The hypothesis behind the protocol entitled """"""""Leukotriene B4 and Glucocorticoid Insensitive Asthma"""""""" is that the upregulation of the 5 lipoxygenase pathway by glucocorticoids (GC) contributes to the unresponsiveness of GC Unresponsive Asthmatics. While this still generally appears to occur, the increase in the 5 lipoxygenase pathway now appears to be more general, occurring in both GC sensitive and insensitive subjects. It can be seen in peripheral blood mononuclear cells and we are pursuing some of the mechanisms at that level. However, because of the overlap in groups, we have shifted our focus to other effects of GCs in GC insensitive asthma. We are now evaluating the """"""""injury repair"""""""" active compounds, transforming growth factor ' (TGF'), matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) in the regulation of the subbasement membrane (SBM). Our early data suggest that GC insensitive asthmatics increase TGF' in response to steroids, while having smaller increases in MMPs (1 and 9) in airway tissue, than seen in GC sensitive asthmatics. These changes were associated with increases in the SBM thickness in GC insensitive asthmatics, following treatment with GCs, while the GC sensitive asthmatics had very little change in SBM thickness. Interestingly, the same increase in TGF-' and decrease in relative MMP activity is seen in severe, GC dependent asthmatics. We are beginning to compare the results in moderate asthmatics to the results seen in mild asthma, to determine the course of a """"""""normal"""""""" wound repair process. These results should give us a better understanding of the activity of the wound repair process in asthma of different types and how GCs further modulate that process.
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