Hypoxia impairs alveolar reabsorption by decreasing ion transport, whereas b2-adrenergics stimulate. Both effects are caused by modulating expression and activity of transporters. Typically, hypoxia mediated gene expression depends on hypoxia-inducible factors (HIF), whereas b2AR-stimulated gene expression requires CREB. Yet, their role in the expression of ion transporters is unclear. We tested whether effects of hypoxia on alveolar transport are prevented by silencing HIF-a, and whether CREB is involved. Interaction between both transcription factors is likely due to requirement for p300 and CBP of both. Adenoviruses expressing shRNA sequences were generated to decrease the expression of HIF-1a, HIF-2a, and CREB1 in primary rat alveolar epithelial cells. Transfected cells were exposed to normoxia and hypoxia (1.5% O2,) with or without terbutaline for 24h and 48h. mRNA expression was measured by qRT-PCR. Ion transport activity was measured in Ussing chambers. Silencing of HIF-1a and CREB1 decreased the mRNA expression of a, b and g ENaC. HIF-1a and CREB1-silencing decreased total short circuit current (ISCtot) and its amiloride sensitive component (ISCDamil) in normoxia and hypoxia after 24h stimulation with terbutalin. In HIF-2a silenced cells no ion transport activity was detectable when cells were exposed to hypoxia (48h) in absence and presence of terbutaline. HIF-1a and CREB1 are involved in controlling expression and activity of ion transporters in alveolar epithelium. Silencing CREB1 prevented the terbutalin induced stimulation of ion transport activity. Inhibition of transport by hypoxia on ion transport activity can not be prevented by silencing HIF-1a and HIF-2a.