CD44 is a widely expressed cell adhesion molecule (CAM) that serves as a principal receptor for hyaluronan (HA), an extracellular matrix glycosaminoglycan. Up regulated expression of CD44 has been noted on epithelial cells, eosinophils and T lymphocytes in patients with asthma. Levels of HA recovered in the bronchoalveolar lavage (BAL) of asthmatics are also increased and correlate with severity of disease. In preliminary studies we investigated the role of CD44 in the development of airway inflammation and airway hyperreactivity (AHR) in antigen-sensitized mice. CD44- deficiency had no effect on the recruitment of leukocytes or production of antigen specific IgE but airway hyperreactivity was markedly reduced compared to wild-type littermate controls. Furthermore, administration of anti-CD44 antibodies to wild-type mice inhibited antigen-induced airway hyperreactivity compared to normal rat Ig treated mice. The goal of the proposed studies is to determine the molecular and cellular mechanisms by which CD44 promotes antigen-induced AHR. We propose the following specific aims: 1. Test the hypothesis that CD44 promotes antigen-induced AHR in mice. We will also test the hypothesis that development of AHR and airway inflammation is associated with functional activation of CD44 and the accumulation of low molecular weight pro-inflammatory fragments of hyaluronan in mice and humans. 2. Determine the relative contributions of CD44 expression on bone marrow-derived hematopoietic cells versus non-hematopoietic parenchymal cells on AHR and define the role of soluble CD44 in airway inflammation and AHR. We will determine if CD44 on either hematopoietic cells or on non-hematopoietic cells alone in bone marrow chimeras promotes airway inflammation and AHR. The contribution of soluble CD44 to antigen-induced airway inflammation and AHR will also be determined. To ascertain the cellular and molecular mechanisms by which CD44 promotes AHR and airway remodeling we will: 3) Determine the role of CD44 in matrix organization; and 4) Test the hypothesis that ligand binding to CD44 affects the synthetic function of airway smooth muscle cells and epithlelial cells by activating NF-kB and Ras-dependent signaling pathways. Since CD44 plays an important role in inflammation and appears to promote AHR but is not required for normal leukocyte circulation, it is particularly attractive as a potential target for novel therapeutic interventions in asthma. An understanding of the cellular and molecular mechanism by which CD44 promotes AHR may therefore provide defined targets for therapeutic interventions.
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