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Treating ARDS & Ebola By Tackling Blood Vessel Leakiness With Drugs

ARDS and Ebola are diseases characterised by fluid leakage through blood vessels during the inflammation process triggered by the immune system to get rid of the pathogens. The leakage plays a critical role in worsening the state of the patients. Researchers have therefore attempted to tackle the leakage as a possible way to relieving the infected people.

Humans have inbuilt mechanisms that assist them in dealing with their outside world. However, these do not always work for the best; glitches in the system might appear, or, invading harmful elements might escape the corrective mechanisms. The same goes for the immune system: some viruses and bacteria might get the better of it.

The human body is designed to combat against harmful invaders like disease-causing viruses and bacteria collectively known as pathogens. A whole system – the immune system – coordinates various activities occurring at the microscopic level to get rid of them. The immune system triggers a number of reactions that bring about the process of inflammation whereby the required cells and chemicals are brought to the site of infection to get rid of the pathogens. For this to occur, blood vessels are made to dilate allowing for an efficient migration of the immune system cells from the blood to the infected tissues. The blood vessels become ‘leaky’ as a consequence of increased permeability for the cells and other substances to move to the sites of infection. After the pathogens are killed, the body returns to its normal state, and the blood vessel barrier is restored to its former position.

However, we do not always have happy endings. Some infections might be so severe that the immune system is not given time to breathe and is ultimately overwhelmed. In such cases, the vasodilation might possibly not stop. If this happens, fluid leaks out further from the blood vessels and fills the tissue area. The fluid leaking is characteristic of diseases like acute respiratory distress syndrome (ARDS) that starts as pneumonia but later worsens in a more severe form as the leaking occurs. Another disease relating to this leaking is Ebola.

Thousands of individual all across the globe suffer from ARDS, and the mortality rate in the US is at 40 %. Ebola is much worse: the leakiness is more often than not fatal to the infected patients, as the patients undergo drastic blood pressure drops.

Fortunately, new therapies have been developed to prevent the leaking from leading to deadly consequences, with the potential of saving many lives.

ARDS results from the massive leakage of blood vessels found in the lungs. This accumulates leading to fluid build-up in the breathing organs, such that the cells involved in gaseous exchange are obstructed from executing their tasks. Modern medicine has brought a solution to this predicament: forcing oxygen into the patients’ lungs through mechanical ventilators. Other than that, we do not have efficient methods to counter the lack of oxygen.

A new study might bring the answer to an easier way out: focusing on the source of the disease, the leaking blood vessels.

The researchers attempted to manipulate the processes that cause leakage to occur.

For a blood vessel to ‘leak’, junctions between endothelial cells lining them must break. This happens when the cells in question are inflamed. For the junctions to stay into place, two proteins are needed: the VE-cadherin and the VE-PTP; the former plays a major role in forming the junctions, and the latter keeps the first protein at the cell surface so it can form the junctions. During inflammation, the junctions break down, causing leakage. Another group of chemicals involved here are the Hypoxia Inducible Factors (HIFs) that are needed in stressful conditions of low oxygen; the pathway involving the HIFs is activated during the leakage process with the proteins. In lung blood vessel cells, a particular type of HIFs, the HIF2α, provide the protection required for the cells making up the blood vessels feeding the breathing organs. When this pathway with the HIFs are activated, the concentration of proteins needed to support the junctions is increased. However, patients with ARDS have a delayed activation of this pathway. Therefore, the researchers attempted to activate the factor before the excessive leakage occurs and before oxygen levels decrease as a consequence.

A drug was used to activate the HIFα under normal oxygen levels in mice and this ‘tricked’ the cells into executing their protective mechanism (which would otherwise have been promoted in conditions where oxygen gas is low in concentration), thereby tightening the blood vessel barrier.

Those mice having had their HIF2α activated with drugs had higher survival rates when they were exposed to the bacteria causing ARDS.

The scientists are positive that this can be reproduced in humans. But, the safety issues still have to be dealt with.

Similar attempts have been done by other researchers for Ebola patients. The fluid leakage was prevented using drugs. However, the results are not definite as yet, but this implies that using drugs to treat leakiness of blood vessels for Ebola patients might be an option.


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