Inflammation of Myofibroblasts and Loss of Elastic Recoil in Severe Asthma

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DESCRIPTION (provided by applicant): Preliminary data suggest severe exacerbation-prone asthma differs from milder asthma in abnormalities specific to the distal lung. We hypothesize that structural cells of the distal airways and alveoli have unique properties that contribute to the generation and maintenance of inflammation and predict a certain pattern of repair in this region leading to the clinical, physiologic and radiologic abnormalities of severe asthma (Figure 18). In order to evaluate these clinical, physiologic and pathobiologic changes (and their response to high dose systemic steroids) we propose 3 aims. In Aim #1, we will continue to expand on the physiologic and structural changes present in severe exacerbation prone asthma. This aim will include comparisons between the physiologic abnormalities specific to severe asthma (hyperinflation/air-trapping, loss of recoil and collapse), the structural changes in the airways and parenchyma observed by digitally qualified and quantified multidetector CT images taken at TLC and FRC/TGV and their relation to inflammatory processes. These changes will then be re-evaluated following the triamcinolone treatment. In Aim #2 we will identify the presence of inflammatory cytokines (IL-13/TNF-a), growth factors (TGF-IS1/2, c-kit/c-kit ligand) and matrix elements (hyaluronan/HAS, IGSF-4, MMPs) in the distal and proximal airway which could contribute to the persistent distal lung eosinophil/mast cell inflammation seen in severe asthma. We will evaluate the relationship of these factors and the associated inflammation to the repair processes occurring in this region and as well as physiologic changes and structural changes measured by CT. Finally, in Aim #3 we will address how phenotypic differences in fibroblasts isolated from the proximal vs. the distal lung (as obtained by endo- and transbronchial biopsies from the same individuals) could contribute to the perpetuation of the inflammatory and repair process in the distal lung. As part of SARP II, we will determine whether there is a shift in the dose response to CS that may help to explain both the persistence of the inflammation in the distal lung and the refractory nature of the disease. Completing these aims should lead to an improved understanding of the contribution of inflammation and injury repair in the small airways/alveoli to the development of severe asthma. These findings may improve therapy as well.