Inflammation triggers a silent mutation to cause deadly lung disease, study shows



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lung

Pulmonary tissue. Credit: Rutgers University

Researchers at the Stanford University School of Medicine discovered that an inflammation as simple as the flu caused by a simple flu could trigger a silent genetic abnormality causing the sudden onset of inflammation. Pulmonary hypertension, a deadly form of hypertension. in the lungs.

"It's kind of doubled," said Amy Tian, ​​Ph.D., senior researcher in pulmonary and critical care. "Basically, the first shot is the mutation, and the second shot is inflammation of the arteries of the lungs.You can be healthy and carry this mutation, and suddenly you get a bacterial or viral infection, and that leads to this terrible disease. "

Tian is the lead author of the study, which will be published on August 29 in circulation. Mark Nicolls, MD, Professor and Head of Pulmonary Medicine and Critical Care, is the lead author of the study.

"This is an important research to understand how" second shots "can kill normally silent genetic mutations," said Nicolls. "It also advances in the scientific understanding of the role of inflammation in pulmonary arterial hypertension."

At present, there is no known cause for pulmonary hypertension, a debilitating condition that causes breathing difficulties, fatigue and chest pain. This can leave patients too weakened to perform simple daily activities, such as climbing stairs. According to the Pulmonary Hypertension Association of America, about 200,000 people a year are hospitalized for the disease in the United States. Pulmonary transplantation is the only cure for severe forms of the disease, but the survival rate is only 30%.

To weaken the heart

Pulmonary arterial hypertension occurs when the arteries that carry blood from the heart to the lungs mysteriously thicken and become more and more clogged, thus weakening the heart, which has to pump very hard for the blood to circulate in the body. After diagnosis, most patients have to wait a few years before dying from heart failure. Some patients are born with the disease, but it often strikes later.

Treatment is limited to vasodilators, drugs that relax the smooth muscle cells of diseased blood vessels in the lungs, allowing more blood to circulate. These medications help prolong survival and relieve some symptoms, but they do not heal. So scientists have been looking for other treatments.

Previous research has shown that the majority of patients with the hereditary form of pulmonary arterial hypertension, which is also the most lethal, carry a BMPR2 gene mutation. It is not known if the mutation played a role in the cause of the disease. Surprisingly, 80% of people with the mutation do not contract the disease and stay perfectly healthy, Nicolls said.

Based on previous research on inflammation in the lungs, Stanford researchers have hypothesized that a pathway producing inflammation could provide the second "shot" that triggers the mutation causing the disease. in some patients. To test the theory, the researchers developed a rat model with a mutation of the BMPR2 gene. They followed the rats for a year and found that the animals remained healthy. However, when the rats received an injection of virus carrying the 5LO enzyme that triggered temporary pulmonary inflammation, they developed pulmonary hypertension.

"At first, the rats carrying this mutation were healthy and ran around the cage," Tian said. "Then we injected the virus into their lungs, which stimulated the production of inflammation in the pulmonary vessels, and they became really sick."

The lung inflammation caused by the virus usually lasts only a few weeks and, in humans, it can also be caused by environmental triggers, such as a severe flu or bacterial infection or even a hiking in high altitude. However, in genetically predisposed rats, the virus caused permanent inflammation, damaging the pulmonary vessels and causing a deadly form of pulmonary hypertension.

"Asthma, severe flu, temporary lung injury due to bacterial or viral infections, can be subject to 5LO mediation," Tian said. "This type of inflammation normally has a relatively short life span, but in these rats, even after the death of the injected virus, damage to endothelial cells in the lining of the blood vessels continued. Inflammation.

These results indicate that limiting potential environmental causes of pulmonary inflammation in patients with genetic risk of pulmonary arterial hypertension could help prevent the development of the disease, the study said.


The blocking molecular pathway reverses pulmonary hypertension in rats


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Stanford University Medical Center

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Study shows inflammation causes silent mutation causing fatal lung disease (August 29, 2019)
recovered on August 29, 2019
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