title: Glutathione Depletion Accelerates Cigarette Smoke-Induced Inflammation and Airspace Enlargement.
abstract: The study objective was to assess age-related changes in glutathione (GSH) adaptive response to cigarette smoke (CS) exposure. Older cigarette smokers show a decline (67%) in lung epithelial lining fluid (ELF) GSH and a 1.8-fold decreased GSH adaptive response to cigarette smoking with a concomitant elevation (47%) of exhaled nitric oxide compared with younger smokers. In order to isolate the changes in tissue GSH from other age-related effects, pharmacological inhibition of the rate limiting step in GSH synthesis was employed to examine the lung's response to CS exposure in young mice. The γ-glutamylcysteine ligase inhibitor L-buthionine-sulfoximine (BSO) was administered in the drinking water (20 mM) to decrease by half the in vivo GSH levels to those found in aged mice and humans. Mice were then exposed to CS (3 h/day) for 5 or 15 days. Biochemical analysis of the ELF and lung tissue revealed an inhibition of the CS-induced GSH adaptive response by BSO with a concurrent increase in mixed protein-GSH disulfides indicating increased cysteine oxidation. The prevention of the GSH adaptive response led to an increase in pro-inflammatory cytokines present in the lung. Airspace enlargement is a hallmark of lung emphysema and was observed in mice treated with BSO and exposed to CS for as little as 15 days, whereas these types of changes normally take up to 6 months in this model. BSO treatment potentiated both lung elastase and matrix metalloproteinase activity in the CS group. These data suggest that age-related decline in the GSH adaptive response can markedly accelerate many of the factors thought to drive CS-induced emphysema.
authors.affiliation: *Department of Medicine, National Jewish Health, Denver, Colorado 80206; Departments of Pharmaceutical Sciences.
authors.forename: Neal S
authors.initials: NS
authors.lastname: Gould
authors.affiliation: *Department of Medicine, National Jewish Health, Denver, Colorado 80206;
authors.forename: Elysia
authors.initials: E
authors.lastname: Min
authors.affiliation: *Department of Medicine, National Jewish Health, Denver, Colorado 80206;
authors.forename: Jie
authors.initials: J
authors.lastname: Huang
authors.affiliation: *Department of Medicine, National Jewish Health, Denver, Colorado 80206; Medicine and Immunology, University of Colorado at Denver, Aurora, Colorado 80045.
authors.forename: Hong Wei
authors.initials: HW
authors.lastname: Chu
authors.affiliation: *Department of Medicine, National Jewish Health, Denver, Colorado 80206;
authors.forename: Jim
authors.initials: J
authors.lastname: Good
authors.affiliation: *Department of Medicine, National Jewish Health, Denver, Colorado 80206; Medicine and.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.affiliation: *Department of Medicine, National Jewish Health, Denver, Colorado 80206; Departments of Pharmaceutical Sciences, Medicine and Immunology, University of Colorado at Denver, Aurora, Colorado 80045 dayb@njhealth.org.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Day
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000032:analysis; D005978:Glutathione / Q000032:analysis / Q000172:deficiency* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced* / Q000503:physiopathology; D008168:Lung / Q000737:chemistry / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D020782:Matrix Metalloproteinases / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012137:Respiratory System / Q000187:drug effects* / Q000503:physiopathology; D012907:Smoking / Q000009:adverse effects*; D055815:Young Adult
chemical_list: D016207:Cytokines; D020782:Matrix Metalloproteinases; D005978:Glutathione
keywords: agents; antioxidants; inhalation toxicology; oxidative injury; respiratory toxicology; systems toxicology