Alveolar liquid clearance is regulated by Na+-uptake through the apically expressed epithelial sodium channel (ENaC) and the basolaterally localized Na+-K+-ATPase in type II alveolar epithelial cells. Dysfunction of these Na+ transporters during pulmonary inflammation and bacterial infection can contribute to formation of life-threatening pulmonary permeability oedema.
Using a combined biochemical, electrophysiological and molecular biological in vitro, and by performing in vivo studies in transgenic mice, Dr. Lucas’ team from the Medical College of Georgia, Georgia Regents University, in collaboration with APEPTICO, scientists from the Department of Pharmacology and Toxicology of the University Vienna and the Emory University, could demonstrate that the TNF-derived “TIP-peptide” directly activates ENaC, but not the Na+-K+-ATPase, upon binding to the carboxy-terminal domain of the α-subunit of the ion channel. Binding of the “TIP-peptide” to ENaC increases open probability and preserves ENaC-α protein expression in the presence of bacterial toxins, by means of blunting the protein kinase C-α pathway. Transgenic mice lacking this TNF-derived domain develop significantly more oedema in the presence of bacterial toxins than wild type animals. All data have been published in the “in press” section of the American Journal of Respiratory and Critical Care Medicine on July 16th 2014 (http://www.atsjournals.org/doi/abs/10.1164/rccm.201405-0833OC#.U8vlPrH7qSo).
Professor Lucas commented: “These results demonstrate a novel TNF-mediated mechanism of direct ENaC activation and indicate a physiological role for the TIP-domain of TNF in the resolution of alveolar oedema during lung inflammation”.
Pulmonary oedema and lung inflammation resulting from pneumonia, aspiration of gastric content, inhalation trauma, near drowning, sepsis, multiple trauma, multiple blood transfusion, burns, acute pancreatitis, drug overdose and other causes, may lead to Acute Respiratory Distress Syndrome (ARDS), a life-threatening condition having a mortality rate of around 35-45% despite modern day care. Currently, there is no effective pharmacotherapy available for treatment of pulmonary oedema and patients having ARDS.
Dr. Bernhard Fischer, CEO of APEPTICO added: ”We are very proud of Dr. Lucas’ scientific achievements. His new discovery comes only a few weeks after the same scientific consortium demonstrated that “TIP-peptide” binding to ENaC increases the open probability of this ion channel”. “APEPTICO develops the “AP301-peptide”, a synthetic version of the lectin-like domain of TNF, as a new life-saving medicine. Most recently we could demonstrate in a clinical phase II proof-of-concept study (ClinicalTrials.gov ID NCT01627613) that orally inhaled “AP301-peptide” (synonym “TIP-peptide”) activates alveolar liquid clearance in mechanically ventilated patients having lung oedema and ARDS,” he added.
APEPTICO announces break-through results in scientific understanding of alveolar liquid clearance regulation by the pulmonary epithelial sodium channel (ENaC)
The sender takes full responsibility for the content of this news item. Content may include forward-looking statements which, at the time they were made, were based on expectations of future events. Readers are cautioned not to rely on these forward-looking statements.
As a life sciences organization based in Vienna, would you like us to promote your news and events? If so, please send your contributions to news(at)lisavienna.at.