Aerobic Exercise Reduces Asthma Phenotype by Modulation of the Leukotriene Pathway.

Ricardo Wesley Alberca-Custódio,Chin Jia Lin,Asghar Abbasi,Manoel Carneiro Oliveira-Junior,Angela Batista Gomes Santos,Milton De Arruda Martins,Flávia Regina Greiffo,Hinnak Northoff,Hugo Caire Castro-Faria-Neto,Ana Paula Ligeiro Oliveira,Nilsa Regina Damaceno-Rodrigues,Breanne Mackenzie,Rodolfo Paula Vieira,Adilson Santos Andrade-Sousa,Gustavo Silveira Graudenz,Marco Idzko,Fernanda Magalhaes Arantes-Costa

doi:10.3389/fimmu.2016.00237

Abstract

Leukotrienes (LTs) play a central role in asthma. Low- to moderate-intensity aerobic exercise (AE) reduces asthmatic inflammation in clinical studies and in experimental models. This study investigated whether AE attenuates LT pathway activation in an ovalbumin (OVA) model of asthma. Sixty-four male, BALB/c mice were distributed into Control, Exercise (Exe), OVA, and OVA + Exe groups. Treadmill training was performed at moderate intensity, 5×/week, 1 h/session for 4 weeks. Quantification of bronchoalveolar lavage (BAL) cellularity, leukocytes, airway remodeling, interleukin (IL)-5, IL-13, cysteinyl leukotriene (CysLT), and leukotriene B4 (LTB4) in BAL was performed. In addition, quantitative analyses on peribronchial leukocytes and airway epithelium for LT pathway agents: 5-lypoxygenase (5-LO), LTA4 hydrolase (LTA4H), CysLT1 receptor, CysLT2 receptor, LTC4 synthase, and LTB4 receptor 2 (BLT2) were performed. Airway hyperresponsiveness (AHR) to methacholine (MCh) was assessed via whole body plethysmography. AE decreased eosinophils (p < 0.001), neutrophils (p > 0.001), lymphocytes (p < 0.001), and macrophages (p < 0.01) in BAL, as well as eosinophils (p < 0.01), lymphocytes (p < 0.001), and macrophages (p > 0.001) in airway walls. Collagen (p < 0.01), elastic fibers (p < 0.01), mucus production (p < 0.01), and smooth muscle thickness (p < 0.01), as well as IL-5 (p < 0.01), IL-13 (p < 0.01), CysLT (p < 0.01), and LTB4 (p < 0.01) in BAL were reduced. 5-LO (p < 0.05), LTA4H (p < 0.05), CysLT1 receptor (p < 0.001), CysLT2 receptor (p < 0.001), LTC4 synthase (p < 0.001), and BLT2 (p < 0.01) expression by peribronchial leukocytes and airway epithelium were reduced. Lastly, AHR to MCh 25 mg/mL (p < 0.05) and 50 mg/mL (p < 0.01) was reduced. Moderate-intensity AE attenuated asthma phenotype and LT production in both pulmonary leukocytes and airway epithelium of OVA-treated mice.

Highlights

Asthma is a chronic airway inflammatory disease affecting more than 300 million people around the world [1]
This study demonstrated for the first time that moderate-intensity aerobic exercise (AE) decreased LT pathway activation in both airway epithelium and in peribronchial leukocytes
While previous animal studies have demonstrated that moderate AE reduces allergic asthma features, such as airway inflammation, exacerbated Th2 immune response, airway remodeling, and AHR, the results of this study suggest for the first time that these outcomes are at least partially linked to the ability of moderate AE to deactivate the LT pathway

Summary

Introduction

Asthma is a chronic airway inflammatory disease affecting more than 300 million people around the world [1]. Clinical manifestations of the disease include wheezing, breathlessness, chest tightness, cough, and variable airflow limitation [1]. These manifestations are attributed to unresolved chronic airway inflammatory processes, leading to airway remodeling and hyperresponsiveness (AHR) [1, 2]. Leukotrienes are centrally involved in exercise-induced bronchoconstriction (EIB) [8, 9]. A growing number of studies performed in animal models of asthma [12,13,14,15,16,17] as well as in the clinic [18,19,20,21] have demonstrated that in contrast to high-intensity aerobic exercise (AE), low- to moderate-intensity AE, significantly reduces flare-ups and leads to increased quality of life

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