PATHOPHYSIOLOGY OF LPS-CD14 COMPLEXES

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(Adapted from the Applicant's Abstract) Bacterial endotoxins (LPS) are recognized as potential initiators of acute lung injury or ARDS. This laboratory's efforts have identified CD14 as a principal component of the mammalian system for recognizing the presence of LPS and initiating host defenses thereto. Two similar but distinct roles for CD134 have been identified. As a soluble plasma glycoprotein sCD14 in complex with LPS, i.e. LPS-sCD14, is an agonist for many LPS responsive cells such as endothelial, epithelial, smooth muscle, and mast cells. As a membrane bound surface glycoprotein of myeloid cells,, LPS-mCD14 complexes also initiate cellular activation, but in this context LPS-sCD14 complexes are not required another plasma LPS binding protein (LBP) has been identified which facilitates the formation of LPS-CD14 complexes. This project seeks to understand more about the mechanism by which LPS-sCD14 complexes initiative activation of endothelial and epithelial cells as cells of particular relevance to the lung. The specific aims are designed to test the hypotheses that: (1) EC have two receptors for LPS; (2) LPS-SCD14 complexes contribute to pulmonary injury; (4) hypoxia inducible factor HIF) could be an intracellular regulator of LPS and cytokine induced injury; and (5) lung surfactant could be an important modulator of the effectiveness of LPS- sCD14's ability to activate EC.