Varsani, Maheshkumar Premji;
(1997)
The role of phospholipase A2 in mast cell activation.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
The mast cell has a pre-eminent role in the immunopathology and pathogenesis of inflammatory conditions, including asthma. However, the precise mechanisms involved in the signal-transduction process in this cell remain unclear. The enzyme phospholipase A₂ (PLA₂) cleaves fatty acid moieties from the sn-2 position of the glycerol phosphate backbone to yield the lyso-phospholipid and free arachidonic acid. The latter may be further metabolised to generate leukotrienes and prostaglandins. In addition, PLA₂ may also be intrinsically involved in stimulus- secretion coupling in the mast cell. Thus some reports, but not others, have claimed that purified preparations of the enzyme may evoke mast cell degranulation. In light of recent phylogenetic classification of the enzyme into different subtypes, its role in mast cell activation has been re-examined in the present study. Purified PLA₂ from bee and cobra (Naja naja) venom produced a dose-dependent release of histamine from different mast cell phenotypes. In some cases, the release was non-cytotoxic whilst, in others, components of the process were cytolytic. The non-cytotoxic release of histamine induced by PLA₂ may be due to the generation of lyso-phosphatidic acid, which has a signalling function in other systems. In contrast, the lytic release of the amine may be caused by the production of lyso-phosphatidylcholine, which is a known surfactant. Suboptimal amounts of the enzyme also potentiated immunological histamine release from rat mast cells, possibly through the generation of lyso-phosphatidylserine. The present study has indicated that the differential effects of PLA₂ on various histaminocytes reflect variations in overall membrane composition leading to the production of one or other lipid metabolite. PLA₂ may also act through the production of arachidonic acid and its further metabolism to 5-hydroperoxyeicosatetraenoic acid, which is thought to modulate secretion. Thus compounds which block the metabolism of arachidonic acid were effective in inhibiting the release of histamine from mast cells. Immunological and non-immunological activation of rat mast cells increased the activity of endogenous PLA₂. Compounds which block the function of PLA₂ also inhibited histamine release from a variety of mast cell phenotypes. Hence, the activation of endogenous PLA₂ may be an essential step in signal transduction in the mast cell. Inhibition of this enzyme may then provide a novel target in the therapeutic modulation of this cell type.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The role of phospholipase A2 in mast cell activation |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Thesis digitised by ProQuest. |
| Keywords: | Health and environmental sciences; Mast cell activation |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10104666 |
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