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The cellular mechanism of corticosteroid resistance in asthma

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PoznanskyMC_1985redux.pdf (8.993Mb)
Date
1985
Author
Poznansky, Mark C.
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Abstract
 
 
Chronic asthmatics norrally respond to oral corticosteroid therapy with an increase in their ventilatory function. However, Grant and his co- workers identified a small proportion of severe chronic asthmatics who did not improve their ventilatory function when given oral corticosteroid. These patients were termed "corticosteroid resistant ". This thesis describes the in vitro and in vivo effects of the corticosteroid, Ilethylprednisolone (INS), on monocytes and Tcells from Corticosteroid Sensitive (CS) and Corticosteroid Resistant (CR) asthmatics.
 
In vitro colony formation by mononuclear cells (MNC) from CS asthmatics was found to be significantly more inhibited by 10⁻⁸ N MPS than was colony formation by MNC from CR asthmatics. This in vitro assay of corticosteroid sensitivity was subsequently used diagnostically to discriuina_te between CS and CR asthmatics. It was demonstrated that the unresponsiveness of MNC from CR asthmatics to MPS in vitro was attributable to the monocytes from these patients. Defects in the corticosteroid sensitivity of T-cells, eosinophils and polymorphs were also observed in vivo and in vitro; their relationship to the monocyte defect was not clarified.
 
Monocytes are thought to affect the Type 1 hypersensitivity reaction seen in asthma by the production of many factors. Two of these factors are of particular relevance to this thesis: lipomodulin, which inhibits prostanoid synthesis and is induced by corticosteroid and Interleukin 1, which supports T- lymphocyte proliferation and is inhibited by corticosteroid. There is therefore reason to believe that the defect in corticosteroid responsiveness demonstrated in monocytes from CR asthmatics in vitro could reduce the therapeutic efficacy of these drugs in patients with this condition.
 
If this is so, these findings emphasise the importance of the actions of corticosteroid on monocyte function in the commoner CS asthma. Further investigation of this phenomenon may have wider implications for other developmental and pathological processes.
 
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http://hdl.handle.net/1842/33579
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