IL-13, MYOFIBROBLASTS & ELASTIC RECOIL IN SEVERE ASTHMA

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DESCRIPTION (provided by applicant): The pathophysiology of severe asthma is poorly understood. A subset of patients with severe asthma, who are predisposed to near fatal events appears to have increases in airway collapsibility and loss of elastic recoil contributing to their severity. We hypothesize that these changes are driven by inflammatory and structural changes in the distal lung which involve the transformation of fibroblasts to myofibroblasts. The associated injury and repair process, involving mast cell proteases and metalloproteinases (MMP), alone or in combination, cleaves elastin and other extracellular matrix (ECM) components. The breakdown products of ECM, in turn, feed back on the myofibroblasts continuing the cycle of elastin production, MMP release/activation and elastin breakdown. These changes alter the alveolar-parenchymal attachments, decreasing elastic recoil and markedly worsening the clinical severity of the asthma. In Specific Aim 1 we will characterize physiologic parameters felt to be important in asthma: airflow limitation, bronchial hyperreactivity, and, in addition, elastic recoil (measured by pressure-volume curves). The asthmatic subjects will undergo endobronchial and transbronchial biopsy to evaluate the cellular and immune inflammatory process in both lung compartments. Resected lung from emphysema patients will be used for comparison. High resolution CT scans will evaluate parenchymal differences among the groups. Specific Aim 2 will measure elastin in the distal lung of the subject groups and the relationship to myofibroblast phenotypic changes. These changes will be compared to MMP and mast cell protease amounts and activity, as well as ECM degradation products in the distal lung. In Specific Aim 3, we will develop an in vitro model of the observed in vivo processes by culturing fibroblasts from proximal and distal lung. Cellular interactions between growth factors, proteases and extracellular matrix will be specifically evaluated. Completing these studies in both asthma and emphysema should offer new targets for the treatment and prevention of severe obstructive lung diseases.