A novel CCR5/CXCR3 antagonist protects intestinal ischemia/reperfusion injury.

Chemokines and chemokine receptors have been demonstrated to be critical regulators in a variety of physiologic and pathologic immune responses. In particular, CCR5 and CXCR3 have been reported to play important roles in the alloimmune response. In this study, we investigated the therapeutic efficacy of a novel small-molecule compound, TAK779, an antagonist targeting both CCR5 and CXCR3 in intestinal ischemia/reperfusion (I/R) injury. We utilized an established murine intestinal I/R injury model. TAK779 treatment significantly improved mouse survival after 60 minutes of intestinal ischemia. We then examined the local intestinal expression of several cytokines and chemokines at 2 hours after reperfusion using real-time PCR. TAK779 treatment downregulated the expression of several cytokines, including TNF-alpha, IFN-gamma, and IL-4, suggesting that the beneficial effect of TAK779 was associated with inhibition of local immune activation. We further examined the systemic response after TAK779 treatment. Lung tissue damage was significantly prevented by the treatment, as determined by lung wet-to-dry weight ratios at 4 hours after intestinal I/R injury. In addition, we observed that CCR5 expression in the lung was significantly downregulated by the treatment, suggesting that TAK779 inhibited the infiltration of CCR5-positive cells into the remote organ. Our data suggest the critical role of CCR5 and CXCR3 in intestinal I/R injury and therapeutic efficacy of a novel small compound, TAK779, for protection against the intestinal I/R injury.

Role of EP4 prostaglandin E2 receptor in the ischemic liver.

Prostaglandin E(2) (PGE(2)) mediates a variety of both innate and adaptive immunity responses through 4 distinct receptors, EP1-4. Recent studies have suggested the physiological and pathological role of EP4 in various inflammatory diseases. In this study, we investigated the importance of the EP4 receptor, and the efficacy of a selective EP4 agonist to alter hepatic ischemia/reperfusion (I/R) injury, an important cause of damage in liver resection and transplantation. We used an established murine I/R injury model, 70% partial hepatic ischemia for 90 minutes in male C57BL/6 mice. The local expression of EP4 messenger RNA (mRNA) in the naive and the ischemic liver at 2 hours after reperfusion was examined using RT-PCR analysis. Some mice received the EP4 selective agonist during I/R. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured as markers of hepatic injury. EP4 expression in the liver was significantly up-regulated at 2 hours after reperfusion. Furthermore, treatment with EP4 agonist significantly inhibited hepatic injury at 6 hours after reperfusion. Our data suggest an inhibitory role of EP4 PGE(2) receptor in hepatic I/R injury and the therapeutic efficacy of a selective EP4 agonist for liver protection.