Fluid homeostasis in the alveolar spaces is maintained by osmotic gradients created by active solute transport via epithelial cells. Abnormalities of solute transport have been implicated in several disease states including respiratory distress syndrome and cystic fibrosis. Transport of sodium through channels located in the apical membranes of alveolar epithelial cells is believed to be the initial and rate limiting step in salt absorption by these tissues. These channels can be found in many vertebrate epithelial tissues ranging from frog skin to mammalian distal nephron. In contrast to a well described role for alveolar type 2 (AT2) cells in lung ion transport, evidence for a definite role for alveolar type 1 (AT1) cells is lacking. The long-term goal of this project is to compare and contrast ion transport by the two epithelial cell types. Preliminary experiments from this laboratory show that AT1 cells express at least three distinct types of cation channels that are capable of transporting sodium. The biophysical characteristics bear some similarities to the channels observed in AT2 cells and other tight epithelia expressing epithelial sodium channel (ENaC). However, there may be important differences in how these channels are regulated in AT1 and AT2 cells, and additional transporters in AT1 cells that are not readily seen in AT2 cells. These findings support a radically different paradigm for salt and water transport in the lung. The primary hypothesis is that AT1 cells make significant contribution to alveolar solute transport via amiloride-sensitive channels, albeit by a different mechanism as compared to AT2 cells. Despite the differences in biophysical characteristics, sodium permeable channels in AT1 cells are assembled from different ENaC subunits and this process is regulated in part by the alveolar environment: It is also hypothesized that significant differences exist in the regulatory mechanisms for solute transport by AT1 and AT2 cells.
The specific aims are: 1) To characterize and contrast the biophysical properties of ion channels in AT1 and AT2 cells at the single channel level, and 2) To examine differences in how these channels are regulated in the two cell types and what impact they have on net salt and water transport in the lung. An understanding of these differences is essential for estimating the overall response of lungs to endogenous and exogenous stimuli that have the potential for altering lung fluid balance, and ultimately, in designing therapeutic strategies to prevent and treat lung edema formation. ? ? ?
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