ALVEOLAR BASEMENT MEMBRANE/CELL INTERACTIONS IN THE LUNG

I型肺泡细胞，覆盖超过90%的肺泡表面 特别容易受到损伤，例如 由空气传播的毒物或氧化应激造成。更换/更新这些设备 损伤后的细胞需要第二次分裂和分化 细胞，II型肺泡细胞。此过程的中断或延迟 导致肺泡修复错误和不可逆转的功能受损 区域。治理这些重大事件的机制(S)尚不清楚， 但初步证据表明，在构成上的差异 与细胞外基质(基底膜)相关的微域 I型细胞与II型细胞相比可以影响已知的 后者对表皮、酸性和碱性成纤维细胞的反应性 增长因素。 在这个提议中要检验的假设是，特定的分子 肺泡基底膜的组成，特别是其 独特的硫酸盐化特性决定了II型细胞的能力 通过以下方式实现其环境的增殖、差异化和调整/修复 酸性和碱性条件下细胞外基质分子的合成 成纤维细胞生长因子和表皮生长因子。我们建议 描述增殖、分化和调节反应的特征 分离的大鼠II型细胞对酸性和碱性成纤维细胞生长的影响 因子和表皮生长因子，在培养过程中保持在 不同的基质底物，只在它们的硫酸盐化水平上有所不同。 硫酸盐化水平将在精选、提纯 通过化学脱硫或在生物合成的基质中制备基质 通过干扰产生的基质成分的正常硫酸盐化 底物产生细胞。II型细胞增殖反应 不同的基质和硫酸盐组成将用5-溴-2-甲基-2-甲基-4-甲基-5-溴-2-甲氧基苯酚测定。 脱氧尿嘧啶核苷掺入；分化将通过形态来确定 和组织化学特征；以及它们的调节/修复 环境将通过第二类细胞胞外生物合成来衡量 矩阵组件。这些研究将阐明分子、结构和 上皮细胞、结缔组织之间的功能关系 基质，以及肺泡中的可溶性生长因子。他们会 为明确细胞外基质的作用机制奠定了基础 关键的再上皮化/修复过程的大分子调控 在损伤和/或疾病后的肺组织中。

Type I pneumocytes, which cover over ninety percent of the alveolar surface of the lung, are 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 II pneumocyte. Interruption or delay of this process results in faulty repair and irreversibly-impaired function in the alveolar region. The mechanism(s) which govern these critical events are not clear, but preliminary evidence suggests that differences in the composition of the extracellular matrix (basement membrane) microdomains associated with the type I cell compared to the type II cell may influence the known responsiveness of the latter to epidermal, and acidic and basic fibroblast growth factors. The hypothesis to be tested in this proposal is that the specific molecular composition of the alveolar basement membrane and, in particular, its unique sulfated characteristics determines the type II cell's capacity to proliferate, differentiate, and regulate/repair its environment by synthesizing extracellular matrix molecules in response to acidic and basic fibroblast growth factors, and epidermal growth factor. We propose to characterize the proliferative, differentiative, and regulative responses of isolated rat type II cells to acidic and basic fibroblast growth factors, and epidermal growth factor, while maintained in culture on different matrix substrata that vary only in their levels of sulfation. The level of sulfation will be specifically reduced in selected, purified matrix preparations by chemical desulfation, or in biosynthesized substrata by interfering with the normal sulfation of matrix components produced by substrata producer cells. Type II cell proliferative responses to different matrix and sulfate compositions will be measured by 5-bromo- deoxyuridine incorporation; differentiation will be defined by morphologic and histochemical characteristics; and regulation/repair of their environment will be measured by type II cell biosynthesis of extracellular matrix components. These studies will elucidate molecular, structural, and functional relationships between epithelial cells, connective tissue matrices, and soluble growth factors in the pulmonary alveolus. They will provide a foundation for defining the mechanisms of extracellular matrix macromolecular regulation of critical re-epithelialization/repair processes in lung tissue following injury and/or disease.