Control of activity and expression of ion transporters in rat lung: Role of HIF and CREB in hypoxia and beta-adrenergic stimulation

• Applicant: Professor Dr. Heimo Mairbäurl
• Subject Area: Pneumology, Thoracic Surgery
• Term: from 2011 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 194361017

ARDS, ALI, cardiovascular diseases, and alveolar hypoxia cause pulmonary edema, alveolar hypoxia, and impair protective mechanisms such as alveolar fluid reabsorption by decreasing activity and expression of transporters. It also induces inflammation, which further inhibits reabsorption. Protective mechanisms such as p2 adrenergic (ß2AR) signaling are impaired, which normally stimulates alveolar reabsorption by increasing expression and activity of ion transporters. Hypoxia-effects on gene expression are mediated by hypoxia-inducible factors (HIF), ß2AR-stimulation induces gene expression via CREB. Their role in the expression of ion transporters is unclear. Since both factors interact via co-activator proteins p300 and CBP, it is important to understand the interactions between effects of hypoxia and p2ARstimulation on alveolar reabsorption and expression of ion transporters, which is of great clinical relevance for treating pulmonary edema. In this project we want to test the hypotheses, that prolonged ß2AR stimulation can prevent the hypoxia-induced inhibition of activity and expression of alveolar ion transporters by CREB-dependent or -independent mechanisms. The roles of CREB and HIF and their interaction will be tested, and whether prolonged ß2AR stimulation prevents effects of hypoxia on alveolar transport. Experiments will be performed on primary rat and human alveolar epithelial cells invitro and on rats in-vivo exposed to hypoxia after treating with the ß2AR-agonist terbutaline for prolonged time to specifically evaluate the role of gene expression. The roles of HIF and CREB will be studied by gene silencing. Readout parameters are expression and activity of ion transporters and ß2AR-signaling.

• DFG Programme: Research Grants