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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
Pediatrics Subcommittee (CHHD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Irvine
United States
Zip Code
Ganesan, Goutham; Cotter, Joshua A; Reuland, Warren et al. (2015) Effect of blood flow restriction on tissue oxygenation during knee extension. Med Sci Sports Exerc 47:185-93
Ashish, Naveen; Bamman, Marcas M; Cerny, Frank J et al. (2015) The clinical translation gap in child health exercise research: a call for disruptive innovation. Clin Transl Sci 8:67-76
Radom-Aizik, Shlomit; Zaldivar Jr, Frank P; Haddad, Fadia et al. (2014) Impact of brief exercise on circulating monocyte gene and microRNA expression: implications for atherosclerotic vascular disease. Brain Behav Immun 39:121-9
Radom-Aizik, Shlomit; Zaldivar, Frank P; Nance, Dwight M et al. (2013) Growth inhibition and compensation in response to neonatal hypoxia in rats. Pediatr Res 74:111-20
Horvath, Peter; Oliver, Stacy R; Ganesan, Goutham et al. (2013) Fasting glucose level modulates cell surface expression of CD11b and CD66b in granulocytes and monocytes of patients with type 2 diabetes. J Investig Med 61:972-7
Radom-Aizik, Shlomit; Zaldivar, Frank; Haddad, Fadia et al. (2013) Impact of brief exercise on peripheral blood NK cell gene and microRNA expression in young adults. J Appl Physiol (1985) 114:628-36
Radom-Aizik, Shlomit; Zaldivar Jr, Frank; Leu, Szu-Yun et al. (2012) Effects of exercise on microRNA expression in young males peripheral blood mononuclear cells. Clin Transl Sci 5:32-8
Adams, Gregory R; Zaldivar, Frank P; Nance, Dwight M et al. (2011) Exercise and leukocyte interchange among central circulation, lung, spleen, and muscle. Brain Behav Immun 25:658-66
Kodesh, Einat; Zaldivar, Frank; Schwindt, Christina et al. (2011) A rat model of exercise-induced asthma: a nonspecific response to a specific immunogen. Am J Physiol Regul Integr Comp Physiol 300:R917-24
Oliver, Stacy R; Rosa, Jaime S; Minh, Timothy D C et al. (2010) Dose-dependent relationship between severity of pediatric obesity and blunting of the growth hormone response to exercise. J Appl Physiol 108:21-7

Showing the most recent 10 out of 34 publications