Scientists may have been wrong about what causes asthma

That inflammation was widely attributed to molecules known as "leukotrienes." These chemicals are released by white blood cells when the airways are irritated or exposed to allergens. Because leukotrienes trigger a chain reaction that tightens the airways, drugs were developed to block their effects and ease breathing.

Now, researchers at Case Western Reserve University say those molecules may not be the primary cause after all.

"We've found molecules that are alike in structure but generated through a completely different chemical pathway in the body," said lead researcher Robert Salomon, the Charles Frederic Mabery Professor of Research in Chemistry. "We think the molecules we're calling 'pseudo leukotrienes,' may be the dominant players in the inflammatory cascade that causes disease."

The findings could lead to new approaches for treating asthma and other inflammatory conditions. Researchers say the work may also have implications for neurological diseases such as Parkinson's and Alzheimer's diseases. The study was funded by the U.S. National Institutes of Health and is available online as a pre-proof ahead of publication in the Journal of Allergy and Clinical Immunology.

How Free Radicals Create a Different Kind of Inflammation

Leukotrienes, long thought to be central to inflammatory diseases, are produced through enzyme-driven processes that modify lipids, or fatty molecules. The newly identified pseudo leukotrienes form in a very different way.

Salomon and his team found that pseudo leukotrienes are created when free radicals add oxygen to lipids. Free radicals are highly reactive molecules that can cause damage if they are not controlled.

"The free radical process is almost like an explosion or a fire," said Salomon, who is also professor of ophthalmology in the Case Western Reserve School of Medicine. "It's just like when oxygen reacts with fuel and you get flames. It can easily get out of control."

According to the researchers, people with asthma may have lower levels of enzymes and antioxidant molecules that normally neutralize free radicals before they cause harm.

Why Current Asthma Drugs May Miss the Target

Both leukotrienes and pseudo leukotrienes trigger inflammation by binding to the same receptor, much like a key turning an ignition to start an engine. Once activated, this process leads to airway constriction in people with asthma.

Medications such as Singulair work by blocking that receptor, preventing the key from fitting and stopping the reaction from starting.

"The real importance of this discovery is the possibility of treating these diseases with drugs that prevent the free radical process or moderate it rather than drugs that block the receptor," Salomon said.

This approach could allow treatments to target harmful inflammation more precisely.

When Inflammation Helps and When It Hurts

Inflammation is not always harmful. It plays a vital role in healing by directing white blood cells to injured tissue. It is also involved in memory and normal development.

Some asthma drugs are currently being used off-label to treat neurological diseases. However, blocking leukotrienes may interfere with their beneficial roles in the body.

"If the molecules that are causing the problem are not the leukotrienes but these other molecules," Salomon said, "a better treatment would be to just stop the formation of these other molecules rather than gumming up the ignition."

Testing the Theory in Patients

To investigate their hypothesis, Salomon and his colleagues relied on decades of experience studying lipid oxidation, along with chemical insight, to predict that pseudo leukotrienes existed. They synthesized the molecules in the lab and developed techniques to detect them in biological samples.

The team analyzed urine samples from people with mild or severe asthma and compared them with samples from individuals without the disease.

Pseudo leukotrienes were not only present in asthma patients, but their levels closely matched disease severity. People with asthma, whether mild or severe, had four to five times higher levels than those without asthma. Researchers suggest these molecules could serve as a biomarker to measure disease severity and track how well treatments are working.

What Comes Next

The research team plans to examine whether pseudo leukotrienes also play a role in other respiratory illnesses. These include respiratory syncytial virus (commonly known as RSV), bronchiolitis in babies, and chronic obstructive pulmonary disease.

The study involved collaborators from multiple institutions. At Case Western Reserve University, the team included Mikhail Linetsky, research professor in chemistry, Masaru Miyagi, professor of pharmacology at the School of Medicine, and graduate students. Contributors from the University of Toledo included Sailaja Paruchuri, professor of physiology and pharmacology, and Lakshminarayan Teegala, assistant professor of physiology and pharmacology. At the Cleveland Clinic Children's Hospital, Fariba Rezaee participated as associate professor of pediatrics and staff physician in the Center for Pulmonary Medicine.