Regulation of Airway Wall Remodeling: Prospects for the Development of Novel Antiasthma Drugs

Abstract

Publisher Summary This chapter describes the evidence for airway wall remodeling in asthma, discusses the pathogenesis of these changes, and identify potential therapeutic approaches to arresting the remodeling process. There is a clear requirement for the development of methodology that allows assessment of airway wall thickening because of smooth muscle hyperplasia/hypertrophy in living subjects. This is expected to facilitate studies examining therapeutic interventions to determining the reversibility of the remodeling process. Also the intracellular signaling pathways that subserve airway smooth muscle proliferation have not been fully defined nor have the key endogenous mitogens been identified. The difficulty in proposing intracellular signaling as a useful target for antiasthma drugs that would prevent airway wall remodeling is in the potential lack of specificity. It seems likely that many of the signals used by airway smooth muscle cells in the transduction of proliferative stimuli can also be common to other cell types. Further studies to elucidate the precise signaling cascade used by this cell type are required to identify whether unique regulatory sites exist. Characterization of phenotypic modulation in airway smooth muscle cells may reveal novel ways of reducing proliferative responses. If airway smooth muscle cells switch to the synthetic phenotype prior to cell-cycle progression, as do vascular smooth muscle cells, then blocking such phenotypic changes could prevent proliferation in a specific manner. Each of the elements of the airway wall remodeling process may be considered as a target for therapeutic intervention. The acute changes are likely to respond to existing anti-inflammatory treatments for asthma, primarily glucocorticoids.