Inflammation in the lungs triggers silent mutation to cause pulmonary hypertension - News-Medical.net

Inflammation in the lungs triggers silent mutation to cause pulmonary hypertension - News-Medical.net
Comon Lung Infections May Trigger PAH in People with At-risk Mutations, Rat Study Finds - Pulmonary Hypertension News
Planning Happy Moments to Drive Away the PH Storms - Pulmonary Hypertension News

Posted: 29 Aug 2019 11:23 AM PDT

Researchers at the Stanford University School of Medicine have found that inflammation in the lungs of rats, triggered by something as simple as the flu, may wake up a silent genetic defect that causes sudden onset cases of pulmonary hypertension, a deadly form of high blood pressure in the lungs.

It's a kind of one-two punch. Basically, the first hit is the mutation, and the second hit is inflammation in the arteries of the lungs. You can be healthy and carrying this mutation, and all of the sudden you get a bacterial or viral infection, and it leads to this terrible disease. "

Amy Tian, PhD, senior research scientist in pulmonary and critical care

Tian is the lead author of the study, which will be published Aug. 29 in Circulation. Mark Nicolls, MD, professor and chief of pulmonary and critical care medicine, is the senior author of the study.

"This is important research for understanding how 'second hits' can render ordinarily silent genetic mutations deadly," Nicolls said. "It also further advances the scientific understanding of the role of inflammation in pulmonary hypertension."

Currently there is no known cause for pulmonary hypertension, a debilitating disease that causes difficulty breathing, fatigue and chest pain. It can leave patients too weakened to perform simple daily activities, such as climbing a flight of stairs. About 200,000 people a year are hospitalized with the disease in the United States, according to the Pulmonary Hypertension Association of America. The only available cure for severe forms of the disease is lung transplantation, but it has only a 30 percent survival rate.

Weakening the heart

Pulmonary hypertension occurs when the arteries that transport blood from the heart to the lungs mysteriously thicken and become increasingly clogged, thereby weakening the heart, which has to pump extra hard to get blood to flow through the body. After diagnosis, most patients face a prognosis of just a few years of life before they die of heart failure. Some patients are born with the disease, but often it strikes in later life.

Treatment is limited to vasodilators, drugs that cause the smooth muscle cells of the diseased blood vessels in the lungs to relax, permitting more blood to flow through. These drugs help to extend survival and relieve some symptoms, but they are not a cure. Thus, scientists have been searching for other therapies.

Past research has shown that the majority of patients with the inherited form of pulmonary hypertension, which is also the most lethal, carry a mutation in the gene BMPR2. Whether the mutation plays a role in causing the disease has been unclear. Surprisingly, 80 percent of people with the mutation don't get the disease and remain perfectly healthy, Nicolls said.

Based on previous research into inflammation in the lungs, the Stanford researchers hypothesized that an inflammation-producing pathway may provide the second "hit" that triggers the mutation to cause the disease in certain patients. To test the theory, the researchers developed a rat model with a mutation in the BMPR2 gene. They followed the rats for a year, and found that the animals remained healthy. Yet when the rats were injected with a virus carrying the 5LO enzyme that triggered temporary lung inflammation, they developed pulmonary hypertension.

"At first, the rats with this mutation were healthy, running around the cage," Tian said. "Then we squirted the virus into their lungs, which stimulated the production of inflammation in the vessels of the lung, and they got really sick."

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

"Asthma, a bad flu, temporary types of lung injury from bacterial or virus infections -- all can be 5LO-mediated," Tian said. "This type of inflammation normally has a pretty short life span. But in these rats, even after the injected virus died, the damage to the endothelial cells in the lining of the blood vessels continued. The cells become the bad player, and they continued to proliferate the inflammation."

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

Stanford Medicine

Comon Lung Infections May Trigger PAH in People with At-risk Mutations, Rat Study Finds - Pulmonary Hypertension News

Posted: 30 Aug 2019 05:00 AM PDT

Lung inflammation caused by a seemingly treatable and common infection may drive the onset of pulmonary arterial hypertension (PAH) in people who carry genetic risk factors for the disease.

A simple viral infection — such as a bad flu — was able to trigger PAH development in rats with a mutation in the Bmpr2 gene, a known genetic risk factor for PAH, Stanford researchers report.

"It's a kind of one-two punch [mechanism]. Basically, the first hit is the mutation, and the second hit is inflammation in the arteries of the lungs. You can be healthy and carrying this mutation, and all of the sudden you get a bacterial or viral infection, and it leads to this terrible disease," Amy Tian, PhD, senior research scientist in pulmonary and critical care at Stanford University School of Medicine and lead study author, said in a news release written by Tracie White.

This finding was reported in the study, "Phenotypically-Silent Bone Morphogenetic Protein Receptor 2 (Bmpr2) Mutations Predispose Rats to Inflammation-Induced Pulmonary Arterial Hypertension by Enhancing The Risk for Neointimal Transformation," published in the journal Circulation.

PAH, a multifactorial disease, develops for reasons difficult to pinpoint in many people. Still, about 20% of patients have familial PAH, a heritable disease form caused by genetic mutations.

Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, which helps to control the growth and survival of cells forming the small blood vessels of the lungs, are major risk factors for familial PAH.

About 20% of those carrying these mutations are expected to develop PAH at some point in their lives, while the remaining 80% are unlikely to ever show signs of the disease. These estimates support the involvement of other factors, either genetic, environmental or a combination of both, in the onset of PAH.

Based on data from previous studies, Stanford researchers hypothesized that lung inflammation triggered by an infection could be one of the environmental factors promoting its onset in individuals with BMPR2 mutations.

To test this theory, they triggered temporary lung inflammation — mimicking the effects of a severe flu or bacterial infection in people — in rats carrying one mutated copy of Bmpr2 gene (the rat equivalent of the human BMPR2 gene) by forcing the overproduction of an enzyme called 5-lipoxygenase (5-LO).

Once lung infection was induced, the rats quickly developed PAH. But when researchers performed the same procedure in rats without a Bmpr2 mutation, none of the animals did so.

"Asthma, a bad flu, temporary types of lung injury from bacterial or virus infections — all can be 5LO-mediated," Tian said. "This type of inflammation normally has a pretty short life span. But in these rats, even after the injected virus died, the damage to the endothelial cells in the lining of the blood vessels continued. The cells become the bad player, and they continued to proliferate [and sustain] the inflammation."

Animals with mutated Bmpr2 but otherwise left alone — never exposed to any type of lung inflammation — were also monitored for a year; these animals also never developed PAH.

"This study offers one explanation of how an environmental injury unleashes the destructive potential of an otherwise-silent genetic mutation," the researchers concluded, and highlights the importance of minimizing exposure to potential sources of lung inflammation in people genetically predisposed to PAH.

Author Details

Joana is currently completing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. She also holds a BSc in Biology and an MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that make up the lining of blood vessels — found in the umbilical cord of newborns.

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Planning Happy Moments to Drive Away the PH Storms - Pulmonary Hypertension News

Posted: 30 Aug 2019 07:00 AM PDT

Surviving day in and day out with a life-threatening illness like pulmonary hypertension (PH), well, simply sucks. My struggles with numerous symptoms and medication side effects weigh me down and rapidly deplete me.

Uptravi (selexipag) and Revatio (sildenafil) can cause horrific side effects, and these are my two primary PH therapies, along with a bucket full of others. When my body aches and the room spins from lightheadedness, I struggle to stay positive. PH life is not what I would've planned for myself, but it's my life, so I must make the best of it.

Naturally, I crave peace and happiness when in the storms. Certainly, there are days when it's challenging to find the "happy things" to focus on. Those with PH still have a life and we must remember to continue living despite illnesses.

As mentioned in my first column, "I Am Worth the PHight," I deserve to have fun and enjoy life, to embrace my best life possible. You deserve the same!

An article about the psychology of happiness mentions that "happiness is a subjective experience." I'm usually that happy-go-lucky kinda girl who wonders why everyone can't just be happy. However, I must remember that happiness looks different for each of us, and that's OK. As the saying goes, "Different strokes for different folks." We are each rare in our own way; that is what makes us interesting.

I find it crucial that I create and plan things I look forward to. The resulting "happy moments" boost me physically, plus help preserve some of my sanity. I try to plan things that support that philosophy, such as an event, project, or short vacation. I have a trip on my calendar for next month. I am so pumped to have three days away with my awesome husband.

Things that I look forward to can vary from the simplest of activities, such as a Netflix binge, to more adventurous things like an overnight trip.

A few happy activities

Family dinners: Anyone who knows me well understands just how important family dinners are to me. I enjoy cooking, eating (of course), and catching up on what's new since the previous family dinner.
Lunch, coffee, and tea dates: I am a foodie, so I am delighted when visiting unusual coffee and tea shops. I adore hanging out with my daughter, hubby, and friends. Lunch dates are fun, too, because it's still early enough in the day that I am not totally exhausted.
Mani and pedi: I take pleasure in visits to the nail salon every few months. This is a treat that makes me feel like a pampered queen. My hands and feet certainly look and feel loads better afterward.
Drives: I have always been fond of going on random drives. Most often, you'll find me by the lake or the beach. But other days, it's a backroad country drive type of day. Some days, weather permitting, you'll find my sunroof open as I soak up the vitamin D. I crave the beams of sunshine as my skin basks in the sunlight. Sunshine makes me happy and can be beneficial to health. Of course, I use sunscreen.
Overnight trips: For the past few years, I was medically unable to fly. Thankfully, that has improved. My family and I have enjoyed overnight excursions throughout the year. As mentioned above, my husband and I are flying away for three days next month. I'm stoked!
Netflix binges on my couch: PJs, comfy blankets, yummy snacks, and my Boo … Ahh, these are perfect days even when I am not feeling my best. I have enjoyed binging with family and friends as well. Some days lead into nights as we binge on shows. Where PJs are welcomed, my happy place is found.

PH life is unpredictable, but planning things to look forward to can improve my attitude. I crave this positivity and optimism in my crazy PH life. I realize there are risks when planning, but I choose to take those risks in an attempt to maintain some "normalcy" and happiness in my life.

What about you? What happy moments do you look forward to?

***

Note: Pulmonary Hypertension News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website. The opinions expressed in this column are not those of Pulmonary Hypertension News or its parent company, BioNews Services, and are intended to spark discussion about issues pertaining to pulmonary hypertension.

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