Severe pneumonia causes a buildup of fluid in the lungs that makes the basics of breathing and getting oxygen out to the body difficult to impossible. Scientists are exploring a new target for treating both barrier leakiness and fluid buildup that, in lab animals and early human trials, seems to restore tight barriers and fluid clearance so we can breathe.
Fluid follows sodium and the investigators are targeting ENaC-alpha, a subunit of natural channels that mediate sodium uptake and play a role in fluid movement, says Dr. Rudolf Lucas.
Researchers propose ENaC-alpha also has a role as a signaling molecule that tightens barrier function in the air sacs and tiny capillaries of our lungs when pneumonia-causing bacteria make both leaky. They have a synthetic version of the tip of a molecule known to target cancer that appears to directly activate ENaC-alpha, and help clear our lungs.
"It closes the barriers in the capillary lining, it improves sodium channel function and liquid clearance in the lung sacs, and we also found it reduces inflammation," Lucas says of activation of ENaC-alpha with their synthetic TIP peptide. Limited clinical experience with the peptide indicates that the sicker the patient, the better it works. Laboratory studies indicate that when they delete ENaC-alpha from cells, the peptide doesn't work, Lucas says.
ENaC, or epithelial sodium channel
ENaC, or epithelial sodium channel, normally helps remove excess fluid from our 300 million air sacs, a demand that increases with pneumonia. The scientists have evidence that ENaC-alpha is a component of both highly selected cation channel, or HSC, and non-selective cation channel, or NSC, which both have a role in sodium uptake and fluid elimination.
They've shown ENaC-alpha is active in the single cell layer, or endothelium, that lines tiny blood vessels in the lungs and helps keep contents inside, in addition to the epithelium, a membrane-like lining inside the lungs' air sacs that aids gas exchange and also works as a natural barrier to keep excess fluid out.
In their new studies, they are looking at what happens when they activate just NSC or HSC as well as both channels, which is what the TIP peptide does. They are also looking at what happens to sodium uptake capacity in the epithelial cells of air sacs when they genetically deplete or overexpress ENaC-alpha.
Then expose the cells to a pneumonia-causing bacterium as well as the toxin the dying bacteria produce. If it continues to work, they want to know if they are correct that it works by inhibiting pathways that can alter filamin-A.
"We had to find something that addresses all these points," Lucas says. In both extensive laboratory studies and some early clinical use in other counties, the TIP peptide seems to do just that. "It looks like the peptide just brings the system back to normal functioning level," he says, noting that there could be some natural brake that helps prevent overactivation.
He also notes that ENaC channels actually normally function at a low rate but when they don't function, it's highly lethal. The TIP peptide is attracted to the sugar coating at the mouth of the sodium channel, and works like a doorstop to keep the channels open in animal models.
In pneumonia, the toxin pneumolysin also directly impacts the sodium channels at a time when there is increased fluid volume in the tiny air sacs, Lucas and team reported in last year in Frontiers in Immunology. Their synthetic peptide, TIP, strengthens human endothelial cells exposed to pneumolysin.