LipoxinA4 attenuates acute pancreatitis-associated acute lung injury by regulating AQP-5 and MMP-9 expression, anti-apoptosis and PKC/SSeCKS-mediated F-actin activation
LipoxinA4 attenuates acute pancreatitis-associated acute lung injury by regulating AQP-5 and MMP-9 expression, anti-apoptosis and PKC/SSeCKS-mediated F-actin activation
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LipoxinA4 通过调节 AQP-5 和 MMP-9 表达、抗细胞凋亡和 PKC/SSeCKS 介导的 F-肌动蛋白激活来减轻急性胰腺炎相关的急性肺损伤
DOI：
10.1016/j.molimm.2018.09.003
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发表时间：
2018-11-01
影响因子：
3.6
通讯作者：
Sun, Hongwei
中科院分区：
文献类型：
--
作者：
Shi, Zhehao;Ye, Wen;Sun, Hongwei
急性胰腺炎（AP）诱导的急性肺损伤（ALI）的一个重要组成部分是炎症，它是机体对各种全身刺激的全身炎症反应的一部分。脂氧素（LX）被认为是介导炎症消退的重要内源性脂质。在以前的研究中，我们发现脂氧素A4（LXA 4）减少AP诱导的肺水肿和肺中TNF-α的产生。然而，其潜在机制仍不清楚。基于上述研究，我们研究了LXA 4干预后AP相关肺损伤的细胞和动物模型中水通道蛋白、基质金属蛋白、细胞凋亡和PKC/SSeCKS信号通路。本研究首次证明LXA 4在体内外均能通过抑制PKC/SSeCKS信号通路有效促进肺微血管内皮细胞F-actin重构并调节其表达。接下来，我们发现LXA 4减弱了AP-ALI小鼠和HPMEC肺组织中的细胞生长抑制和细胞凋亡。此外，我们还证实LXA 4可以通过调节AQP-5和MMP-9的表达来稳定肺微血管内皮细胞的通透性。综上所述，LXA 4的抗炎作用可能是通过抑制PKC/SSeCKS通路和细胞凋亡来减少肺泡液渗出，并通过调节AQP-5和MMP-9的表达来维持肺泡液的清除。因此，LXA 4能够对AP诱导的ALI发挥保护作用。
An essential component of acute pancreatitis(AP)-induced acute lung injury(ALI) is the inflammation that is part of the body's systemic inflammatory response to a variety of systemic stimuli. Lipoxins(LXs) are considered important endogenous lipids that mediate the resolution of inflammation. In previous studies, we found that Lipoxin A4 (LXA4) reduced AP-induced pulmonary oedema and TNF-alpha production in lung. However, the underlying mechanism remains unclear. Due to the above studies, we investigated the aquaporin, matrix metalloprotein, apoptosis and PKC/SSeCKS signal pathway in cellular and animal models of AP-associated lung injury following LXA4 intervention. In this study, we first proved LXA4 could effectively promote F-actin reconstruction and regulate its expression in pulmonary microvascular endothelial cells both in vivo and vitro via suppressing PKC/SSeCKS signalling pathway. Next, we found that LXA4 attenuated cell growth inhibition and apoptosis in lung tissues of AP-ALI mice and HPMECs. Additionally, we demonstrated that LXA4 could regulate the expression of AQP-5 and MMP-9 to stabilize the permeability of pulmonary microvascular endothelial cell. In summary, our results suggest that the anti-inflammatory eff ;ects of LXA4 may be due to the inhibition of both the PKC/SSeCKS pathway and apoptosis to reduce alveolar fluid exudation and to the regulation of AQP-5 and MMP-9 expression to maintain the clearance of alveolar fluid. Thus, LXA4 is capable of exerting protective eff;ects on AP-induced ALI.