ALVEOLAR BASEMENT MEMBRANE/CELL INTERACTIONS IN THE LUNG

I型肺泡细胞，覆盖肺泡表面的90%以上 特别容易受到损伤，例如 空气传播的有毒物质或氧化应激。 更换/更新这些 细胞损伤后需要分裂和分化的第二个 细胞，即II型肺细胞。 这一进程的中断或延迟 导致修复错误和不可逆转的功能受损， 地区 控制这些关键事件的机制尚不清楚， 但初步证据表明， 细胞外基质（基底膜）微区与 与II型细胞相比，I型细胞可以影响已知的 后者对表皮、酸性和碱性成纤维细胞的反应性 生长因子 在这项提议中要检验的假设是， 肺泡基底膜的组成，特别是其 独特的硫酸化特性决定了II型电池的能力， 增殖、分化和调节/修复其环境， 合成细胞外基质分子， 成纤维细胞生长因子和表皮生长因子。 我们建议 表征增殖、分化和调节反应 分离的大鼠II型细胞的酸性和碱性成纤维细胞生长 因子和表皮生长因子，同时保持在培养物上， 不同的基质基质，仅在其硫酸化水平上不同。 硫酸化的水平将具体减少在选定的，纯化的 通过化学沉淀或在生物合成基质中制备的基质制剂 通过干扰基质组分的正常硫酸化， 基质生产细胞 II型细胞增殖反应 不同的基质和硫酸盐组成将通过5-溴- 脱氧尿苷掺入;分化将通过形态学 和组织化学特征;以及它们的调节/修复 环境将通过II型细胞生物合成胞外 基质成分 这些研究将阐明分子，结构， 上皮细胞、结缔组织、 基质和肺泡中的可溶性生长因子。 他们将 为明确细胞外基质的作用机制提供了基础 关键上皮再形成/修复过程的大分子调节 在肺组织损伤和/或疾病后。

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.