Mackay, Graham Angus; (1993) Some studies on the inhibition of mediator release from mast cells. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

The mast cell has been implicated in the aetiology of a range of allergic and inflammatory diseases including asthma. However, the regulatory processes which control the cell's activity remain unclear. In the present study, the effect of cyclic nucleotide modulation on mast cell function was assessed. It was hoped that this would not only indicate the importance of both cyclic adenosine and guanosine monophosphate in cellular regulation but also give further information into the mode of action of a range of anti-allergic agents particularly disodium cromoglycate (DSCG). Exogenously applied cyclic adenosine monophosphate produced negligible inhibition of histamine release from rat peritoneal mast cells (RPMC) unlike the cell permeable derivatives of the cyclic nucleotide which were effective inhibitors. Unexpectedly, cyclic guanosine monophosphate (cGMP) produced a dose-dependent attenuation of histamine release from RPMC. However, this inhibition was strikingly reduced if the cells were preincubated with cGMP before stimulation. Such inhibition and marked tachyphylaxis closely resembles the effects of DSCG on RPMC. Further comparison between cGMP and DSCG revealed that they shared parallel kinetics of tachyphylaxis, underwent cross-tachyphylaxis and were ineffective inhibitors of histamine release from mast cells isolated from the mouse, guinea-pig and human. These results suggest that cGMP and DSCG mediate mast cell stabilisation through similar mechanisms. Biochemical analysis of the RPMC phosphodiesterase (PDE) profile revealed that the predominant enzymes were PDE IV and PDE V although some PDE III was also present. Whole cell functional studies, using selective PDE inhibitors, demonstrated that the PDE V targeted drug, zaprinast, produced a particularly potent inhibition of RPMC secretion which paralleled the effects noted using both DSCG and cGMP. Zaprinast's attenuatory activity seems likely to be removed from an interaction with PDE V as a range of equipotent PDE V inhibitors had variable inhibitory effects on RPMC. Thus, modulation of cyclic nucleotide levels at both intra- and extra-cellular sites can have marked effects on the activation state of mast cells. Moreover, the results yield useful information to the elucidation of DSCG's mechanism of action. The uncovering of this mechanism may result in the development of more effective anti-allergic agents which share DSCG's low in vivo toxicity.

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