AEROBIC EXERCISE REDUCES SEVERE ASTHMA PHENOTYPE

Abstract

TOPIC: Allergy and Airway TYPE: Original Investigations PURPOSE: Severe asthma is characterized by higher rates of airway hyperresponsiveness and concomitantly increased eosinophilic and neutrophilic airway and systemic inflammation in which bradykinin plays a central role. Aerobic exercise (AE) is the main component in a pulmonary rehabilitation inhibiting airway inflammation and hyperresponsiveness in mild and moderate asthmatics. In addition, AE in mouse models of allergic asthma is proven to reduce eosinophilic airway inflammation, airway remodeling, and hyperresponsiveness, by controlling exacerbated Th2 immune response. However, whether AE could inhibit a severe asthma phenotype is unknown METHODS: House dust mite (HDM; 200ug/mouse; 3x/week; 6 weeks) Dermatophagoides pteronisynuss was used. Eight C57Bl/6 male mice (Control; n=2x10), (Exercise; n=2x10), (Asthma; n=2x10) and (Asthma+Exercise; n=2x10) were assessed after 6 weeks protocol (2 initial weeks of intra-tracheal HDM without AE) followed by 4 weeks of treadmill AE (1h/session, 5x/week, moderate intensity) + (4 weeks of intra-tracheal HDM) RESULTS: The results showed that AE reduced HDM-increased total leukocytes, eosinophils, neutrophils, lymphocytes, and macrophages (p<0.01) in bronchoalveolar lavage (BAL) and total leukocytes, eosinophils, neutrophils, lymphocytes, and monocytes (p<0.01) in whole blood. The cytokines IL-1beta, IL-4, IL-5, IL-13, IL-17, IL-33, TNF-alpha (p<0.01) were reduced both in BAL and in plasma in HDM+Ex group compared with HDM group, while IL-10 was increased. The density of peribronchial eosinophils, neutrophils, lymphocytes and macrophages (p<0.01) and the percentage of airway collagen fibers, epithelial and smooth muscle thickness (p<0.01) were reduced in HDM+Ex group compared with HDM group. The levels of bradykinin in BAL and in lung homogenate (p<0.01) and the expression at mRNA levels by qRT-PCR of B1 receptor (p<0.001) were reduced in HDM+Ex group compared with HDM group. The lung mechanics revealed that exercise improved airway resistance (RAW; p<0.001), tissue resistance (HTIS; p<0.001), and tissue elastance (GTIS; p<0.001). In addition, once AE-induced IL-10 release, we tested the hypothesis that AE-induced IL-10 could inhibit bradykinin-induced airway epithelial cells (BEAS-2B), lung fibroblast cells (MRC5), and freshly isolated human eosinophils and neutrophils activation, measured by IL-1beta release. The results demonstrated that IL-10 inhibited bradykinin-induced IL-1beta release by BEAS-2B, MRC5, human eosinophils and neutrophils. In addition, IL-10 inhibited bradykinin-induced increased expression of B1 receptor in BEAS-2B, MRC5, human eosinophils, and neutrophils CONCLUSIONS: In conclusion, AE can inhibit severe asthma phenotype in vivo and in vitro, and further clinical trials to confirm these findings in severe asthmatic patients are guaranteed. CLINICAL IMPLICATIONS: The possible involvement of Bradikinin may be one of the keys to understanding the mechanisms of severe asthma and aerobic physical exercise may inhibit the action of the severe asthma phenotype. DISCLOSURES: no disclosure on file for Francine Almeida; No relevant relationships by Nilsa Regina Damaceno-Rodrigues, source=Web Response no disclosure on file for Fernanda Degobbi Tenorio Quirino Santos Lopes; No relevant relationships by RENILSON FERREIRA, source=Web Response No relevant relationships by Sara Hamaguchi, source=Web Response no disclosure on file for João Bosco Pesquero; No relevant relationships by 119 Maysa Alves Rodrigues Rangel, source=Web Response No relevant relationships by Anamei Silva-Reis, source=Web Response no disclosure on file for Rodolfo de Paula Vieira