Effects of aerobic exercise on molecular aspects of asthma: involvement of SOCS-JAK-STAT.

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.

Exercise deactivates leukocytes in asthma.

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.

In vivo hydroquinone exposure impairs allergic lung inflammation in rats.

Hydroquinone (HQ) is naturally found in the diet, drugs, as an environmental contaminant and endogenously generated after benzene exposure. Considering that HQ alters the immune system and its several source of exposures in the environment, we hypothesized that prolonged exposure of HQ could affect the course of an immune-mediated inflammatory response. For this purpose, male Wistar rats were intraperitoneally exposed to vehicle or HQ once a day, for 22 days with a 2-day interval every 5 days. On day 10 after exposure with vehicle or HQ, animals were ovalbumin (OA)-sensitized and OA-aerosolized challenged on day 23. HQ exposure did not alter the number of circulating leukocytes but impaired allergic inflammation, evidenced by lower number of leukocytes in the bronchoalveolar lavage fluid 24h after OA-challenge. Reduced force contraction of ex vivo tracheal segments upon OA-challenge and impaired mesentery mast cell degranulation after in situ OA-challenge were also detected in tissues from HQ exposed animals. The OA-specificity on the decreased responses was corroborated by normal trachea contraction and mast cell degranulation in response to compound 48/80. In fact, lower levels of circulating OA-anaphylactic antibodies were found in HQ exposed rats, as assessed by passive cutaneous anaphylaxis assay. The reduced level of OA-anaphylactic antibody was not dependent on lower number or proliferation of lymphocytes. Nevertheless, lower expression of the co-stimulatory molecules CD6 and CD45R on OA-activated lymphocytes from HQ exposed rats indicate the interference of HQ exposure with signaling of the humoral response during allergic inflammation. Together, these data indicate specific effects of HQ exposure manifested during an immune host defense.

Effects of amphetamine on immune-mediated lung inflammatory response in rats.

OBJECTIVE: The present study analyzed the effects of acute amphetamine (AMPH) treatment on immune-mediated lung inflammatory response in rats. METHODS: There were four experiments. In the first and second experiments, rats were treated with AMPH (1 mg/kg) or 0.9% NaCl, and locomotor activity (experiment 1) and serum AMPH concentrations (experiment 2) were measured 1 or 12 h after treatment. In the third experiment, rats which were immunized with ovalbumin (OVA) were treated 14 days later with 0.9% NaCl or AMPH (1 mg/kg). Twelve hours after these treatments, all animals were submitted to challenge by 1% OVA inhalation being analyzed afterwards for bronchoalveolar lavage fluid (BAL), peripheral blood and bone marrow cellularity. In the fourth and final experiment, rats were treated and studied as for experiment 3, except that half of the animals within each group were previously treated with metyrapone prior to the OVA challenge. RESULTS: In the non-immunized rats, AMPH treatment induced an increase in locomotor activity synchronized to high serum AMPH concentrations 1 h after, but not 12 h after treatment. In OVA-challenged rats, AMPH treatment decreased the total number of inflammatory cells, recovered in both BAL and peripheral blood and increased the total number of bone marrow cells. These effects, observed 1 day after OVA challenge, were abrogated by previous metyrapone treatment. CONCLUSION: AMPH treatment changed HPA-axis responsiveness to the stress condition imposed by the OVA challenge decreasing lung and blood leukocytes cellularity most probably via corticosterone actions on bone marrow activity.