Severe asthma is defined by fixed airflow limitation and marked airways hyperresponsiveness, characterized by excessive airways narrowing with potentially fatal consequences. Pathologically, the remodeled airway wall shows epithelial loss, increased smooth muscle, inflammatory cell infiltrations and a thicker basement membrane due to collagen deposition. This thickening is thought to be characteristic and discriminatory for the disease. It is presumed that this fibroproliferative response is progressive and leads to irreversible airflow limitation - but this linkage is unproven. Novel features of the proposed murine system of chronic antigen exposure includes a progressive increase in airflow limitation and hyperresponsiveness. Fibrosis, especially collagen deposition, and thickening of the airway and basement membrane are observed. We hypothesize that: 1) certain aspects of airways fibrosis will be directly linked to airways dysfunction, especially airways hyperresponsiveness; 2) the fibrosis is caused by the growth factor TGFBeta(s) and; 3) the mechanism of hyperresponsiveness in this model are several and interrelated. These physiological mechanisms include loss of elastic recoil, increased peripheral resistance and loss of airway/parenchymal interdependence. This latter mechanism is the interrelationship between airways smooth muscle contractility which may be unchanged and the load on the smooth muscle pulls which is decreased due to loss of recoil. These mechanisms interrelate to result in excessive airways narrowing with fatal consequences.
The Specific Aims of the project are: First, to determine the causal link between collagen deposition and airways hyperresponsiveness by exploring temporal and dose responses to antigen exposure as will as agents affecting collagen synthesis and function. Second, to determine the role of TGFBeta(s) in orchestrating the fibrotic response. And, the third specific aim is to determine the physiological mechanisms which accounts for the antigen-induced excessive airways narrowing. New insights into the structure/function relationship accounting for persistent and often progressive hyperresponsiveness and airflow limitation due to antigen exposure should result. The results should provide rationales for new and novel approaches to the treatment of severe and progressive asthma.
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