Researchers find potential new target for acute respiratory distress syndrome

Date: Jan-12-2015 There is a molecular mechanism that tightens the bonds between the cells lining the lung's blood vessels so closely that no

fluid can leak through into the lungs. The researchers who found it believe the mechanism may offer a possible target to treat the

serious condition acute respiratory distress syndrome - a key feature of which is fluid build-up in the lungs.

Acute respiratory distress syndrome is a life-threatening condition where the lungs cannot take enough oxygen into the blood to give to the rest of the body.

Acute respiratory distress syndrome (ARDS) is a life-threatening condition where the lungs cannot take in enough oxygen. It is fatal

in up to half of cases. It usually develops as a complication of another condition - for example an infection such as pneumonia or

following an injury to the lung.

In ARDS, fluid builds up in the air sacs or alveoli, preventing enough oxygen from passing into the bloodstream for the rest of the

body to use.

Currently, the standard treatment for ARDS is supportive care - often in an intensive care unit (ICU). Patients usually have to be

on a ventilator that gives high doses of oxygen and keeps the damaged lungs under pressure.

Therapies include drugs to treat infection and reduce inflammation, and removal of fluid from the lungs. However, few are able to

successfully reverse the fluid leakage.

Small molecule triggered lung blood vessel cell-tightening mechanism in mice

In the Journal of Clinical Investigation, Jalees Rehman, associate professor of medicine and pharmacology in the School of

Medicine at the University of Illinois at Chicago, and colleagues describe how in mice, they successfully triggered the cell-

tightening mechanism that stops fluid leaking into the lungs with the help of a small molecule called Fg4497.

When they exposed mice to an infectious agent that causes fluid to enter the lungs, they found the ones treated with Fg4497 had

higher rates of survival and less fluid build-up than untreated mice.

The immune system becomes a problem in ARDS because in order to fight the infection, the barrier formed by the blood vessels becomes

temporarily porous in order to allow white blood cells to leave the bloodstream and enter the lungs. To do this, the cells of the blood

vessels become looser.

But sometimes, the cells do not resume their former tightness and the barrier continues to be too porous, resulting in the

persistent leakiness seen in many patients with severe pneumonia or bloodstream infections, as Prof. Rehman explains:

"It's a vicious cycle of inflammation and leakiness of the lung blood vessels that is very hard to control. It's as if the lung is

drowning in its body's own fluids. Being able to prevent this by stabilizing and restoring the integrity of the blood vessel barrier

could help save lives."

Cells keep together with the help of what are called "adherens junctions." The team already knew that another molecule called VE-PTP

was important for keeping the junctions stable. When they carried out experiments with cells from human lung blood vessels, they found

low oxygen switched on a gene that increased VE-PTP.

When they bred mice to lack the gene - called HIF2alpha - the team found their blood vessels leaked much more than mice that had the

gene. HIF2alpha (hypoxia-inducible factor alpha) responds to decreases in oxygen.

They also ran tests where they exposed the mice to bloodstream infections and then gave them Fg4497 - a molecule that mimics the

low-oxygen condition that triggers HIF2alpha. They found levels of VE-PTP went up, the mice's blood vessels leaked less, they had less

fluid in their lungs, and more of them survived, compared to mice not given the drug.

The researchers suggest the normal reaction when lungs fill up with fluid and reduce blood oxygen is that blood vessels tighten

their cells' adherens junctions in order to stop the fluid leakage. But this ability - which is triggered by low oxygen - may either be

switched off or too slow in patients with ARDS.

"It seems that the blood vessel cells have their own way of tightening up the barrier when they are in a low oxygen stress

situation," Prof. Rehman notes.

Although the study was done in mice, Prof. Rehman says he and his colleagues hope the findings will lead to drugs that help human

patients with ARDS by switching back on the body's natural response to low blood oxygen.

"These drugs could be given to high-risk patients and hopefully prevent the formation of ARDS by activating the internal protective

barrier tightening mechanism," he adds.

The National Institutes of Health and the American Heart Association helped fund the study.

Medical News Today recently learned about another study led by the University of California San Diego School of Medicine,

which claims fat cells under the skin protect the body against infection. Writing in the journal

Science, the researchers describe how they found adipocytes or fat cells produce antimicrobial peptides that keep pathogens at

bay.

Written by Catharine Paddock PhD

Not to be reproduced without permission.

Follow @twitter

window.twttr = (function (d, s, id) {
var t, js, fjs = d.getElementsByTagName(s)[0];
if (d.getElementById(id)) return;
js = d.createElement(s); js.id = id;
js.src= "https://platform.twitter.com/widgets.js";
fjs.parentNode.insertBefore(js, fjs);
return window.twttr || (t = { _e: [], ready: function (f) { t._e.push(f) }
}(document, "script", "twitter-wjs"));

Courtesy: Medical News Today Note: Any medical information available in this news section is not intended as a substitute for informed medical advice and you should not take any action before consulting with a health care professional.