ABSTRACT
BACKGROUND: Aerobic training (AT) decreases airway inflammation in asthma, but the underlying cellular and molecular mechanisms are not completely understood. Thus, this study evaluated the participation of SOCS-JAK-STAT signaling in the effects of AT on airway inflammation, remodeling and hyperresponsiveness in a model of allergic airway inflammation. METHODS: C57Bl/6 mice were divided into Control (Co), Exercise (Ex), HDM (HDM), and HDM+Exercise (HDM+ Ex). Dermatophagoides pteronyssinus (100ug/mouse) were administered oro-tracheally on days 0, 7, 14, 21, 28, 35, 42 and 49. AT was performed in a treadmill during 4 weeks in moderate intensity, from day 24 until day 52. RESULTS: AT inhibited HDM-induced total cells (p<0.001), eosinophils (p<0.01), neutrophils (p<0.01) and lymphocytes (p<0.01) in BAL, and eosinophils (p<0.01), neutrophils (p<0.01) and lymphocytes (p<0.01) in peribronchial space. AT also reduced BAL levels of IL-4 (p<0.001), IL-5 (p<0.001), IL-13 (p<0.001), CXCL1 (p<0.01), IL-17 (p<0.01), IL-23 (p<0.05), IL-33 (p<0.05), while increased IL- 10 (p<0.05). Airway collagen fibers (p<0.01), elastic fibers p<0.01) and mucin (p<0.01) were also reduced by AT. AT also inhibited HDM-induced airway hyperresponsiveness (AHR) to methacholine 6,25mg/ml (p<0.01), 12,5mg/mL (p<0.01), 25mg/mL (p<0.01) and 50mg/mL (p<0.01). Mechanistically, AT reduced the expression of STAT6 (p<0.05), STAT3 (p<0.001), STAT5 (p<0.01) and JAK2 (p<0.001), similarly by peribronchial leukocytes and by airway epithelial cells. SOCS1 expression (p<0.001) was upregulated in leukocytes and in epithelial cells, SOCS2 (p<0.01) was upregulated in leukocytes and SOCS3 down-regulated in leukocytes (p<0.05) and in epithelial cells (p<0.001). CONCLUSIONS: AT reduces asthma phenotype involving SOCSJAK- STAT signaling.
Subject(s)
Asthma/metabolism , Janus Kinases/metabolism , Physical Conditioning, Animal , STAT Transcription Factors/metabolism , Signal Transduction , Suppressor of Cytokine Signaling Proteins/metabolism , Animals , Disease Models, Animal , Eosinophils/cytology , Interleukins/metabolism , Lymphocytes/cytology , Methacholine Chloride , Mice , Mice, Inbred C57BL , Neutrophils/cytology , Respiratory Hypersensitivity/metabolismABSTRACT
Leukocytes play a central role in asthma physiopathology. Aerobic training (AT) reduces leukocytes recruitment to the airways, but the effects of AT on some aspects of leukocytes activation in asthma are unknown. Therefore, the effects of 4 weeks of AT on airway inflammation, pulmonary and systemic Th2 cytokines levels, leukocytes expression of pro and anti-inflammatory, pro-fibrotic, oxidants and anti-oxidants mediators in an experimental model of asthma was investigated. AT reduced the levels of IL-4, IL-5, IL-13 in bronchoalveolar lavage fluid (BALF) (p<0.001), serum levels of IL-5, while increased BALF and serum levels of IL-10 (p<0.001). In addition, AT reduced leukocytes activation, showed through decreased expression of Th2 cytokines (IL-4, IL-5, IL-13; p<0.001), chemokines (CCL5, CCL10; p<0.001), adhesion molecules (VCAM-1, ICAM-1; p<0.05), reactive oxygen and nitrogen species (GP91phox and 3-nitrotyrosine; p<0.001), inducible nitric oxide synthase (iNOS; p<0.001), nuclear factor kB (NF-kB; p<0.001) while increased the expression of anti-inflammatory cytokine (IL-10; p<0.001). AT also decreased the expression of growth factors (TGF-beta, IGF-1, VEGF and EGFr; p<0.001). We conclude that AT reduces the activation of peribronchial leukocytes in a mouse model of allergic asthma, resulting in decreased airway inflammation and Th2 response.
