title: Simvastatin alleviates airway inflammation and remodelling through up-regulation of autophagy in mouse models of asthma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors: Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Wen
authors: 0000-0003-1414-0605
authors: W
authors: Gu
authors: Department of Gastrointestinal Surgery, Jiading Hospital of Traditional Chinese Medicine, Shanghai, China.
authors: Rong
authors: R
authors: Cui
authors: Department of Respiratory Medicine, People's Hospital of Rizhao, Rizhao, China.
authors: Tao
authors: T
authors: Ding
authors: Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Xiaoming
authors: X
authors: Li
authors: Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Juan
authors: J
authors: Peng
authors: Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Weiguo
authors: W
authors: Xu
authors: Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Fengfeng
authors: F
authors: Han
authors: Department of Respiratory Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors: Xuejun
authors: X
authors: Guo
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D001249:Asthma / Q000188:drug therapy* / Q000503:physiopathology; D000071182:Autophagosomes; D001343:Autophagy / Q000187:drug effects*; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism; D000071186:Beclin-1 / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy*; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000502:physiology; D010047:Ovalbumin / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation
chemical_list: C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C480860:Map1lc3b protein, mouse; D008869:Microtubule-Associated Proteins; C025946:3-methyladenine; D007371:Interferon-gamma; D010047:Ovalbumin; D019821:Simvastatin; D000225:Adenine
keywords: animal model; asthma; inflammation; respiratory structure and function