Vaspin protects against LPS‑induced ARDS by inhibiting inflammation, apoptosis and reactive oxygen species generation in pulmonary endothelial cells via the Akt/GSK‑3β pathway.
Vaspin protects against LPS‑induced ARDS by inhibiting inflammation, apoptosis and reactive oxygen species generation in pulmonary endothelial cells via the Akt/GSK‑3β pathway.
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DOI：
10.3892/ijmm.2017.3176
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发表时间：
2017-12
影响因子：
5.4
通讯作者：
Deng X
中科院分区：
文献类型：
--
作者：
Qi D;Wang D;Zhang C;Tang X;He J;Zhao Y;Deng W;Deng X
急性呼吸窘迫综合征(ARDS)的特征是富含蛋白质的液体无节制地外渗，这是由于肺内皮细胞(ECs)屏障的破坏和功能障碍引起的。内脏脂肪组织衍生丝氨酸蛋白酶抑制因子(Vaspin)是一种新型的多效性脂肪因子，已被报道对肥胖相关的全身性血管疾病具有良好的疗效，但其对ARDS的作用尚不清楚。在本研究中，小鼠全身注射表达vaspin的腺病毒载体(Ad-vaspin)，观察其对脂多糖(LPS)诱导的小鼠ARDS的影响。检测细胞因子[肿瘤坏死因子-α、白介素6、白介素10]水平及细胞间黏附分子-1、黏附连接的表达。此外，用重组人(Rh)-vaspin处理人肺微血管内皮细胞(HPMECs)，进一步探讨其分子基础和作用机制。检测炎性细胞因子(肿瘤坏死因子-α和白介素6)和内皮细胞特异性黏附分子[血管细胞黏附分子-1和E-选择素]的基因表达水平，核因子-κB的活化，细胞存活率和细胞凋亡率。此外，还检测了AJs的表达和细胞骨架的组成，烟酰胺腺嘌呤二核苷酸磷酸(NADPH)氧化酶的表达和活性以及活性氧自由基(ROS)的产生。结果表明，Ad-vaspin通过激活蛋白激酶B/糖原合成酶-3β通路，减轻小鼠肺组织炎症反应和肺内皮细胞屏障功能障碍，从而对脂多糖诱导的急性呼吸窘迫综合征具有保护作用。此外，rh-vaspin处理HPMEC可减轻炎症、细胞凋亡和ROS的产生，而不改变AJs和细胞骨架结构，并伴随着Akt/Gsk3β通路的激活。综上所述，本研究表明，vaspin通过抑制肺内皮细胞的炎症、细胞凋亡和ROS的产生，至少部分地通过激活Akt/Gsk3β通路，逆转EC屏障功能障碍，从而对内毒素诱导的急性呼吸窘迫综合征具有保护作用。这些发现提供了vaspin与ARDS患者EC功能障碍之间的因果联系的证据，并建议对ARDS患者进行潜在的治疗干预。
Acute respiratory distress syndrome (ARDS) is characterized by uncontrolled extravasation of protein-rich fluids, which is caused by disruption and dysfunction of the barrier of pulmonary endothelial cells (ECs). Visceral adipose tissue-derived serine protease inhibitor (vaspin) is a novel adipokine with pleiotropic properties, which has been reported to exert beneficial effects against obesity-associated systemic vascular diseases; however, its effects on ARDS remain unknown. In the present study, mice were subjected to systemic administration of adenoviral vector expressing vaspin (Ad-vaspin) to examine its effects on lipopolysaccharide (LPS)-induced ARDS in vivo. Histological analysis was then conducted, and cytokine [tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-10] levels, and intercellular cell adhesion molecule-1 (ICAM-1) and adherens junctions (AJs) expression were detected. In addition, human pulmonary microvascular ECs (HPMECs) were treated with recombinant human (rh)-vaspin to further investigate its molecular basis and underlying mechanism. The mRNA expression levels of inflammatory cytokines (TNF-α and IL-6) and endothelial-specific adhesion markers [vascular cell adhesion molecule-1 and E-selectin], activation of nuclear factor-κB, and cell viability and apoptosis were then examined. Furthermore, the expression of AJs and organization of the cytoskeleton, as well as expression and activity of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and generation of reactive oxygen species (ROS) were determined. The results indicated that Ad-vaspin protected against LPS-induced ARDS by alleviating the pulmonary inflammatory response and pulmonary EC barrier dysfunction in mice, which was accompanied by activation of the protein kinase B (Akt)/glycogen synthase kinase (GSK)-3β pathway. In addition, pretreatment of HPMECs with rh-vaspin attenuated inflammation, apoptosis and ROS generation without alterations in AJs and cytoskeletal organization following LPS insult, which was accompanied by activation of the Akt/GSK3β pathway. In conclusion, the present study demonstrated that vaspin protects against LPS-induced ARDS by reversing EC barrier dysfunction via the suppression of inflammation, apoptosis and ROS production in pulmonary ECs, at least partially via activation of the Akt/GSK3β pathway. These findings provide evidence of a causal link between vaspin and EC dysfunction in ARDS, and suggest a potential therapeutic intervention for patients with ARDS.
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DOI：
10.4021/jocmr841w
发表时间：
2012-04
期刊：
Journal of clinical medicine research
影响因子：
--
作者：
Kobat MA;Celik A;Balin M;Altas Y;Baydas A;Bulut M;Aydin S;Dagli N;Yavuzkir MF;Ilhan S
通讯作者：
Ilhan S
影响因子：
5.8
作者：
Lucas, Rudolf;Verin, Alexander D.;Black, Stephen M.;Catravas, John D.
通讯作者：
Catravas, John D.
影响因子：
10
作者：
Anzueto, A.;Frutos-Vivar, F.;Ferguson, N. D.
通讯作者：
Ferguson, N. D.
影响因子：
3.2
作者：
Konter J;Baez E;Summer RS
通讯作者：
Summer RS
影响因子：
9.6
作者：
Gadek, JE;Pacht, ER
通讯作者：
Pacht, ER