PATHOPHYSIOLOGY OF LPS-CD14 COMPLEXES

细菌内毒素（LPS）被认为是急性肺损伤或ARDS的潜在启动物。本实验室的努力已经确定CD14是哺乳动物系统识别LPS存在并启动宿主防御的主要组成部分。CD134的两个相似但不同的作用已经被确定。sCD14作为一种可溶性血浆糖蛋白与LPS复合物，即LPS-sCD14，是许多LPS应答细胞（如内皮细胞、上皮细胞、平滑肌细胞和肥大细胞）的激动剂。作为髓细胞的膜结合表面糖蛋白，LPS- mcd14复合物也可以启动细胞活化，但在这种情况下，LPS- scd14复合物并不需要另一种血浆LPS结合蛋白（LBP），它可以促进LPS- cd14复合物的形成。该项目旨在进一步了解LPS-sCD14复合物激活内皮细胞和上皮细胞的机制，这些细胞与肺有特殊的相关性。具体目的是为了验证以下假设：(1)EC有两个LPS受体；(2) LPS-SCD14复合物参与肺损伤；(4)缺氧诱导因子（HIF）可能是LPS和细胞因子诱导损伤的细胞内调节因子；(5)肺表面活性剂可能是LPS- sCD14激活EC能力的重要调节剂。

(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.