS induces pulmonary microvascular endothelial cell barrier dysfunction by upregulating ceramide production.
LPS induces pulmonary microvascular endothelial cell barrier dysfunction by upregulating ceramide production.
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DOI：
10.1016/j.cellsig.2022.110250
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发表时间：
2022-01
影响因子：
4.8
通讯作者：
Jianjun Jiang;Huijuan Ouyang;Qun Zhou;Sihui Tang;Pu Fang;Guofang Xie;Jin Yang;Gengyun Sun
中科院分区：
文献类型：
--
作者：
Jianjun Jiang;Huijuan Ouyang;Qun Zhou;Sihui Tang;Pu Fang;Guofang Xie;Jin Yang;Gengyun Sun
神经酰胺在肺微血管内皮细胞（PMVEC）屏障功能障碍中的具体作用尚不清楚。在本研究中，泛半胱天冬酶抑制剂预处理显着减少LPS诱导的PMVEC凋亡，并有助于刺激PMVEC屏障重建后12小时，但在前8小时对PMVEC屏障功能障碍没有影响。进一步的研究表明，丙咪嗪，一种酸性鞘磷脂酶（ASMase）抑制剂，显着抑制LPS诱导的屏障功能障碍，而针对丝氨酸棕榈酰转移酶亚基1（SPTLC 1）的siRNA和药理学抑制剂myriocin没有抑制早期急性屏障功能障碍，但显着抑制PMVEC凋亡和凋亡依赖性延迟屏障功能障碍。此外，LPS通过诱导瞬时受体电位通道6（TRPC 6）过表达和通过ASMase/神经酰胺途径的钙内流来激活RhoA，并且RhoA的激活进一步诱导PMVEC的细胞骨架重排和细胞间连接的破坏，最终导致早期急性PMVEC屏障功能障碍。然而，关于凋亡依赖性迟发性屏障功能障碍，在细胞旁细胞中神经酰胺诱导的从头合成途径诱导PMVEC凋亡，其中Txnip过表达抑制Trx活性，随后在LPS诱导的PMVEC凋亡的背景下激活ASK 1，作用于神经酰胺诱导的p38 MAPK和JNK激活的上游。同时，在LPS或外源性C8神经酰胺诱导的大鼠ALI中，神经酰胺通过诱导Txnip/TRX/ASK 1/P38和JNK通路在肺损伤中发挥重要作用。因此，Txnip/TRX/ASK 1/p38和JNK通路可能参与了LPS诱导的ALI中神经酰胺介导的PMVEC凋亡。
The specific role of ceramides in pulmonary microvascular endothelial cell (PMVEC) barrier dysfunction remains unclear. In the present study, pretreatment with pan-caspase inhibitors significantly reduced LPS-induced PMVEC apoptosis and helped to stimulate PMVEC barrier reconstruction after 12 h but had no effect on PMVEC barrier dysfunction in the first 8 h. Further studies showed that imipramine, an acid sphingomyelinase (ASMase) inhibitor, significantly inhibited LPS-induced barrier dysfunction, while an siRNA targeting serine palmityl transferase subunit 1 (SPTLC1) and the pharmacological inhibitor myriocin did not inhibit early acute barrier dysfunction but significantly inhibited PMVEC apoptosis and apoptosis-dependent delayed barrier dysfunction. In addition, LPS was shown to activate RhoA by inducing transient receptor potential channel 6 (TRPC6) overexpression and calcium influx through the ASMase/ceramide pathway, and activation of RhoA further induced the cytoskeletal rearrangement of PMVECs and destruction of intercellular junctions, ultimately leading to early acute PMVEC barrier dysfunction. However, regarding apoptosis-dependent delayed barrier dysfunction, the ceramide-induced de novo synthesis pathway in paracellular cells induced the apoptosis of PMVECs, in which Txnip overexpression inhibited Trx activity and subsequently activated ASK1 in the context of LPS-induced PMVEC apoptosis, acting upstream of the ceramide-induced activation of p38 MAPK and JNK. At the same time, in rats with LPS- or exogenous C8 ceramide-induced ALI, ceramide was demonstrated to play an important role in lung injury by inducing the Txnip/TRX/ASK1/P38 and JNK pathways. Thus, the Txnip/TRX/ASK1/p38 and JNK pathways might be involved in ceramide-mediated PMVEC apoptosis in LPS-induced ALI.