Thrombin and activated coagulation factor X stimulate the release of cytokines and fibronectin from nasal polyp fibroblasts via protease-activated receptors
Thrombin and activated coagulation factor X stimulate the release of cytokines and fibronectin from nasal polyp fibroblasts via protease-activated receptors
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DOI：
10.2500/ajra.2017.31.4400
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发表时间：
2017-01-01
影响因子：
2.6
通讯作者：
Shimizu, Takeshi
中科院分区：
文献类型：
--
作者：
Shimizu, Shino;Tojima, Ichiro;Shimizu, Takeshi
背景：慢性鼻窦炎合并鼻息肉（CRSwNP）患者的鼻分泌物和鼻息肉中存在高凝血酶活性和过量纤维蛋白沉积，鼻上皮细胞和浸润性嗜酸性粒细胞表达组织因子。活化凝血因子不仅在血栓形成中发挥重要作用，而且通过与蛋白酶活化受体（PAR）的相互作用在炎症中发挥重要作用。然而，活化凝血因子对鼻息肉成纤维细胞（NPF）细胞因子和细胞外基质释放的影响尚不清楚。目的：本研究的目的是分析活化凝血因子受体PARs在NPFs上的表达，并确定凝血酶和活化凝血因子X （FXa）在NPFs释放细胞因子和纤维连接蛋白中的作用。方法：从CRSwNP患者中获取NPFs，检测NPFs中PARs的信使RNA （mRNA）和蛋白表达。然后，我们研究凝血酶或FXa是否刺激培养的NPFs释放转化生长因子(TGF) β 1、纤维连接蛋白、eotaxin-1、白细胞介素（IL） 6或IL-8。我们还研究了PAR激动剂对细胞因子和纤维连接蛋白释放的影响。结果：NPFs表达所有4种par的mRNA和蛋白：PAR-1、PAR-2、PAR-3和PAR-4。凝血酶和FXa均能显著刺激培养的NPFs释放TGF β 1、纤维连接蛋白、eotaxin-1、IL-6和IL-8。PAR-1和PAR-2激动剂刺激TGF - β 1、纤维连接蛋白、eotaxin-1、IL-6和IL-8的分泌。PAR-3激动剂刺激TGF β 1、纤维连接蛋白和eotaxin-1的释放。PAR-4激动剂不诱导这些分子的释放。结论：NPFs通过释放细胞因子和细胞外基质蛋白在CRSwNP的病理生理过程中发挥重要作用，如鼻息肉形成和炎症细胞浸润。活化的凝血因子，凝血酶和FXa，刺激这些细胞因子和纤维连接蛋白通过PARs从NPFs释放。
Background: Nasal epithelial cells and infiltrating eosinophils express tissue factor, and high thrombin activity and excess fibrin deposition are found in nasal secretion and in nasal polyp from patients with chronic rhinosinusitis with nasal polyp (CRSwNP). Activated coagulation factors play important roles not only in thrombosis but also in inflammation through interaction with protease-activated receptors (PAR). However, little is known about the effects of activated coagulation factors on the release of cytokines and extracellular matrix from nasal polyp fibroblasts (NPF).Purpose: The purpose of this study was to analyze the expression of PARs, which are receptors for activated coagulation factors, on NPFs and to determine the roles of thrombin and activated coagulation factor X (FXa) in the release of cytokines and fibronectin from NPFs.Methods: NPFs were obtained from patients with CRSwNP, and the messenger RNA (mRNA) and protein expression of PARs in these NPFs were examined. We then investigated whether thrombin or FXa stimulates the release of transforming growth factor (TGF) beta 1, fibronectin, eotaxin-1, interleukin (IL) 6, or IL-8 from cultured NPFs. The effects of PAR agonists on the release of cytokines and fibronectin were also examined.Results: NPFs expressed the mRNA and proteins of all four PARs: PAR-1, PAR-2, PAR-3, and PAR-4. Both thrombin and FXa significantly stimulated the release of TGF beta 1, fibronectin, eotaxin-1, IL-6, and IL-8 from cultured NPFs. PAR-1 and PAR-2 agonists stimulated the secretion of TGF beta 1, fibronectin, eotaxin-1, IL-6, and IL-8. PAR-3 agonist stimulated the release of TGF beta 1, fibronectin, and eotaxin-1. PAR-4 agonist did not induce the release of these molecules.Conclusion: NPFs play important roles in the pathophysiology of CRSwNP such as in nasal polyp formation and inflammatory cell infiltration by releasing cytokines and extracellular matrix proteins. Activated coagulation factors, thrombin and FXa, stimulate the release of these cytokines and fibronectin from NPFs via PARs.