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NIH-Funded Study Seeks to Develop Therapeutic to Mitigate Asthma Symptoms for People With Obesity

Fernando Holguin, MD, is leading research to study the effect of naturally occurring compounds on asthma symptoms.

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Written by Rachel Sauer on February 8, 2022

Asthma is a chronic condition that can cause airways in the lungs to become inflamed and narrowed. A common perception of obesity is that it involves low-grade systemic inflammation.

Together, the common thinking goes, asthma and obesity might indicate increased inflammation in the lungs.

However, “the reality is nothing’s as simple as we think,” explains Fernando Holguin, MD, a professor of pulmonary sciences and critical care at the University of Colorado School of Medicine. “Research has found that contrary to popular thought, people with obesity tend to have fewer markers of allergic inflammation, fewer of the things we normally think about allergic asthma.”

This is one of the data-supported findings that has inspired Holguin’s research of more than 15 years, studying how and why obesity can make asthma symptoms worse, and what treatments or therapeutics may mediate these effects. He is principal investigator on a five-year, single-site phase II clinical trial that recently received funding from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI). The study, called “LIMA: Lipid Inflammatory Mediators in Asthma,” is studying a new therapeutic intervention for people with asthma and obesity.

In the study, participants take an oral nitro fatty acid that has been shown to have powerful anti-inflammatory effects, Holguin says. “When you take it orally, it has to potential to make many of your inflammatory genes quiet down. We’re looking to see if they have a mitigating effect on asthma symptoms for people with obesity.”

Holguin also is co-leading a NIH-funded study in partnership with Duke University looking at the effects of L-citrulline, an amino acid available over the counter, on asthma symptoms in people with obesity. The study is named Sandia, the Spanish word for watermelon, because L-citrulline is abundant in the fruit.

Studying nitric oxide levels

The genesis for Holguin’s ongoing research traces back to when he and other researchers were studying nitric oxide, a gas that all humans exhale, and why its levels increase in people having an asthma flare-up.

“We were using nitric oxide as a tracer for disease control and severity, and we found that a higher body mass index was associated with a decrease in the amount of nitric oxide exhaled,” Holguin explains. “We need a certain level of nitric oxide to maintain lung function, maintain blood vessel function, but it can be harmful if levels are too high.”

He and the research team found that in people with asthma and obesity, the metabolic function that generates nitric oxide may not function adequately and instead may generate reactive oxidative species that can stress the lungs.

Based on these findings, he and other researchers began studying safer ways to replenish nitric oxide in the lungs and whether that would have a mitigating effect on asthma symptoms in the lungs.

Using L-citrulline, an amino acid that research has shown generates nitric oxide, Holguin led a proof-of-concept pilot study with 40 participants that demonstrated L-citrulline increases nitric oxide levels, improved lung function and decreased asthma symptoms. The ongoing Sandia study is an expansion of the pilot study.

Working to provide tangible benefit

For their current research studying nitro fatty acids, in partnership with the University of Pittsburgh, Holguin and his co-researchers are studying whether these compounds down-regulate inflammation responses in people with asthma and obesity.

Holguin also is partnering in research to understand the biologic mechanisms and gene expression of asthma in people who have obesity, as well as research studying metabolic syndrome.

The goal for the research involving L-citrulline and nitro fatty acids is not to replace existing asthma therapies, but to supplement them and improve quality of life for people who have asthma and obesity.

“My dream as an investigator is to say our research provided some tangible benefit to people,” Holguin says. “So much of what we do just gets published and it’s nice, but to be able to say this actually made a difference is the goal we’re working toward.”

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Fernando Holguin, MD