Immunologic and inflammatory mechanisms that drive asthma progression to remodeling

Abstract

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.

Figure 1. Asthma Progression in adults

Population based studies of asthma progression in adults (e.g. reference 6)_shows an increased rate of decline in lung function compared to non-asthma controls (Panel A).Asthmatics may remodel their airways at different rates (Hypothetical Model) suggesting that certain genetic factors and/or environmental factors (exacerbations, viral infections, tobacco smoke, etc) may contribute to enhanced remodeling in a subset of asthmatics (Panel B)

Figure 2. Immune and inflammatory mechanisms and asthma progression

Asthma progression may be due to persistent airway inflammation and/or impaired repair mechanisms. Allergen inhalation induces activation of Th2 cells which express cytokines including IL-5 which generates TGF-β+ eosinophils that promote features of remodeling. Treg cells (natural and adaptive) have the ability to inhibit Th2 responses. Theoretically a deficiency of Treg function in asthma could promote continued Th2 mediated inflammation.

Figure 3. Eosinophil and asthma progression

Eosinophils express receptors which induce their proliferation (IL-5R), chemo-attraction 1003 into tissues (CCR-3), and apoptosis (Siglec-8). Targeting such receptors can modulate levels of eosinophilic inflammation and the ability of eosinophils to express TGF-β an 1005 important pro-remodeling cytokine.