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Etodolac, a selective cyclooxygenase-2 (COX-2) inhibitor, is a non-steroidal anti-inflammatory drug. COX-2 is a key factor in the progression of inflammation. Although inflammation is an essential pathologic feature of cardiac allograft rejection, the role of COX-2 in this process remains unclear. The aim of this study was to investigate the expression of COX and the effects of etodolac in a mouse cardiac allograft model. Balb/c mice (H-2d) were used as recipients and C57BL/6 (H-2b) mice as heart donors. Heart function was evaluated daily after transplantation by regular abdominal palpation of the heart and by laparotomy in cases where the beating became weak. Rejection was defined as total cessation of cardiac muscle contraction. COX-2 expression was analyzed by immunohistochemistry. Cardiac isograft was well tolerated (>150 days, n=5), while non-treated cardiac allograft was rapidly rejected (mean 10.9±2.4, n=7). In the etodolac-treated cardiac allograft (10 mg/kg/day by hypodermic injection), survival was extended to 18.53±2.1 days (n=7). The necrotic area and the grade of COX-2 immunostaining were more significantly reduced in the etodolac-treated cardiac allograft than in the non-treated cardiac allograft at day 14. These results indicate that etodolac contributes to protection against rejection after heart transplantation. Etodolac could therefore be used to suppress graft rejection by means of its anti-inflammatory properties.

Sphingosine-1 phosphate receptor (S1PR) has come to the fore as a mediator of extracellular signaling through its interaction with G-protein-coupled receptors, which results in the induction of peripheral T-cell depletion. The mechanisms involved in renal ischemia-reperfusion (I/R) injury are complex, but appear to involve the early participation of bone marrow-derived cells, such as T lymphocytes. In this study, we investigated the expression of SIPR in a rat model of renal I/R injury. By means of a laparotomy, the right kidney was harvested and the left renal artery and vein were clamped. The kidney was reperfused after 90 min of ischemia, and rats were sacrificed at 0, 3, 6, 12 and 24 h after reperfusion. S1PR expression was analyzed by immunohistochemistry, and was observed only in endothelial cells of the normal kidneys. From 0 to 3 h after reperfusion, S1PR expression gradually became stronger in endothelial cells, reaching its peak intensity at 3 h after reperfusion. Twelve hours after reperfusion, necrosis had extended throughout the ischemic kidney, and nearly all the tubular epithelial cells had been destroyed. From 3 to 12 h after reperfusion, S1PR expression gradually weakened. At 24 h after reperfusion, levels of S1PR expression had almost reached those of the normal kidneys. In conclusion, S1PR was found to be expressed in a rat model of renal I/R injury. Several hours after achieving the maximum level of S1PR expression, the maximum level of renal I/R injury was observed. These results suggest a relationship between S1PR and renal I/R injury.

The metabolism of arachidonic acid by either cyclooxygenase or lipoxygenase is believed to play an important role in carcinogenesis. Leukotriene (LT) D4 is a pro-inflammatory mediator derived from arachidonic acid through various enzymatic steps, and 5-lipoxygenase is an important factor in generating LTD4. We investigated LTD4 receptor (cysteinylLT1 receptor; CysLT1R) expression in testicular cancer (TC), as well as the effects of the CysLT1R antagonist on cell proliferation in a TC cell line. CysLT1R expression in tissue from TC patients and normal testes (NTs) was detected using immunohistochemistry and RT-PCR. The effects of the CysLT1R antagonist on TC cell growth were examined using the MTT assay. Flow cytometry was used to determine whether or not the CysLT1R antagonist induces apoptosis. Immunohistochemistry indicated that CysLT1R expression was strong in all types of TC tissues, but very weak in NT tissues. The TC cell line expressed CysLT1R mRNA as detected by RT-PCR. MTT and flow cytometry revealed that the CysLT1R antagonist caused marked inhibition of TC cells through early apoptosis. In conclusion, CysLT1R was induced in TC. The results suggest that the CysLT1R antagonist may mediate potent anti-proliferative effects against TC cells. Thus, CysLT1R may become a new therapeutic target for the treatment of TC.

Angiotensin II receptor blockers (ARBs) are widely used as hypertensive therapeutic agents. However, it has been reported that Telmisartan (a type of ARB) additionally activates peroxisome proliferator-activated receptor (PPAR)-γ. We previously reported that PPAR-γ ligand induced the growth arrest of renal cell carcinoma (RCC) cells through apoptosis, and that Telmisartan had the potential to inhibit prostate cancer cell growth through apoptosis. In this study, we evaluated the effects of Telmisartan and other ARBs on cell proliferation in an RCC cell line using normal proximal tubular endothelial cells (PRTECs) and the human RCC (Caki-1) cell line. The effects of Telmisartan as well as of other ARBs (Candesartan, Valsartan, Irbesartan and Losartan) on RCC cell growth were examined by MTT assay. Flow cytometry and Hoechst staining were used to determine whether or not the ARBs induced apoptosis. Telmisartan caused marked inhibition in RCC cells in a concentration- and time-dependent manner. Treatment with 100 µM of Telmisartan induced early apoptosis and DNA fragmentation in the RCC cells, but not in the PRTECs. None of the other ARBs had an effect on cell proliferation in the RCC cells or the PRTECs. Telmisartan may mediate potent antiproliferative effects against RCC cells through PPAR-γ. Thus, Telmisartan is a potential target for prevention and treatment in RCC.