Although histologic features of
airway remodeling have been well characterized in
asthma, the immunologic and inflammatory mechanisms that drive progression of
asthma to remodeling are still incompletely understood. Conceptually,
airway remodeling may be a result of persistent
inflammation and/or
aberrant tissue repair mechanisms. It is likely that several immune and inflammatory cell types and mediators are involved in mediating
airway remodeling. In addition, different features of
airway remodeling are likely mediated by different inflammatory pathways. Several important candidate mediators of remodeling have been identified, including
TGF-beta and T(H)2
cytokines (including IL-5 and
IL-13), as well as
vascular endothelial growth factor, a disintegrin and
metalloproteinase 33, and
matrix metalloproteinase 9. Mouse models of
airway remodeling have provided important insight into potential mechanisms by which
TGF-beta activation of the Smad-2/3 signaling pathway may contribute to
airway remodeling. Human studies have demonstrated that anti-IL-5 reduces levels of airway eosinophils expressing
TGF-beta, as well as levels of
airway remodeling as assessed by bronchial biopsies. Further such studies confirming these observations, as well as alternate studies targeting additional individual cell types,
cytokines, and mediators, are needed in human subjects with
asthma to determine the role of candidate
mediators of inflammation on the development and progression of
airway remodeling.