Simvastatin alleviates airway inflammation and remodelling through up-regulation of autophagy in mouse models of asthma

Respirology. 2017 Apr;22(3):533-541. doi: 10.1111/resp.12926. Epub 2016 Oct 26.

Abstract

Background and objective: Statins have been widely used in inflammatory diseases including asthma, because of their anti-inflammatory and immunomodulatory properties. It has been shown that simvastatin induces autophagy and cell death in some circumstances. However, the possible cross-talk between simvastatin and autophagic processes in lung disease is largely unknown. Thus, we investigated the impact of simvastatin on airway inflammation and airway remodelling and the possible relationship of these processes to a simvastatin-induced autophagic pathway in mouse models of asthma.

Methods: Ovalbumin (OVA)-sensitized and challenged mice were treated with simvastatin and sacrificed. The autophagy-related proteins Atg5, LC3B and Beclin1 were quantified, as well as the autophagy flux in bronchial smooth muscle cells (BSMCs). The relationship between airway inflammation and the autophagic process was investigated.

Results: We show that simvastatin treatment mediates activation of autophagy in BSMCs, which is correlated with airway inflammation and airway remodelling in mouse models of asthma. Simvastatin increases autophagy-related protein Atg5, LC3B and Beclin1 expression and autophagosome formation in lung tissue. Simvastatin-induced autophagy is associated with increased interferon-gamma (IFN-γ) and decreased IL-4, IL-5 and IL-13 cytokines production in BSMCs, as well as reversed extracellular matrix (ECM) deposition. In contrast, autophagy inhibitor 3-methyladenine (3-MA) eliminates the therapeutic effect of simvastatin.

Conclusion: These findings demonstrate that simvastatin inhibits airway inflammation and airway remodelling through an activated autophagic process in BSMCs. We propose a crucial function of autophagy in statin-based therapeutic approaches in asthma.

Keywords: animal model; asthma; inflammation; respiratory structure and function.

MeSH terms

  • Adenine / analogs & derivatives
  • Adenine / pharmacology
  • Airway Remodeling / drug effects*
  • Animals
  • Asthma / drug therapy*
  • Asthma / physiopathology
  • Autophagosomes
  • Autophagy / drug effects*
  • Autophagy-Related Protein 5 / metabolism
  • Beclin-1 / metabolism
  • Cytokines / biosynthesis
  • Disease Models, Animal
  • Extracellular Matrix / metabolism
  • Female
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
  • Inflammation / drug therapy*
  • Interferon-gamma / biosynthesis
  • Mice
  • Mice, Inbred BALB C
  • Microtubule-Associated Proteins / metabolism
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / physiology
  • Ovalbumin / pharmacology
  • Simvastatin / pharmacology*
  • Simvastatin / therapeutic use
  • Up-Regulation

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Beclin-1
  • Becn1 protein, mouse
  • Cytokines
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • 3-methyladenine
  • Interferon-gamma
  • Ovalbumin
  • Simvastatin
  • Adenine