Alveolar epithelial fluid and electrolyte transport are fundamental for the resorption of edema fluid and restoration of gas exchange after lung injury. The sodium pump (Na,K-ATPase), along with the apical sodium channel, are vital components in electrolyte and therefore fluid transport Na,K-ATPase is abundant on the basolateral surface of type II cells and is responsible for ion transport. Using a hyperoxic model of human acute lung injury, steady state levels of sodium pump mRNA and protein concentrations increased in peripheral lung invivo and in type II cells in vitro. In addition, Na,K-ATPase activity is increased in vivo. Therefore, it appears that an increase in Na,K-ATPase mRNA results in an increase in functional protein and this process is regulated pretranslationally. However, the factors that result in this increase in steady state levels of Na,K-ATPase mRNA are not understood. We hypothesize that hyperoxia regulates the gene expression of the Na,K-ATPase alpha-1 and beta subunits by either increased transcription rates or increased mRNA stability. We will measure Na,K-ATPase stability and transcription rates, comparing normoxic cells to hyperoxic type II cells. We then will seek to identify the regulatory proteins and genomic sequences that are necessary for this regulation. This increase in Na,K-ATPase and sodium transport may serve an homeostatic protective mechanism against alveolar flooding. Therefore, understanding the mechanisms of Na,K-ATPase regulation may permit therapeutic manipulation to speed the recovery of pulmonary edema and possibly improve recovery and provide insight into the mechanisms by which oxygen can regulate gene expression. This project will increase my knowledge of gene regulation and Na,K-ATPase molecular biology in relation to the common clinical problems of lung injury and pulmonary edema. This will equip me with the skills and knowledge to become an independent investigator and advance my career as an academic physician.
| Wendt, C H; Towle, H; Sharma, R et al. (1998) Regulation of Na-K-ATPase gene expression by hyperoxia in MDCK cells. Am J Physiol 274:C356-64 |
| Wendt, C H; Sharma, R; Bair, R et al. (1998) Oxidant effects on epithelial Na,K-ATPase gene expression and promoter function. Environ Health Perspect 106 Suppl 5:1213-7 |
