Intermedin promotes pulmonary edema resolution by upregulating the Na,K-ATPase

Patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) present with impaired gas exchange due to alveolar flooding caused by disruption of the alveolo-capillary barrier. Clearance of alveolar edema and restoration of alveolo-capillary barrier function are crucial for the survival of patients. Recently, intermedin (IMD) was described to stabilize endothelial permeability and thus we sought to investigate the effect of IMD on alveolar epithelial barrier function.

Isolated, ventilated and perfused mouse lungs were applied to monitor alveolar epithelial barrier function and fluid transport. Initially excess liquid was deposited into the alveolar space by using a microsprayer. To distinguish between active transport of small solutes and passive flux, clearance of 22Na- and 3H-mannitol, epithelial lining fluid volume and wet to dry-weight ratios were analyzed. Administration of IMD into the alveolar space resulted in a rapid and significant increase of 22Na transport resulting in enhanced alveolar edema clearance leaving the epithelial paracellular permeability unimpaired. Subsequent analysis revealed that the specific Na,K-ATPase inhibitor, ouabain, could completely prevent this effect. Experiments in isolated rat alveolar epithelial type II cells and cultured human and rat lung epithelial cells showed increased cell surface abundance of the catalytic α-subunit of the Na,K-ATPase upon IMD treatment. Furthermore, protein kinase A (PKA) was identified as a crucial element of the IMD-induced Na,K-ATPase and alveolar fluid clearance upregulation. PKA is predominantly regulated by the intracellular cAMP-concentration. Surprisingly, the IMD-induced activation of PKA was independent of cAMP but was dependent on nuclear factor kappa-light-chain-enhancer of activated B cells (NF κB) signaling as IMD promoted ubiquitination and subsequent degradation of the NF κB inhibitory protein IκBα.

We conclude that IMD enhances alveolar fluid clearance in intact mouse lungs by promoting exocytosis of the Na,K-ATPase in a PKA-dependent, but cAMP-independent manner. Also considering the previously reported beneficial effects on the endothelial barrier function IMD may have potential in the treatment of ALI/ARDS.