van der Vliet's Study Finds Potential New Treatment Target for Obesity-Associated Asthma

April 19, 2023 by Jennifer Nachbur

A new study in the American Journal of Physiology-Lung Cellular and Molecular Physiology by Albert van der Vliet, Ph.D., professor of pathology and laboratory medicine, and colleagues is honing in on why people with asthma often have worse symptoms if they are obese.

Albert van der Vliet, Ph.D. (left), and Aida Habibovic in van der Vliet's lab at the University of Vermont's Larner College of Medicine.

A new study by Albert van der Vliet, Ph.D., professor of pathology and laboratory medicine, and a team of University of Vermont (UVM) researchers is honing in on why people with asthma often have worse symptoms if they are obese. The research was published ahead of print in the American Journal of Physiology-Lung Cellular and Molecular Physiology and was highlighted as an APSselect article for March 2023.
According to the U.S. Centers for Disease Control and Prevention, obesity “is associated significantly with the development of asthma, worsening asthma symptoms, and poor asthma control.” Research by the American Lung Association has found that people with a body mass index (BMI) in the obese range do not respond in the same way to asthma medications as people with a lower BMI. Nonetheless, say the authors of this new study, “the mechanisms by which obesity leads to worsened asthma symptoms still remain poorly understood.”
This new research demonstrates that the gene DUOX1 likely contributes to the connection between obesity and asthma.
DUOX1 encodes for Dual oxidase 1, an enzyme that converts oxygen to reactive oxygen species, such as hydrogen peroxide. Reactive oxygen species are thought to be damaging to cells because they can oxidize many important biomolecules. They are also generated intentionally, however, by specific enzymes called NADPH oxidase, which reside in inflammatory cells, due to their ability to help kill pathogenic bacteria. For example, DUOX1 is a specific form of NADPH oxidase, which is primarily present in epithelial cells that line mucosal surfaces, such as in the respiratory tract, and has host defense functions similar to that of other NADPH oxidases in inflammatory cells.
Past research by van der Vliet and others has demonstrated that DUOX1 also plays an important role in maintaining epithelial integrity by mediating innate wound responses to various forms of environmentally induced injury. This is not simply due to cytotoxic effects of reactive oxygen species, but rather by controlled production of hydrogen peroxide, which can then activate redox-based cellular signaling mechanisms that regulate cell migration or production of proinflammatory cytokines or genes involved in wound repair processes.
Van der Vliet, who with former graduate students David Heppner, Ph.D., and Karamatullah Danyal, M.D., Ph.D., was awarded a patent for “Covalent inhibitors of dual oxidase 1 (DUOX 1)” in 2018, has been conducting research in this field for more than two decades. He and his colleagues have previously demonstrated an important role for DUOX1 in maintaining epithelial integrity and in innate allergic responses. In addition, his lab has found that alterations in DUOX1 expression have been associated with such chronic diseases as asthma, COPD, and lung cancer. 
“Our findings may offer further justification of implicating DUOX1 as an appropriate alternative therapeutic target, particularly in cases of obesity-associated asthma in which other treatment strategies have proven ineffective,” the study’s authors say. 
To assess the role of DUOX1 in obesity-related asthma, the research team looked at a combination of human, animal, and in vitro studies, and collected human nasal samples from obese and non-obese participants with allergen-induced asthma before and after exposure to an irritant. In mice, they compared unmodified mice, mice that do not produce DUOX1 at all, and mice in which DUOX1 can be selectively turned off. Mice were fed either a high- or low-fat diet. After 14 weeks of feeding, mice were exposed either to an irritant to induce an allergic response or to a saline control. The research team then analyzed a variety of their tissues. In a separate study, mice were repeatedly exposed to the irritant to induce a model of chronic exposure.  
In humans, statistical analysis “revealed a significant positive association” between body mass index and markers of DUOX1 activity. Multiple markers of DUOX1 activity and of inflammation were higher in the participants with asthma compared to controls and still higher in the participants with both asthma and obesity. The mouse and in vitro studies further verified these findings. Obese mice showed greater DUOX1 activity. When DUOX1 was not present, many of the inflammatory markers seen in asthmatic reactions were either not present or significantly reduced even in obese animals. 
“Increased epithelial expression and activation of DUOX1 represents an important factor in [allergic inflammation in the context of diet-induced obesity],” conclude the authors. In addition to van der Vliet, who is senior author on the paper, coauthors include Aida Habibovic, lab research technician in pathology and laboratory medicine; Milena Hristovatemporary lab research technician in pathology and laboratory medicine; Carolyn Morris, Ph.D., faculty scientist in medicine; Miao-Chong Joy Lin, Ph.D., faculty scientist in medicine; Litiele Cruz, Ph.D., visiting scholar in pathology and laboratory medicine; Jennifer Ather, senior lab research technician in pathology and laboratory medicine; Miklós Geiszt, M.D., Ph.D., Semmelweis University, Hungary; Vikas Anathy, Ph.D., associate professor of pathology and laboratory medicine; University Distinguished Professor of Pathology and Laboratory Medicine Yvonne Janssen-Heininger, Ph.D.; Matthew Poynter, Ph.D., professor of pathology and laboratory medicine; and Anne Dixon, M.A., B.M.B.Ch., professor and interim chair of medicine. 

(This article was adapted with permission from a press release produced by the American Physiological Society.)

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