ALVEOLAR BASEMENT MEMBRANE/CELL INTERACTIONS IN THE LUNG

I型肺泡细胞，占肺泡面积的90%以上 肺表面的，特别容易受伤的，如 由空气传播的毒物或氧化应激引起的。更换/更新 损伤后的这些细胞需要分裂和分化 第二个细胞是肺气细胞。此过程的中断或延迟 结果导致局部上皮增生，不可逆的再狭窄- 肺泡区功能受损。治理机制(S) 这些关键事件尚不清楚。我们已经证明了存在一个 肺泡硫酸盐化成分之间的特殊关系 基底膜和某些生长因子的水平显示 细胞外基质(ECM)底物中硫酸盐的含量直接影响 通过促进(低硫酸盐)或延缓(高硫酸盐)促进II型细胞 硫酸盐对成纤维细胞生长因子(FGFs)的体外反应我们现在 建议碱性成纤维细胞生长因子和转化生长因子-β 硫酸盐ECM以不同方式作用于II型细胞 核扩散改变其当地环境的能力，从而 明确上皮修复和牙槽骨的有效性 稳定状态。这项建议中要检验的具体假设是： 肺泡基底膜中硫酸盐含量低的区域 联合应用转化生长因子-β可促进II型细胞增殖。 相反，高硫酸盐区域与转化生长因子~抑制相一致 增殖，促进基底膜成分的生物合成 碱性成纤维细胞生长因子和硫酸肝素蛋白多糖(HSPG)，并改变 生物合成ECM的硫酸盐化和硫酸盐化碳水化合物结构。 这些过程构成了细胞调节的关键机制 正态和超塑性状态下的数及其函数 肺泡。我们将研究核扩散的调控机制 不同硫酸盐化ECM底物对II型细胞的作用 或缺少FGFs和/或转化生长因子-β人工和生物合成的ECM 天然不经硫酸盐化、硫酸盐处理或化学处理 硫酸盐化/脱硫化作为培养基质及其效果 关于细胞的能力：1)改变其基底膜成分 通过生物合成β-成纤维细胞生长因子和特定的细胞外基质，2)硫酸盐和修饰 相关的ECM，以及3个区域内的局部增殖性事件 在不同的生长因子条件下测量的培养物。这些 研究将阐明分子、结构和功能 上皮细胞、细胞外基质与生长因子的关系及其作用机制 它们调节肺泡的区域环境。他们会 为确定细胞外机制提供必要的数据 基质大分子对关键的上皮更新过程的调控 在正常肺组织中以及在损伤和/或疾病之后。

Type I pneumocytes, which cover over ninety percent of the alveolar surface of the lung, particularly susceptible to injury, such as that induced by air-borne toxicants or oxidant stress. Replacement/ renewal of these cells following injury requires division and differentiation of a second cell, the type pneumocyte. Interruption or delay of this process results in local epithelial hyperplasia, faulty re- an irreversibly- impaired function in the alveolar region. The mechanism(s) which govern these critical events are not clear. We have shown that there is a specific relationship between sulfated components of the alveolar basement membrane and certain growth factors by showing that the level of sulfate in extracellular matrix (ECM) substrata directly influences type II cells by either promoting (low sulfate) or retarding (high sulfate responses to fibroblast growth factors (FGFs) in vitro. We now propose that basic (b)FGF and transforming growth factor beta(TGF-beta) act in different ways with sulfated ECMs to regulate type II cell proliferation an capacity to alter its local environment, thereby defining the effectiveness of epithelial repair and alveolar stabilization. The specific hypothesis to be tested in this proposal is: Regions of low levels of sulfate the alveolar basement membrane in concert with TGF-beta promote proliferation of type II cells. Conversely, regions of higher sulfate in concert with TGF~ repress proliferation, promote biosynthesis of the basement membrane components bFGF and heparin sulfate proteoglycan (HSPG), and modify the level of sulfation and sulfated carbohydrate structure of biosynthesized ECMs. These processes constitute a critical mechanism for regulation of cell numbers and their functions under normal an hyperplastic states in the alveolus. We will examine the regulatory mechanisms of proliferation in type II cells exposed to different sulfated ECM substrata in the presence or absence of FGFs and/or TGF-beta Artificial and biosynthesized ECMs that are naturally not sulfated, sulfated, or chemically sulfated/desulfated will be used as culture substrata, and their effects on the cells' capacity to: 1) alter its basement membrane composition through biosynthesis of beta-FGF and specific ECMs, 2) sulfate and modify relevant ECMs, and 3 regulate local proliferative events within regions of cultures measured under different growth factor conditions. These studies will elucidate molecular, structural, and functional relationships between epithelial cells, ECMs and growth factors and how they regulate the regional environment of the alveolus. They will provide essential data for defining the mechanisms of extracellular matrix macromolecular regulation of critical epithelial renewal processes in normal lung tissue, and following injury and/or disease.