BW755C inhibits the 5-lipoxygenase in E-mast cells without affecting degranulation.

The inhibitory effect of the drug BW755C on the 5-lipoxygenase pathway was analyzed for bone marrow-derived murine mast cells, termed E-mast cells. The drug prevented the formation of 5-HETE from exogenous [14C]arachidonic acid when IgE-sensitized cells were challenged by the antigen. BW755C also prevented formation of leukotriene C4 in a dose-dependent fashion when IgE-sensitized mast cells, preincubated with the drug, were activated with either the specific antigen or the ionophore. Leukotriene C4 inhibition occurred with a minimal drug preincubation period of 1 min before the cells were subjected to antigen-dependent activation. BW755C did not affect the degranulation response of these cells. Thus in an intact cell system BW755C prevents 5-lipoxygenation of arachidonic acid. Furthermore, this study reveals that even with transmembrane activation of E-mast cells through their IgE-Fc receptors, granule secretion is not dependent upon corresponding metabolites from the 5-lipoxygenase pathway.

New role for heparan sulfate: regulator of leukotriene generation in mouse E-mast cells.

In this work, bovine heparan sulfate, pig mucosa heparin and squid chondroitin sulfate-E glycosaminoglycans (GAGs) were compared as to their affect on the synthesis of leukotrienes C4 (LTC4) and B4 (LTB4) as well as on the production of prostaglandin D2 (PGD2) in cultured mouse E-mast cells (E-MC). The maximum percent increase in LTC4 generation in cells treated with 0.2 micrograms heparan sulfate was 52 +/- 3% (mean +/- S.E., n = 5). Whereas 0.5 micrograms of the GAG increased the production of LTB4 by 50% Ten micrograms of heparin slightly increased the LTC4 production (33%) whereas lower doses were found to be ineffective. No significant increase in LTC4 production was demonstrated when the IgE sensitized E-MC were treated with chondroitin sulfate-E GAG prior to the antigen challenge. Neither one of the three GAGs, at the various doses used, affected the antigen induced exocytosis of beta-hexosaminidase from the IgE sensitized E-MC. After 15 min preincubation with heparan sulfate, antigen induced release of PGD2 from 1 X 10(6) sensitized cells was inhibited from 5.4 ng +/- 0.1 ng into 3.5 ng +/- 0.1 ng at 0.5 micrograms/ml GAG. All of the three types of GAGs used were uneffective when the E-MC were activated by calcium ionophore A23187.