Division of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois.
Department of Respirology, Graduate School of Medicine, Chiba University , Chiba , Japan.
Am J Physiol Lung Cell Mol Physiol. 2018 Nov 1;315(5):L834-L845. doi: 10.1152/ajplung.00031.2018. Epub 2018 Sep 6.
Acute respiratory distress syndrome (ARDS) is a severe clinical condition marked by acute respiratory failure and dysregulated inflammation. Pulmonary vascular endothelial cells (PVECs) function as an important pro-inflammatory source in ARDS, suggesting that modulation of inflammatory events at the endothelial level may have a therapeutic benefit. Dipeptidyl peptidase-4 (DPP4) inhibitors, widely used for the treatment of diabetes mellitus, have been reported to have possible anti-inflammatory effects. However, the potential anti-inflammatory effects of DPP4 inhibition on PVEC function and ARDS pathophysiology are unknown. Therefore, we evaluated the effects of sitagliptin, a DPP4 inhibitor in wide clinical use, on LPS-induced lung injury in mice and in human lung ECs in vitro. In vivo, sitagliptin reduced serum DPP4 activity, bronchoalveolar lavage protein concentration, cell number, and proinflammatory cytokine levels after LPS and alleviated histological findings of lung injury. LPS decreased the expression levels of CD26/DPP4 on pulmonary epithelial cells and PVECs isolated from mouse lungs, and the effect was partially reversed by sitagliptin. In vitro, human lung microvascular ECs (HLMVECs) expressed higher levels of CD26/DPP4 than human pulmonary arterial ECs. LPS induced the release of TNFα, IL-6, and IL-8 by HLMVECs that were inhibited by sitagliptin. LPS promoted the proliferation of HLMVECs, and sitagliptin suppressed this response. However, sitagliptin failed to reverse LPS-induced permeability in cultured ECs or lung epithelial cells in vitro. In summary, sitagliptin attenuates LPS-induced lung injury in mice and exerts anti-inflammatory effects on HLMVECs. These novel observations indicate DPP4 inhibitors may have potential as therapeutic drugs for ARDS.
急性呼吸窘迫综合征（ARDS）是一种以急性呼吸衰竭和失调性炎症为特征的严重临床病症。肺血管内皮细胞（PVECs）作为 ARDS 中的一个重要促炎源，提示在内皮水平调节炎症事件可能具有治疗益处。二肽基肽酶-4（DPP4）抑制剂广泛用于治疗糖尿病，据报道具有潜在的抗炎作用。然而，DPP4 抑制对 PVEC 功能和 ARDS 病理生理学的潜在抗炎作用尚不清楚。因此，我们评估了广泛临床应用的 DPP4 抑制剂西他列汀对 LPS 诱导的小鼠肺损伤和体外人肺 ECs 的影响。在体内，西他列汀降低了 LPS 后血清 DPP4 活性、支气管肺泡灌洗液蛋白浓度、细胞数和促炎细胞因子水平，并缓解了肺损伤的组织学发现。LPS 降低了小鼠肺上皮细胞和从肺中分离的 PVEC 上 CD26/DPP4 的表达水平，西他列汀部分逆转了这一作用。在体外，人肺微血管内皮细胞（HLMVECs）表达的 CD26/DPP4 水平高于人肺动脉内皮细胞。LPS 诱导 HLMVECs 释放 TNFα、IL-6 和 IL-8，西他列汀抑制了这一作用。LPS 促进 HLMVECs 的增殖，西他列汀抑制了这种反应。然而，西他列汀未能逆转 LPS 诱导的体外培养 ECs 或肺上皮细胞的通透性。总之，西他列汀减轻了 LPS 诱导的小鼠肺损伤，并对 HLMVECs 发挥抗炎作用。这些新的观察结果表明，DPP4 抑制剂可能有作为 ARDS 治疗药物的潜力。
