PATHOPHYSIOLOGY OF LPS-CD14 COMPLEXES

细菌内毒素（LPS）被认为是急性肺损伤或ARDS的潜在引发剂。本实验室的努力已经鉴定出CD 14是哺乳动物系统的主要成分，用于识别LPS的存在并启动宿主对其的防御。CD 134有两个相似但不同的作用。作为与LPS复合的可溶性血浆糖蛋白，即LPS-sCD 14，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。作为骨髓细胞的膜结合表面糖蛋白，LPS-mCD 14复合物也启动细胞活化，但在这种情况下，LPS-sCD 14复合物不是必需的，已经鉴定了另一种血浆LPS结合蛋白（LBP），其促进LPS-CD 14复合物的形成。该项目旨在了解更多关于LPS-sCD 14复合物主动激活内皮细胞和上皮细胞的机制，这些细胞与肺特别相关。具体的目的是为了验证以下假设：（1）EC具有两种LPS受体;（2）LPS-SCD 14复合物有助于肺损伤;（4）缺氧诱导因子HIF）可能是LPS和细胞因子诱导的损伤的细胞内调节剂;以及（5）肺表面活性物质可能是LPS-SCD 14激活EC的能力的有效性的重要调节剂。

(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.