ALVEOLAR BASEMENT MEMBRANE/CELL INTERACTIONS IN THE LUNG

肺的肺泡区域的上皮细胞易受 损伤，如由空气中的毒物或氧化应激引起的损伤。 损伤后这些细胞替换的中断导致 修复错误和不可逆转的肺泡功能受损。 已知肺泡基底膜的硫酸化成分 通过促进（低硫酸盐）直接影响上皮，或 延缓（高硫酸盐）对成纤维细胞生长因子（FGF）的反应。 因此，硫酸化分子可以调节细胞的有序序列。 损伤后的事件，包括生长因子结合，信号传导， 转导事件，基因表达，磺基转移酶的表达， 最后，细胞群重新稳定， 生物合成ABM组分。 在此背景下，当前 建议将测试假设，高硫酸盐含量的 细胞外基质抑制FGF-1的特异性相互作用， FGF-2与其受体和蛋白磷酸化事件有关 早期信号传导，导致特定基因 肝素结合生长因子及其受体的表达， 相关的细胞外基质分子。 这些过程构成了 调节细胞数量的关键机制及其在 肺泡中的正常和疾病状态。 分离的原代培养物 大鼠II型细胞将维持在特定的人工基质上 在存在和不存在以下物质的情况下具有确定的硫酸化水平： FGF-1或FGF-2。 控制关键细胞反应的机制 通过探测生长因子， 受体结合相互作用，导致DNA 转录和磺基转移酶的表达，简而言之， 刺激后的长期培养，以及氧气后的全肺培养- 诱发的损害。 这些研究的结果将有助于确定 细胞外基质大分子调控细胞外基质的机制 正常肺组织和损伤后的上皮更新过程 或者疾病

The epithelium of the alveolar region of the lung is susceptible to injury, such as that induced by airborne toxicants or oxidative stress. Interruption of the replacement of these cells following injury results in faulty repair and irreversibly impaired function of the alveolus. Sulfated components of the alveolar basement membrane are known to directly influence the epithelium by promoting (low sulfate) or retarding (high sulfate) responses to fibroblast growth factors (FGFs). Accordingly, sulfated molecules may modulate the orderly sequence of events following injury which include growth factor binding, signal transductive events, gene expression, expression of sulfotransferases, and conclude with restabilization of cell populations and normal biosynthesis if ABM components. Against this background, the current proposal will test the hypothesis that high sulfate content of extracellular matrices repress both specific interaction of FGF-1 and FGF-2 with their receptors and protein phosphorylation events related to early signal transduction, concluding in reduction in specific gene expression of heparin-binding growth factors, their receptors, and related extracellular matrix molecules. These processes constitute a critical mechanism of regulating cell numbers and their functions under normal and disease states in the alveolus. Primary cultures of isolated rat type II cells will be maintained on specific artificial substrata possessing defined levels of sulfation in the presence and absence of FGF-1 or FGF-2. The mechanism that control critical cell responses to specifically varied conditions will be studied by probing growth factor receptor binding interactions, transductive events that lead to DNA transcription, and sulfotransferase expression in these cells in short term culture following stimulation, and in whole lungs following oxygen- induced damage. Results of these studies will help define the mechanisms of extracellular matrix macromolecular regulation of critical epithelial renewal processes in normal lung tissue and following injury or disease.