Differential Expression of Prostaglandin E2 Receptors in Porcine Kidney Transplants
Differential Expression of Prostaglandin E2 Receptors in Porcine Kidney Transplants
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DOI：
10.1016/j.transproceed.2019.05.016
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发表时间：
2019-07-01
影响因子：
0.9
通讯作者：
Nahman, N. Stanley, Jr.
中科院分区：
文献类型：
--
作者：
Harner, Andrew;Wang, Youli;Nahman, N. Stanley, Jr.
背景同种异体肾移植的急性排斥反应是由适应性免疫反应和明显的炎症反应引起的。类二十烷酸前列腺素E2（PGE 2）调节炎症反应，由环氧合酶2（考克斯-2）产生，并结合4种G蛋白偶联的E前列腺素类细胞表面受体（EP 1 - 4）之一。受体活化导致促炎（EP 1和EP 3）或抗炎（EP 2和EP 4）反应。我们推测COX-PGE2-EP信号通路的组分的表达与猪同种异体肾移植模型中的急性排斥反应相关。采用免疫印迹法和免疫组化法对同种异体移植（n = 18）和自体移植（n = 5）的考克斯-2酶和EP受体蛋白表达进行定量。采用线性回归分析将EP受体表达与Banff排斥分类相关联。晚期排斥反应的猪表现出血清PGE2代谢物的显著增加，而排斥反应较少的猪表现出较高的组织PGE2代谢物浓度。考克斯-2表达与排斥反应分级呈负相关（R =-0.877）。排斥反应降低了EP2和EP4的表达。对于两种受体，与排斥程度呈显著负相关（EP 2和EP 4分别为R =-0.760和R =-0.891）。排斥反应对促炎性受体EP 1和EP 3无影响。考克斯-2和抗炎性EP 2和EP 4受体的下调与非匹配猪肾移植的急性排斥反应相关，表明考克斯-2-PGE 2-EP通路可能调节该模型中的炎症。增强EP 2和/或EP 4活性可能为控制急性同种异体移植排斥反应的炎症提供新的治疗方法。
Background. Acute rejection of a kidney allograft results from adaptive immune responses and marked inflammation. The eicosanoid prostaglandin E2 (PGE2) modulates the inflammatory response, is generated by cyclooxygenase 2 (COX-2), and binds to 1 of the 4 G protein-coupled E prostanoid cell surface receptors (EP1-4). Receptor activation results in in proinflammatory (EP1 and EP3) or anti-inflammatory (EP2 and EP4) responses. We theorized that expression of the components of the COX-PGE2-EP signaling pathway correlates with acute rejection in a porcine model of allogeneic renal transplantation.Method. COX-2 enzyme and EP receptor protein expression were quantitated with western blotting and immunohistochemistry from allotransplants (n = 18) and autotransplants (n = 5). Linear regression analysis was used to correlate EP receptor expression with the Banff category of rejection.Results. Pigs with advanced rejection demonstrated significant increases in serum PGE2 metabolites, while pigs with less rejection demonstrated higher tissue concentrations of PGE2 metabolites. A significant negative correlation between COX-2 expression and Banff category of rejection (R = -0.877) was shown. Rejection decreased expression of EP2 and EP4. For both receptors, there was a significant negative correlation with the extent of rejection (R = -0.760 and R = -0.891 for EP2 and EP4, respectively). Rejection had no effect on the proinflammatory receptors EP1 and EP3.Conclusion. Downregulation of COX-2 and the anti-inflammatory EP2 and EP4 receptors is associated with acute rejection in unmatched pig kidney transplants, suggesting that the COX-2-PGE2-EP pathway may modulate inflammation in this model. Enhancing EP2 and/or EP4 activity may offer novel therapeutic approaches to controlling the inflammation of acute allograft rejection.