The roles of epigenetics, the lung microbiome, pharmacometabolomics, obesity and airway remodeling in asthma were reviewed May 19 in session D8: “Genes, Bugs and Drugs: Emerging Concepts in Asthma and Pathobiology.”
The Role of Epigenetics in Asthma
The effect epigenetics could have in the control and treatment of asthma was addressed by David A. Schwartz, M.D., M.P.H., who is director of the Jewish Health Center for Genes, Environment and Health in Denver.
“Epigenetics are molecules that allow the control of gene expression at the right time, in the right place and in the right amount for a variety of diseases, including asthma,” Dr. Schwartz said in his presentation, “Epigenetics in Asthma: It’s Role in the Development of Airway Hyper-responsiveness.
Three mechanisms are key in epigenetics: DNA methylation, which silences genes by methylating the cytosine of a CpG motif; noncoding RNAs, which interfere with transcription and post-transcriptional regulation of gene expression; and histone modification, which is the methylation, acetylation or phosphorylation of histone that can regulate transcription of genes.
Dr. Schwartz reviewed the effect of in utero methylation on agouti mice, whose color was controlled by the amount of methyl used in studies even though the mice were genetically identical.
Genes can also be affected by environmental exposures and aging, he said. For example, research has shown that monozygotic twins have almost identical methylation until age 3, but have divergent methyl patterns after age 50.
With this background, researchers have developed a hypothesis that epigenetics can have an influence on asthma because hypermethylation enhances the risk of allergic airway disease, Dr. Schwartz said. In short, controlling the amount of methyl could reverse airway disease.
“We think that this may be helpful in terms of not only thinking about disease pathogenesis and intervention but also thinking about how one would go about preventing this disease and how one would go about intervening in this disease in developed countries as opposed to developing countries,” Dr. Schwartz said.
Respiratory Viruses Linked to Asthma
The role of respiratory virus infections in the development of asthma was discussed by Peter J. Sterk, M.D., Ph.D., of the Department of Respiratory Medicine at the Academic Medical Center of the University of Amsterdam, the Netherlands.
In his presentation, “Role of the Lung Microbiome in the Development of Asthma,” Dr. Sterk reviewed a study showing that wheezing with rhinovirus before age 3 was a predictor of asthma at age 6. Yet another study showed that febrile lower respiratory infection and any wheezy lower respiratory infection are strong predictors of wheezing at age 5.
Several other studies also offer clues about associations between viruses and the onset of asthma, he said, with sputum proving to be the most effective way to collect samples to test for viruses.
Winding his way through several studies that determined the best ways to test for viruses, Dr. Sterk concluded that respiratory virus infections are strongly associated with the development of asthma, that respiratory viruses and bacteria are present in the lower airways in asthma and are associated with a rapid decline in FEV, and that lower airways have a complex microbiome, with much more research needed to define its role in the onset, maintenance and therapeutic responses in asthma.
Obesity and Asthma
Obesity has long been associated with poor asthma control, but recent studies show that weight loss—especially through bariatric surgery—can have a positive effect on improving control of the disease.
Anne Dixon, M.A., B.M., B.Ch., who is an associate professor of medicine at the University of Vermont, discussed the impact of weight on asthma in her presentation “Obesity: Its Contribution To An Asthma Phenotype.” Dr. Dixon reviewed data showing that obese asthmatics have a five-fold rate of hospitalization for asthma versus non-obese asthmatics, and that “significant weight loss” is associated with improved asthma control.
Yet another study showed that obese asthmatics have a decreased response to corticosteroids compared with non-obese asthmatics. An interesting finding in the studies, she said, is that obesity is not associated with increased allergic airway inflammation, and that it may actually dampen allergic airway inflammation.
Pharmacometabolomics and Asthma
The promise of personalized treatments through metabolomics and why asthma is a disease in which metabolomics could be a good treatment option were discussed in “Pharmacometabolomics in Asthma: Impact on Heterogeneity of Treatment Response.”
John Lima, PharmD, who is director of the Center for Pharmacogenomics and Translational Research at Nemours Children’s Clinic, Jacksonville, Florida, defined metabolomics as the study of small molecules present in cells, tissues, organs and biological fluids that compose the metabolome. It measures the downstream products of protein, gene and environmental interactions.
Taking the study a step further, he defined pharmacometabolomics as the prediction of the outcome of a drug or xenobiotic intervention in an individual based on a mathematical model of pre-intervention metabolite signatures. It could be used to increase the knowledge of biochemical pathways, which can lead to identification of new drug targets and drug discovery.
Because asthma is likely to be heterogeneous at the molecular level, asthma metabolomics can serve as biomarkers of molecular asthma phenotypes and predictors of response to asthma drugs, making the disease promising for the application of pharmacometabolomics, Dr. Lima said.
Causes of Asthma Exacerbations
Research into histoblood group antigens and susceptibility to infection was reviewed in “The Role Of Mucin Glycans in Asthma Exacerbations,” by John Vincent Fahy, M.D., who is professor-in-residence at the University of California, San Francisco.
Mucin blood group phenotypes are thought to determine whether a person is a secretor or a non-secretor, Dr. Fahy said. Studies have also shown that asthma patients who are secretors have more frequent exacerbations than non-secretors.
In addition, research continues to study the role of lectins and intelectins, which some viruses use to attach themselves to the cells of the host organism during infection, he said.
Responses to Airway Injury in Asthma
How airways can be damaged and repaired was examined in “Mechanisms of Resolution and Repair Throughout the Airways in Asthma,” by Monica Kraft, M.D., who is a professor of medicine and vice chair of research at Duke University Medical Center.
The anatomy of airways was examined to show how injury could occur because of exposure to allergens, infections or environmental irritants. These insults to the airway epithelium can lead to the production of mediators that can perpetuate inflammation in asthma and lead to permanent structural changes, Dr. Kraft said.
Examples of new entities involved in this process include IL-33 and Il-17. IL-33 is produced by airway epithelial cells in the setting of injury and is thought to lead to enhanced airway responsiveness in both the initiation and perpetuation of inflammation. IL-17 is thought to be an important mediator in the setting of epithelial injury, particularly in severe asthma, because it attracts neutrophils to the area of injury, she said.
The host may have problems responding to these insults because part of the immune system called the innate immune system is responsible for host defense, Examples of dysfunction of the innate immune system in asthma include a deficiency in interferon in asthma, Dr. Kraft said.
Components of the adaptive immune system, which is responsible for T helper 2 inflammation seen in asthma, can also affect airway structure and function. IL-13 can change the phenotype of the airway fibroblast to an invasive phenotype seen in malignancy and increase the accumulation of hyaluronan fragments, which contribute to persistence of inflammation Dr. Kraft said.
The response to airway injury activates several innate pathways and adaptive immune pathways that begin with injury to the airway epithelial cell. Researchers think there may be a defect or overactivity of several immune pathways, leading to persistence of inflammation and airway structural changes, Dr. Kraft said in her conclusion.