Prostaglandin D2 Modulates Neuronal Excitation of the Trigeminal Ganglion to Augment Allergic Rhinitis in Guinea Pigs.

Prostaglandin D2(PGD2) is involved in the pathogenesis of allergic rhinitis. However, the sensory nervous system-mediated contributions of PGD2to the symptoms of allergic rhinitis remain unclear. We investigated the involvement of PGD2in these symptoms and in neuronal excitation by in vivo and ex vivo experiments. In an ovalbumin-induced model of allergic rhinitis in guinea pigs, the number of sneezing, nasal rubbing, and nasal secretion events were assessed after the nasal cavity instillation of PGD2, histamine, or a combination of PGD2and histamine. In situ hybridization for PGD2receptor 1 (DP1) mRNA transcripts and immunohistochemical analysis of histamine H1receptor protein expression in guinea pig trigeminal ganglion (TRG) were performed. The effects of DP1receptor activation on the excitability of TRG neurons to electrical and histamine stimuli were assessed using whole-cell patch-clamp recordings. Histamine induced more sneezing, nasal rubbing, and nasal secretion events than PGD2 PGD2augmented histamine-induced responses, whereas pretreatment with a DP1receptor-selective antagonist completely suppressed PGD2-induced augmentation. DP1receptor mRNA transcripts and H1receptor protein expression could be detected in TRG neurons. Moreover, a DP1receptor agonist caused significant increases in the number of histamine-induced action potentials and depolarization, and reduced the current threshold in small-diameter neurons. Our findings show that PGD2-DP1receptor signaling augments the symptoms of allergic rhinitis via the sensory nervous system by modulating nasal neuronal activation to various stimuli, such as histamine. These findings suggest that DP1receptor antagonist has therapeutic potential for the treatment of allergic rhinitis.

Role of Prostaglandin D2 and DP1 Receptor on Japanese Cedar Pollen-Induced Allergic Rhinitis in Mice.

Although we previously demonstrated the contribution of the DP1receptor in nasal obstruction using animals sensitized with ovalbumin in the presence of adjuvant, the contribution of the DP1receptor in sneezing is unclear. Here, we developed a mouse model of Japanese cedar (JC:Cryptomeria japonica) pollinosis to evaluate the symptoms of sneezing. To achieve this, we used JC pollen crude extract in the absence of adjuvant to sensitize mice to develop a model closer to the pathophysiology of human JC pollinosis. The immunologic and pharmacologic features of this model are highly similar to those observed in JC pollinosis in humans. Using this model, we found that DP1receptor antagonists suppressed JC pollen extract-induced sneezing and that a DP1receptor agonist induced sneezing. Moreover, JC pollen extract-induced sneezing was diminished in DP1receptor knockout mice. In conclusion, we developed a novel mouse model of allergic rhinitis that closely mimics human JC pollinosis. A strong contribution of DP1receptor signaling to sneezing was demonstrated using this model, suggesting that DP1receptor antagonists could suppress sneezing and nasal obstruction, and therefore these agents could be a new therapeutic option for allergic rhinitis.

Effect of a selective inhibitor of secretory phospholipase A2, S-5920/LY315920Na, on experimental acute pancreatitis in rats.

We investigated the efficacy of a potent inhibitor of secretory phospholipase A2 (sPLA2), S-5920/LY315920Na, in an experimental model of acute pancreatitis in rats. Combined intraductal injection of sodium taurocholate (5 mg/rat) and porcine pancreatic sPLA2-IB (300 microg/rat) caused severe hemorrhagic necrotizing pancreatitis resulting in high mortality, along with rapid increases of catalytic PLA2 and lipase activities in plasma and ascites and with gradual increases of plasma amylase and aspartate aminotransferase levels over 9 h after the pancreatitis. Prophylactic intravenous treatment with S-5920/LY315920Na significantly reduced mortality at 7 days, and strongly abrogated PLA2 activities in both plasma and ascites along with significant reduction of lipase activity, amylase, aspartate aminotransferase, and hemorrhage at 6 h. It also significantly reduced histological damage such as edema and parenchymal and fat necroses of the pancreatic tissue. This sPLA2 inhibitor could become an effective agent for the treatment of severe acute pancreatitis.

Role of group IIA phospholipase A2 in rat colitis induced by dextran sulfate sodium.

Although group IIA phospholipase A(2) has been suggested to be implicated in inflammatory bowel disease, its pathophysiological role in colitis remains unclear. We investigated whether group IIA phospholipase A(2) had pro-inflammatory roles in dextran sulfate sodium-induced colitis in the rat. Secretory phospholipase A(2) activity was markedly increased in the distal colon with two peaks. Strong immunostaining for group IIA phospholipase A(2) was found in subepithelial tissue and lamina propria at early stage and in deeper tissues of the erosion area at later stage. Treatment with a specific group IIA phospholipase A(2) inhibitor, S-3013/LY333013 (methyl[[3-(aminooxoacetyl)-2-ethyl-1-(phenylmethyl)]-1H-indol-4yl]oxy) acetate), reduced erosion area, shortening of colon and colonic inflammation, and strongly inhibited the increase in secretory phospholipase A(2) activity and moderately reduced myeloperoxidase activity in the colon in vivo, while eicosanoid levels were not affected. Marked group IIA phospholipase A(2) expression in the erosion area and the improvement of colitis by the group IIA phospholipase A(2) inhibitor strongly suggest that this enzyme plays pro-inflammatory roles in this colitis model.