Harner Andrew, Wang Youli, Fang Xuexiu, Merchen Todd D, Cox Philip B, Ho Sam, Kleven Daniel, Thompson Thomas, Nahman N Stanley
Department of Surgery Medical College of Georgia at Augusta University, Augusta, Georgia.
Department of Medicine Medical College of Georgia at Augusta University, Augusta, Georgia.
Transplant Proc. 2019 Jul-Aug;51(6):2124-2131. doi: 10.1016/j.transproceed.2019.05.016.
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.
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.
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.
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.
肾移植急性排斥反应由适应性免疫反应和显著炎症引起。类花生酸前列腺素E2（PGE2）可调节炎症反应，由环氧化酶2（COX-2）产生，并与4种G蛋白偶联前列素细胞表面受体（EP1-4）之一结合。受体激活导致促炎（EP1和EP3）或抗炎（EP2和EP4）反应。我们推测，在猪同种异体肾移植模型中，COX-PGE2-EP信号通路各组分的表达与急性排斥反应相关。
采用蛋白质印迹法和免疫组织化学法对同种异体移植肾（n = 18）和自体移植肾（n = 5）中的COX-2酶和EP受体蛋白表达进行定量分析。采用线性回归分析将EP受体表达与Banff排斥分级相关联。
排斥反应严重的猪血清PGE2代谢产物显著增加，而排斥反应较轻的猪组织中PGE2代谢产物浓度较高。COX-2表达与Banff排斥分级之间存在显著负相关（R = -0.877）。排斥反应使EP2和EP4的表达降低。对于这两种受体，其与排斥反应程度均存在显著负相关（EP2和EP4的R分别为-0.760和-0.891）。排斥反应对促炎受体EP1和EP3无影响。
在非匹配的猪肾移植中，COX-2以及抗炎性的EP2和EP4受体的下调与急性排斥反应相关，提示COX-2-PGE2-EP途径可能在该模型中调节炎症反应。增强EP2和/或EP4活性可能为控制急性移植排斥反应的炎症提供新的治疗方法。
