title: Augmentation of S-Nitrosoglutathione Controls Cigarette Smoke-Induced Inflammatory-Oxidative Stress and Chronic Obstructive Pulmonary Disease-Emphysema Pathogenesis by Restoring Cystic Fibrosis Transmembrane Conductance Regulator Function.
abstract: OBJECTIVE
  Cigarette smoke (CS)-mediated acquired cystic fibrosis transmembrane conductance regulator (CFTR)-dysfunction, autophagy-impairment, and resulting inflammatory-oxidative/nitrosative stress leads to chronic obstructive pulmonary disease (COPD)-emphysema pathogenesis. Moreover, nitric oxide (NO) signaling regulates lung function decline, and low serum NO levels that correlates with COPD severity. Hence, we aim to evaluate here the effects and mechanism(s) of S-nitrosoglutathione (GSNO) augmentation in regulating inflammatory-oxidative stress and COPD-emphysema pathogenesis.
  
  
  RESULTS
  Our data shows that cystic fibrosis transmembrane conductance regulator (CFTR) colocalizes with aggresome bodies in the lungs of COPD subjects with increasing emphysema severity (Global Initiative for Chronic Obstructive Lung Disease [GOLD] I - IV) compared to nonemphysema controls (GOLD 0). We further demonstrate that treatment with GSNO or S-nitrosoglutathione reductase (GSNOR)-inhibitor (N6022) significantly inhibits cigarette smoke extract (CSE; 5%)-induced decrease in membrane CFTR expression by rescuing it from ubiquitin (Ub)-positive aggresome bodies (p < 0.05). Moreover, GSNO restoration significantly (p < 0.05) decreases CSE-induced reactive oxygen species (ROS) activation and autophagy impairment (decreased accumulation of ubiquitinated proteins in the insoluble protein fractions and restoration of autophagy flux). In addition, GSNO augmentation inhibits protein misfolding as CSE-induced colocalization of ubiquitinated proteins and LC3B (in autophagy bodies) is significantly reduced by GSNO/N6022 treatment. We verified using the preclinical COPD-emphysema murine model that chronic CS (Ch-CS)-induced inflammation (interleukin [IL]-6/IL-1β levels), aggresome formation (perinuclear coexpression/colocalization of ubiquitinated proteins [Ub] and p62 [impaired autophagy marker], and CFTR), oxidative/nitrosative stress (p-Nrf2, inducible nitric oxide synthase [iNOS], and 3-nitrotyrosine expression), apoptosis (caspase-3/7 activity), and alveolar airspace enlargement (Lm) are significantly (p < 0.05) alleviated by augmenting airway GSNO levels. As a proof of concept, we demonstrate that GSNO augmentation suppresses Ch-CS-induced perinuclear CFTR protein accumulation (p < 0.05), which restores both acquired CFTR dysfunction and autophagy impairment, seen in COPD-emphysema subjects.
  
  
  METHODS
  GSNO augmentation alleviates CS-induced acquired CFTR dysfunction and resulting autophagy impairment.
  
  
  CONCLUSIONS
  Overall, we found that augmenting GSNO levels controls COPD-emphysema pathogenesis by reducing CS-induced acquired CFTR dysfunction and resulting autophagy impairment and chronic inflammatory-oxidative stress. Antioxid. Redox Signal. 27, 433-451.
authors.affiliation: 1 College of Medicine, Central Michigan University , Mt. Pleasant, Michigan.
authors.forename: Manish
authors.initials: M
authors.lastname: Bodas
authors.affiliation: 1 College of Medicine, Central Michigan University , Mt. Pleasant, Michigan.
authors.forename: David
authors.initials: D
authors.lastname: Silverberg
authors.affiliation: 1 College of Medicine, Central Michigan University , Mt. Pleasant, Michigan.
authors.forename: Kyla
authors.initials: K
authors.lastname: Walworth
authors.affiliation: 1 College of Medicine, Central Michigan University , Mt. Pleasant, Michigan.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Brucia
authors.affiliation: 1 College of Medicine, Central Michigan University , Mt. Pleasant, Michigan.|2 Department of Pediatrics and Pulmonary Medicine, The Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Vij
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D066329:Protein Aggregates / Q000187:drug effects; D011656:Pulmonary Emphysema / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D011758:Pyrroles / Q000494:pharmacology; D026422:S-Nitrosoglutathione / Q000008:administration & dosage* / Q000494:pharmacology; D012906:Smoke / Q000009:adverse effects*; D062789:Tobacco Products
chemical_list: D001549:Benzamides; C505032:CFTR protein, human; C571360:N6022; D066329:Protein Aggregates; D011758:Pyrroles; D012906:Smoke; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D026422:S-Nitrosoglutathione
keywords: CFTR; COPD; GSNO; GSNOR; NO; emphysema