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.
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