Intraalveolar fibrosis is a stereotypical reaction to lung injury. However, in many patients this reparative process is ineffective due to failure to adequately eliminate airspace fibrotic tissue or due to progressive fibrosis. Progressive alveolar fibrosis is directly and indirectly one of the leading causes of death in patients with ARDS. Therefore, therapeutic strategies designed to promote regression or elimination of airspace fibrotic tissue as a novel approach for the treatment of patients with ARDS may be effective. Pilot studies suggest that timely intervention with corticosteroids during the repair phase of ARDS may hasten resolution of airspace fibrosis and improve patient survival. Unfortunately, corticosteroid use in this patient population is potentially hazardous due to the increased risk of life-threatening infection. Nevertheless, these studies lend credence to strategies designed to promote regression of airspace fibrosis as a novel therapeutic approach for the treatment of patients with late ARDS. We have discovered that the cell surface matrix receptor, CD44, mediates lung myofibroblast invasion into fibrin matices. Immunohistochemical studies of lung tissue from patients who died with alveolar fibrosis show CD44 expressing mesenchymal cells in newly formed fibrotic tissue linking CD44 with the fibrotic response and implicating CD44 with anti-CD44 antibody triggers lung myofibroblast apoptosis. This suggests that the ligation state of CD44 may play a role in the regulation of fibroblast viability. We have shown that fibroblast apoptosis results in part, but not solely from detachment indicating that anti-CD44 antibody triggers an additional pro- apoptotic signal. Studies have linked apoptosis due to disruption of adhesion with increases in the elevation of cyclin A and activation of cyclin A dependent kinases. Work within our laboratory indicates that ligation of CD44 with antibody is associated with increases in both cyclin A and p21. Preliminary studies indicate that experimental down-regulation of cyclin A and p21 markedly attenuates anti-CD44 antibody induced apoptosis identifying an important functional role for these proteins. In our competing renewal, we plan to examine the molecular basis by which anti-CD44 antibody induces fibroblast apoptosis. Discovery of how ligation of CD44 engages the fibroblast apoptotic pathway may provide insight into the development of therapeutic agents which promote regression of airspace fibrosis in patients failing to recover from ARDS.
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