The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates Endothelial Inflammation and Microvascular Thrombosis in a Sepsis Mouse Model.
The Dipeptidyl Peptidase-4 Inhibitor Linagliptin Ameliorates Endothelial Inflammation and Microvascular Thrombosis in a Sepsis Mouse Model.
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DOI：
10.3390/ijms23063065
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发表时间：
2022-03-12
影响因子：
5.6
通讯作者：
Lin SJ
中科院分区：
文献类型：
--
作者：
Wang SC;Wang XY;Liu CT;Chou RH;Chen ZB;Huang PH;Lin SJ
脓毒症的病理生理学涉及炎症和高凝状态，其导致微血管血栓形成和器官灌注受损。二肽基肽酶（DPP）-4抑制剂，例如，利格列汀是已知发挥抗炎作用的常用抗糖尿病药物。然而，这些药物是否具有抗血栓形成作用，在脓毒症中保持器官灌注仍有待研究。在本研究中，使用利格列汀处理人脐静脉内皮细胞（HUVEC），以检查其在肿瘤坏死因子（TNF）-α处理下的抗炎和抗血栓形成作用。为了验证体外实验的结果并为所确定的机制提供体内证据，使用脂多糖（LPS）诱导的全身炎症反应综合征的小鼠模型，并测量肺微循环血栓形成。在TNF-α处理的HUVEC和LPS注射小鼠中，利格列汀通过核因子-κB（NF-κB）依赖性途径抑制白细胞介素-1 β（IL-1β）和细胞间粘附分子1（ICAM-1）的表达。利格列汀通过Akt/内皮型一氧化氮合酶途径减弱组织因子表达。在注射LPS的小鼠中，利格列汀预处理显著减少了肺微循环中的血栓形成。这些抗炎和抗血栓形成作用与血糖水平无关。总之，目前的结果表明，利格列汀在脓毒症小鼠模型中对内皮炎症和微血管血栓形成具有保护作用。
The pathophysiology of sepsis involves inflammation and hypercoagulability, which lead to microvascular thrombosis and compromised organ perfusion. Dipeptidyl peptidase (DPP)-4 inhibitors, e.g., linagliptin, are commonly used anti-diabetic drugs known to exert anti-inflammatory effects. However, whether these drugs confer an anti-thrombotic effect that preserves organ perfusion in sepsis remains to be investigated. In the present study, human umbilical vein endothelial cells (HUVECs) were treated with linagliptin to examine its anti-inflammatory and anti-thrombotic effects under tumor necrosis factor (TNF)-α treatment. To validate findings from in vitro experiments and provide in vivo evidence for the identified mechanism, a mouse model of lipopolysaccharide (LPS)-induced systemic inflammatory response syndrome was used, and pulmonary microcirculatory thrombosis was measured. In TNF-α-treated HUVECs and LPS-injected mice, linagliptin suppressed expressions of interleukin-1β (IL-1β) and intercellular adhesion molecule 1 (ICAM-1) via a nuclear factor-κB (NF-κB)–dependent pathway. Linagliptin attenuated tissue factor expression via the Akt/endothelial nitric oxide synthase pathway. In LPS-injected mice, linagliptin pretreatment significantly reduced thrombosis in the pulmonary microcirculation. These anti-inflammatory and anti-thrombotic effects were independent of blood glucose level. Together the present results suggest that linagliptin exerts protective effects against endothelial inflammation and microvascular thrombosis in a mouse model of sepsis.
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DOI：
10.4049/jimmunol.1201806
发表时间：
2012-11-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Osuchowski MF;Craciun F;Weixelbaumer KM;Duffy ER;Remick DG
通讯作者：
Remick DG
葡萄糖激活禁食小鼠迷走神经对高血糖和炎症的控制
影响因子：
4.6
作者：
Joseph, Biju;Shimojo, Guilherme;Ulloa, Luis
通讯作者：
Ulloa, Luis
影响因子：
4.1
作者：
Hwang, Hwan-Jin;Chung, Hye Soo;Yoo, Hye Jin
通讯作者：
Yoo, Hye Jin
DOI：
10.1073/pnas.88.11.4651
发表时间：
1991-06-01
影响因子：
11.1
作者：
KUBES, P;SUZUKI, M;GRANGER, DN
通讯作者：
GRANGER, DN
影响因子：
5.6
作者：
Li Y;Li R;Feng Z;Wan Q;Wu J
通讯作者：
Wu J