CLEVELAND—For decades, scientists have thought they understood the biochemical machinery that causes asthma—inflammation in the lungs that constricts airways and makes it hard to breathe.
Molecules called "leukotrienes"—chemicals that get released from white blood cells when something irritates your airways or you inhale an allergen—were labeled the culprits. Medications have been developed to block the molecular cascade they initiate that leads to difficulty breathing.
But researchers from Case Western Reserve University think these molecules may not be the bad actors 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 research opens new avenues for treating asthma as well as other inflammatory diseases, possibly including neurological diseases like Parkinson's and Alzheimer's diseases. The research, funded by the U.S. National Institutes of Health, is available online as a pre-proof ahead of publication in the Journal of Allergy and Clinical Immunology .
The 'flames' of oxidation
The presumed culprits in inflammatory diseases—the leukotrienes—are formed under the control of enzymes that transform lipids, or fatty molecules. By contrast, the pseudo leukotrienes Salomon and his team discovered, are formed by adding oxygen to lipids by molecules called "free radicals."
"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."
People who suffer from asthma may lack enzymes and antioxidant molecules that normally keep a damper on free radicals by scavenging for and destroying them.
The leukotrienes and their mimics initiate inflammation by fitting into a receptor, like a key in an ignition, starting a molecular cascade that constricts the airways of asthmatics. Effective asthma drugs like Singulair block the ignition so the key won't fit.
"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.
Inflammation: a curse or a benefit?
Not all inflammation is harmful. The body needs inflammation to direct white blood cells to the site of a wound to heal, and it is also involved in memory and development.
Asthma drugs are being repurposed off-label to treat neurological diseases. But these treatments could also block the beneficial effects of the leukotrienes.
"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."
The study
Salomon and his colleagues used their decades of experience studying the oxidation of lipids—and some chemical intuition—to guess that pseudo leukotrienes existed. They made the molecules in the laboratory to develop methods to detect them.
They obtained urine samples from patients designated with mild or severe asthma and compared them to urine from people who don't suffer from the disease.
Not only were pseudo leukotrienes found in the asthma patients' urine, but also the amounts correlated directly to the severity of the disease. Severe asthma sufferers or even those suffering mild asthma had four to five times more than the controls. The researchers suggest this could be a new biomarker to test for the severity of disease and monitor the effectiveness of therapies.
The researchers next plan to investigate whether these pseudo leukotrienes are involved in other respiratory diseases, like respiratory syncytial virus (commonly known as RSV) and bronchiolitis in babies, and chronic obstructive pulmonary disease.
The team
Collaborators included, at Case Western Reserve: Mikhail Linetsky , research professor in chemistry and Masaru Miyagi , professor of pharmacology at the School of Medicine, and graduate students. At the University of Toledo: 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, associate professor of pediatrics and a staff physician in the Center for Pulmonary Medicine.
