Rats develop tolerance to otherwise lethal hyperoxia (> 95% O2] during pre-exposure to adaptive levels of oxygen (80 - 85% O2). Tolerance to oxidant injury includes the ability to clear alveolar edema and improved survival. Since Na+-K+-ATPase regulates sodium and fluid reabsorption across the alveolar epithelium, we hypothesized that oxygen tolerance might be associated with changes in expression of Na+-K+-ATPase. Adult rats were exposed to 85% O2 for seven days then >95% O2 for 4 days. Animals were killed at various times during adaptive and lethal hyperoxia exposures. Total RNA was prepared from whole lungs and ATII cells. Northern blots of whole lung and ATII cell RNA were probed with the cDNA's for α1 and β1 subunits of Na+-K+-ATPase. The α1 subunit mRNA increased in whole lung 2-fold after the 85% O2 exposure and 5-fold after two additional days in >95% O2 The β, subunit mRNA increased in whole lung 2-fold after the 85% O2 exposure and 3-fold after two additional days in >95% O2 Expression of the α1 subunit mRNA decreased in ATII cell RNA after the 85% O2 exposure and returned to control level after 4 subsequent days in > 95% O2 The increase in α1 and β1 subunit mRNA's is similar to the increase in the epithelial sodium channel subunit mRNA previously reported (PNAS 92: 8418, 1995). We speculate that increased sodium transport from the alveolar space is due in part to upregulation of Na+-K+-ATPase expression and increases resistance to oxidant injury of the lung.