The respiratory distress syndrome (RDS) is a major cause of mortality in premature infants. A surfactant deficiency accompanies RDS, leading to alveolar instability and impaired air-exchange. This is a disease of immaturity, characterized by delayed differentiation of both the type II epithelial cell, the source of pulmonary surfactant, and the type I epithelial cell. Epithelialmesenchymal interactions, mediated through changes in the extracellular matrix (ECM) macromolecules which form the epithelial basal lamina (BL), may be involved in control of the differentiation of both these epithelial cell types. To test this hypothesis, the Specific Aims of this proposal are to determine: (1) compositional changes in the epithelial BL as they relate to the differentiation of the type I and II cells; (2) the cellular origin of BL macromolecules at different stages of development; (3) if direct cell-cell and/or cell-matrix contacts are necessary for BL formation and cytodifferentiation; (4) if particular BL macromolecules have a functional role in epithelial cell differentiation; and, (5) the ability of ECM formed by differentiating cells or particular adult cell types to induce precocious differentiation of type I or type II cells. To address these Specific Aims, culture systems which are structurally simpler than whole lung have been developed which both support de novo epithelial BL formation, as well as mimic in vivo cytodifferentiation. BL changes which may accompany type I or type II cell differentiation will be identified, and a series of epithelial/mesenchymal recombination experiments will then be carried out using hydrated collagen gel culture systems developed for this purpose. Ultrastructural analyses of these developing cultures will elucidate the cellular source of BL macromolecules, and the possible role of the mesenchyme in BL formation. Finally, exposure of undifferentiated epithelia to various matrix preparations will begin to clarify the particular ECM macromolecules critical to the cytodifferentiation process. Such studies will provide the baseline data necessary for future experiments directed toward elucidation of the mechanisms involved in such putative ECM modulation of alveolar epithelial cytodifferentiation.
| Harmon, J T; Jamieson, G A (1988) Platelet activation by thrombin in the absence of the high-affinity thrombin receptor. Biochemistry 27:2151-7 |
