PATHOPHYSIOLOGY OF LPS-CD14 COMPLEXES

(改编自申请人的摘要)细菌内毒素(LPS)被认为是急性肺损伤或ARDS的潜在诱因。该实验室的工作已确定CD14是哺乳动物系统的主要组成部分，用于识别内毒素的存在并启动宿主对其的防御。CD134的两个相似但不同的角色已经被确定。作为一种可溶性的血浆糖蛋白，即与内毒素形成的复合体，即内毒素-sCD14，是许多内毒素应答细胞的激动剂，如内皮细胞、上皮细胞、平滑肌细胞和肥大细胞。作为一种膜结合的髓系细胞表面糖蛋白，内毒素-mCD14复合体也可启动细胞活化，但在此背景下不需要内毒素-sCD14复合体，另一种血浆内毒素结合蛋白(LBP)已被发现，它有助于形成内毒素-CD14复合体。这个项目试图更多地了解内毒素-sCD14复合体启动内皮细胞和上皮细胞激活的机制，这些细胞与肺有特殊的相关性。(1)内皮细胞具有两种内毒素受体；(2)内毒素-CD14复合体参与肺损伤；(4)低氧诱导因子(HIF)可能是内毒素和细胞因子诱导的损伤的细胞内调节因子；(5)肺表面活性物质可能是内毒素-CD14‘S激活内皮细胞能力的重要调节剂。

(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.