This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Surfactant deficiency and injury is an important component in the pathogenesis of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Analysis of bronchoalveolar lavage (BAL) samples from ALI and ARDS patients reveal multiple abnormalities including decreased total surfactant phospholipid with a disproportionately greater decrease in phosphatidylglycerol (PG). As the principal anionic phospholipid in surfactant, PG is critical to maintain optimal surface activity through its interactions with surfactant protein B (SP-B). Secretory phospholipases A2 (sPLA2) are potent mediators of surfactant injury, and are increased in the BAL fluid in ALI/ARDS. In BAL studies with asthmatics, we have demonstrated that sPLA2 activity is increased and that PG depletion correlates with surfactant dysfunction. Our in vitro studies using recombinant sPLA2's have demonstrated that hydrolysis of individual surfactant phospholipids differs between the multiple sPLA2's known to present in the lung and circulating leukocytes. Depletion of PG, not production of lysophospholipids, appears to be the principal mechanism for sPLA2-mediated surfactant dysfunction for sPLA2's that preferentially hydrolyze PG. The large sPLA2 family differs not only by substrate specificity, but also by the cells of origin and the regulation of their secretion and responsiveness to inflammatory cytokines.This proposal will examine the hypothesis that specific secretory phospholipases A2 released during the inflammatory phase of ALI and ARDS hydrolyze pulmonary surfactant phospholipids, decrease phosphatidylglycerol and play a major role in limiting endogenous surfactant function and clinical recovery from acute respiratory failure.
Showing the most recent 10 out of 577 publications
