1 We have examined the generation of intracellular reactive oxygen species (ROS) and release of histamine by rat peritoneal mast cells (RPMC) in response to stimulation with antigen (ovalbumin), compound 48/80, nerve growth factor (NGF) and substance P (SP). 2 We have also examined the eects of the non-speci®c nitric oxide synthase inhibitor, L-NAME (100 mM) upon the release of histamine and generation of intracellular ROS in response to the named secretagogues. 3 Ovalbumin (100 ± 1000 mg ml 71 ), compound 48/80 (0.1 ± 100 mg ml 71 ), NGF (0.1 ± 100 mg ml 71 ), and SP (5 ± 50 mM), caused a concentration-dependent release of histamine from RPMC. 4 Ovalbumin (1 ng ml 71 ± 0.1 mg ml 71), compound 48/80 (1 ± 100 mg ml 71 ), NGF (1 pg ml 71 ± 1 mg ml 71 ), and SP (0.005 ± 50 mM) caused a concentration-dependent generation of intracellular ROS by RPMC. 5 Pre-incubation of RPMC with L-NAME (100 mM) caused a signi®cant enhancement of both histamine release and intracellular ROS from RPMC in response to ovalbumin, compound 48/80, NGF and SP. 6 Our data demonstrate that NGF, SP and ovalbumin are capable of causing intracellular ROS generation by RPMC at lower concentrations than those causing signi®cant histamine release and we speculate that this may contribute to the activation of cytokine production. 7 The data also show that NO modulates histamine release, and ROS generation in response to the secretagogues used. This may have signi®cance in pathologies where NO synthesis is decreased, leading to an increased activation of mast cells.

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These results indicate that stimulation of adenosine A3 receptors both enhances degranulation in vitro and directly produces degranulation of rat mast cells in vivo.

Dosing rats with TNBS-induced colitis using sulphasalazine or marimastat produced a significant reduction in tissue injury and inflammation.

D prostanoid receptor 2 (DP 2 ) [also known as chemoattractant receptor-homologous molecule expressed on T helper 2 (Th2) cells (CRTH2)] is selectively expressed by Th2 lymphocytes, eosinophils, and basophils and mediates recruitment and activation of these cell types in response to prostaglandin D 2 (PGD 2 ). (5-Fluoro-2-methyl-3-quinolin-2-ylmethylindo-1-yl)-acetic acid (OC000459) is an indole-acetic acid derivative that potently displaces [ 3 H]PGD 2 from human recombinant DP 2 (K i ϭ 0.013 M), rat recombinant DP 2 (K i ϭ 0.003 M), and human native DP 2 (Th2 cell membranes; K i ϭ 0.004 M) but does not interfere with the ligand binding properties or functional activities of other prostanoid receptors (prostaglandin E 1-4 receptors, D prostanoid receptor 1, thromboxane receptor, prostacyclin receptor, and prostaglandin F receptor). OC000459 inhibited chemotaxis (IC 50 ϭ 0.028 M) of human Th2 lymphocytes and cytokine production (IC 50 ϭ 0.019 M) by human Th2 lymphocytes. OC000459 competitively antagonized eosinophil shape change responses induced by PGD 2 in both isolated human leukocytes (pK B ϭ 7.9) and human whole blood (pK B ϭ 7.5) but did not inhibit responses to eotaxin, 5-oxo-eicosatetraenoic acid, or complement component C5a. OC000459 also inhibited the activation of Th2 cells and eosinophils in response to supernatants from IgE/anti-IgE-activated human mast cells. OC000459 had no significant inhibitory activity on a battery of 69 receptors and 19 enzymes including cyclooxygenase 1 (COX1) and COX2. OC000459 was found to be orally bioavailable in rats and effective in inhibiting blood eosinophilia induced by 13,14-dihydro-15-keto-PGD 2 (DK-PGD 2 ) in this species (ED 50 ϭ 0.04 mg/kg p.o.) and airway eosinophilia in response to an aerosol of DK-PGD 2 in guinea pigs (ED 50 ϭ 0.01 mg/kg p.o.). These data indicate that OC000459 is a potent, selective, and orally active DP 2 antagonist that retains activity in human whole blood and inhibits mast cell-dependent activation of both human Th2 lymphocytes and eosinophils.