Autophagy Is Associated with the Severity of Asthma in an Ovalbumin-Specific Mouse Model of Allergic Asthma

Background: Autophagy has been investigated to be involved in many inflammatory diseases, but its expression and clinical significance in asthma has rarely been studied. The aim of this study was to evaluate the role of autophagy and the therapeutic potentials in an OVA-specific mouse model of severe allergic asthma. Method: BALB/c mice were sensitized by intraperitoneal injection of ovalbumin (OVA) on days 0 and 14, followed by aerosolized primary OVA challenges on day 28 - 30. Two weeks after the primary allergen challenges, mice received a secondary allergen challenges with two different concentrations (1% or 2%) of OVA solution on days 44 - 46. Forty eight hours after the last OVA challenge, mice were assessed for airway responsiveness (AHR) to inhaled methacholine, cell composition and cytokine levels in bronchoalveolar lavage (BAL) fluid. LC3 expression in lung homogenate was measured by Western blot to evaluate the development of autophagy. Finally, 3-methyladenine (3-MA), and Atg5 knockdown were applied to investigate the potential role of autophagy in severe allergic asthma of mice. Results: The AHR, total airway inflammatory cell number and eosinophilia in BAL fluid were significantly higher in 2% OVA challenged mice compared to those of 1% OVA challenged mice (P < 0.01 and P < 0.05, respectively) indicating that 2% OVA challenges could induce a mouse model presenting more severe eosinophilic asthma. The severe allergic asthma mice showed significant higher LC3 expression compared to that of mild asthma mice. Additionally, more prominent autophagosomes were noted in the cytoplasm of eosinophilis. Inhibition of autophagy by 3-MA treatment and Atg5 knockdown could induce significant improvement of AHR, eosinophilia and IL-5 levels in BAL fluid and airway inflammation in histology. Anti-IL-5 antibody treatment significantly reduced eosinophil counts and IL-5 levels in BAL fluid, as well as LC3 expression in the lung tissue homogenate. Conclusions: Our findings suggest that the expression of autophagy is correlated with the severity of asthma through eosinophilic inflammation, and autophagy inhibitions may provide novel therapeutic targets for the treatment of severe allergic asthma.