Slow reacting substance of anaphylaxis (SRS-A), a mediator of bronchospasm in asthma, is formed via a novel lipoxygenase-leukotriene pathway. We have discovered the conditions for a cytosolic system from RBL-l cells to generate the leukotrienes including the biologically active SRS. 1. We propose to utilize this cytosolic system to study the leukotriene pathway: a. We will determine the structural requirements for fatty acid as substrates and inhibitors of the enzyme system and develop receptor antagonists. b. We propose to show that separate enzymatic steps are involved in the leukotriene pathway and pharmacologically modulate each step. c. We will study the involvement of GSH S-transferase in SRS formation by using S-transferase inhibitors, GSH analogs and by showing that readdition of the GSH S-transferase, after separating the enzymes, will return the SRS forming activity. The work with the GSH analogs also has the potential to identify SRS synthesis and receptor antagonists. d. We will study the interaction of the two GSH dependent enzymes, S-transferase and PGD isomerase, in these cells. e. We intend to continue the investigation of the formation of a novel polar material which we discovered to be synthesized from arachidonic acid. 2. We will attempt to correlate the experiments with the RBL-l cytosol with functional processes and organ systems: a. We will test the effect of dietary fatty acid manipulation on SRS release from rat lung. b. We will study the effect of leukotrienes on the mast cell release reaction. c. We will investigate the leukotriene pathway and its modulation in sensitized guinea pig lung.
| Malaviya, R; Malaviya, R; Jakschik, B A (1997) Control of mast-cell 5-lipoxygenase. Am J Ther 4:225-8 |
| Xu, L; Malaviya, R; Olsen, K M et al. (1993) Effect of culture conditions on mast cell eicosanoid synthesis. Prostaglandins 45:385-98 |
| Jakschik, B A; Harrington, L F; Malaviya, R (1992) Leukotriene formation by mouse connective tissue mast cells. Eicosanoids 5:39-43 |
| Needleman, P; Turk, J; Jakschik, B A et al. (1986) Arachidonic acid metabolism. Annu Rev Biochem 55:69-102 |
| Wei, Y F; Evans, R W; Morrison, A R et al. (1985) Double bond requirement for the 5-lipoxygenase pathway. Prostaglandins 29:537-45 |
