The mechanisms of intractable asthma

Overwhelming evidence now points to asthma as a chronic inflammatory disease involving the airways. The T lymphocyte takes primacy in driving the inflammatory response through upregulation of cytokines, specifically those encoded in the IL-4 gene cluster: IL-4 and IL-13 (IgE isotype switching); IL-3, IL-5 and GM-CSF (eosinophil and basophil recruitment); and IL-9 (mast cell maturation). Additional cytokines of importance include TNFa and a range of related C-x-C and C-C cytokines. Although allergens are involved in initiating the Th-2 T-cell response, other factors are likely to operate that expand and maintain the inflammatory reaction. These include a potential role for superantigens and autoimmune mechanisms as well as the recruitment of accessory cytokine producing cells, especially mast cells and eosinophils. Leucocytes recruited from the microvasculature through interactions with specific adhesion molecules release an array of mediators, which in addition to causing bronchoconstriction also lead to damage to the epithelium and underlying structures. Neutral proteases from mast cells, metalloproteases from eosinophils and an array of mediators from the formed elements of the airway all contribute to the tissue destruction remodelling process. It was concluded that asthma is a dynamic disease process involving an interplay between inflammation and repair processes and that the differing proportions of these could account for the various disease phenotypes associated with severity and progression