The goal of this research is to determine whether 10 weeks of exercise training can benefit asthmatic children with a history of exercise-induced bronchoconstriction (EIB). We will, for the first time, test hypotheses focused on mechanisms of asthma and EIB that involve genomic (including epigenetic) regulation of circulating neutrophils and monocytes. Physical activity is a double-edged sword for the child with asthma. On the one hand, exercise is a common trigger of wheezing, occurring in as many as 80% of affected children. On the other hand, exercise and fitness training seem to benefit asthma control in many children. The underlying mechanisms responsible for EIB remain unknown. In addition, critical exercise-asthma treatment issues are enigmatic and poorly studied in children and adolescents, including rare but tragic instances of ElB-associated death, reduced fitness and levels of physical activity, and the lack of validated paradigms of return-to-play following an exercise-associated asthma attack. The study is based on exciting new data showing that (1) first-responding innate immune cells (such as neutrophils and monocytes) play key roles in bronchoconstriction, (2) gene and cytokine expression in circulating neutrophils is abnormal in asthma, and (3) brief exercise alters gene and microRNA expression levels and inflammatory-functional profiles of these cells. In healthy individuals, pro-inflammatory genes and gene pathways are upregulated by exercise, but balanced by anti-inflammatory genes and, perhaps, by the translational """"""""silencing"""""""" effect of microRNAs. This precise regulation ensures that exercise-associated inflammatory processes gone awry, such as exercise-associated anaphylaxis or EIB, do not occur every time a child engages in vigorous play. Collectively, these new insights lead to the premise that in asthma, neutrophils and monocytes (and perhaps other leukocyte subtypes) respond to exercise with inordinately activated pro-inflammatory pathways. Moreover, exercise training may benefit such children by conditioning inflammatory control mechanisms in neutrophils and monocytes. This down regulation may attenuate subsequent components of the inflammatory cascade that leads to bronchoconstriction and, ultimately, airway remodeling. We will gauge gene and microRNA expression, and functional responses in circulating neutrophils and monocytes, using a brief exercise challenge developed specifically to mimic real-life patterns of physical activity. In addition, we will study the impact of asthma on epigenetic regulation of DNA and chromatin structure in circulating neutrophils and monocytes. Inflammation will be measured in the exhaled breath and circulating leukocytes using novel approaches. The 10-week exercise-training intervention is built on effective social cognitive and self-determination approaches to health behavior change. The intervention utilizes local school and community venues and the expertise of talented PE teachers, thereby enhancing its future applicability. This research will lead to improved clinical uses of exercise as preventive and adjunctive therapy in the current epidemic of childhood asthma.

Public Health Relevance

Despite new therapies available for treating asthma and progress in understanding its causes, the prevalence of childhood asthma, the healthcare use associated with it, and the disruptions it causes to family and community life have not decreased substantially over the past two decades. Exercise is a major trigger of asthma attacks in susceptible children, but the reasons why exercise can cause asthma attacks remain unclear. This research will explore as yet untested biological mechanisms of exercise-induced asthma attacks. In addition, we will try to find practical and effective ways of using exercise-training to benefit the 6.5 million children currently afflicted with asthma in the US.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD048721-08
Application #
8616385
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
Project End
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
8
Fiscal Year
2014
Total Cost
$133,442
Indirect Cost
$24,673
Name
University of California Irvine
Department
Type
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
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