Studies on the biochemical pharmacology of mast cells dispersed from the human large intestine

Rees, Paul Hywel (1989) Studies on the biochemical pharmacology of mast cells dispersed from the human large intestine. University of Southampton, Doctoral Thesis.

Abstract

In this study, viable, intact, mast cells have been dispersed from the nucosal and muscle layers of the human large intestine using collagenase and hyaluronidase. Mucosal and muscle mast cells were 59% and 90% formalin-resistant respectively and in both populations the tryptase/chymase-containing (MC_TC) protease sub-type was predominant. In common with other human mast cells, those dispersed from both the mucosa and muscle released histamine and prostaglandin D₂ (PGD₂) when stimulated by anti-IgE and A23187. However, both populations were insensitive to compound 48/80, substance P and morphine. Histamine and PGD₂ release from the mucosa was inhibited by sodium cromoglycate (SCG), nedocromil sodium, salbutamol and isobutylmethylxanthine (IBMX). In rodent mice cells, sensitivity to formalin fixation, protease content and the ability to responsd to non-immunological stimulation are closely related. Comparison of the results presented in this thesis with other studies suggest that this relationship cannot be extrapolated to human mast cells as intestinal mast cells, like those of the skin, were predominantly MC_TC, but were insensitive to non-immunological secretagogues contrasting with this population. Therefore, in the large intestine, protease content and the ability to respond to non-immunological stimulation appear to develop independently of one another. In rodents, sensitivity to SCG-like drugs is also closely related to protease content and reactivity to non-immunological secretagogues. The inhibition observed with SCG contrasts with rat intestinal mast cells but shows similarity with those dispersed from the human lung although these two populations contain different protease sub-types. However, human lung mast cells develop rapid tachyphylaxis to the effects of SCG which was not observed in intestinal mucosal mast cells. Also, human dispersed skin mast cells, which contain predominantly MC_TC are insensitive to SCG. The results obtained with salbutamol and IBMX show close similarity with other human mast cells and provide further evidence that raising mast cell cytosolic cyclic AMO is inhibitory to the secretory process. In conclusion, the results presented in this thesis add further complexity to the study of human mast cell heterogeneity and suggest that histochemical, pharmacological and secretory characteristics, which are closely related in rodent mast cells, may not be similarly related in man.

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