Hypoxia impairs alveolar reabsorption by decreasing expression and activity of ion transporters. Inhibition is blunted by b2-adrenergic stimulation. Hypoxia mediated gene expression depends on hypoxia-inducible factors (HIF), whereas b2AR-stimulated gene expression requires CREB. Both factors interact via common co-activators.Their role in controlling expression of ion transporters is unclear.

We tested the possible involvement of HIF in hypoxia induced impairment of alveolar barrier function and ion transport as well as its role in b2AR stimulation by silencing HIF-1a and HIF-2a in primary alveolar epithelial cells. Specific shRNAs were applied by adenoviral infection, and silenced cells were exposed to hypoxia (1.5%) and terbutaline.

Hypoxia decreased mRNA expression of Na-K/ATPase, which was partially prevented by silencing HIF-1a and HIF-2a. In control cells terbutaline increased Na/K-ATPase mRNA in normoxia and hypoxia. Silencing prevented this upregulation in hypoxic cells. Hypoxia-induced decrease in transepithelial resistance was augmented by HIF-silencing. The barrier was totally disrupted when silenced cells were also treated with terbutaline. Hypoxia-increased LDH release was more pronounced in HIF-silenced cells, and was augmented by terbutaline. HIF-1a but not HIF-2a silencing decreased the mRNA expression of BNIP3.

It can be speculated that in hypoxic alveolar epithelium HIF-1a and HIF-2a are required to prevent loss of barrier function and Na/K-ATPase mediated reabsorption. Thus, absence of HIF seems to cause cell damage. Damage is even aggravated when HIF-deficient cells are stimulated with b2-adrenergics which stimulate ion transport, and increase ATP demand and mitochondrial activity at low PO₂.

(Supported by DFG (Ma 1503/28-1) to HM)