title: ATG5, autophagy and lung function in asthma.
abstract: Reactive oxidative species (ROS) are essential in cellular survival; however, excessive production and chronic exposure to ROS pose serious health threats. Excessive production of ROS is thought to play a pivotal role in the pathogenesis of asthma, where exhaled levels of ROS have been found to positively correlate with disease severity. Autophagy is induced by ROS to remove oxidized proteins or organelles to minimize tissue damage, and presents itself as a good candidate pathway for investigation in asthma pathogenesis. Given the role of oxidative stress in the pathogenesis of asthma and disease severity, we hypothesized that autophagy is associated with asthma pathogenesis, and sought to detect its presence using both genetic and histological approaches. We found variant rs12212740, an intronic SNP of ATG5, to be associated with asthma and forced expiratory volume in 1 second (FEV(1)) percent predicted in the French Canadian population and with FEV(1) in an American Caucasian cohort. Furthermore, double-membrane autophagosomes were more easily detected in fibroblast and epithelial cells from a bronchial biopsy tissue of a moderately severe asthma patient compared with corresponding cells of a healthy subject. Asthma is associated with a cytokine milieu [e.g., interleukin (IL)-13] that promotes transforming growth factor-β1 (TGFβ1) affiliated airway remodeling, and agonistic relationships existed among these cytokines and ROS. Hence, autophagy may be a cellular mechanism that promotes TGFβ1 airway remodeling and loss of lung function in asthma.
authors.affiliation: McGill University Health Centre, Meakins-Christie Laboratories, Montreal, Quebec Canada.
authors.forename: Audrey
authors.initials: A
authors.lastname: Poon
authors.forename: David
authors.initials: D
authors.lastname: Eidelman
authors.forename: Catherine
authors.initials: C
authors.lastname: Laprise
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
mesh_terms: D056151:Airway Remodeling; D001249:Asthma / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress
chemical_list: C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; D008869:Microtubule-Associated Proteins