title: Heterozygosity in the glutathione synthesis gene Gclm increases sensitivity to diesel exhaust particulate induced lung inflammation in mice.
abstract: BACKGROUND
  Inhalation of ambient fine particulate matter (PM₂.₅) is associated with adverse respiratory and cardiovascular effects. A major fraction of PM₂.₅ in urban settings is diesel exhaust particulate (DEP), and DEP-induced lung inflammation is likely a critical event mediating many of its adverse health effects. Oxidative stress has been proposed to be an important factor in PM₂.₅-induced lung inflammation, and the balance between pro- and antioxidants is an important regulator of this inflammation. An important intracellular antioxidant is the tripeptide thiol glutathione (GSH). Glutamate cysteine ligase (GCL) carries out the first step in GSH synthesis. In humans, relatively common genetic polymorphisms in both the catalytic (Gclc) and modifier (Gclm) subunits of GCL have been associated with increased risk for lung and cardiovascular diseases.
  
  
  OBJECTIVE
  This study was aimed to determine the effects of Gclm expression on lung inflammation following DEP exposure in mice.
  
  
  METHODS
  We exposed Gclm wild type, heterozygous, and null mice to DEP via intranasal instillation and assessed lung inflammation as determined by neutrophils and inflammatory cytokines in lung lavage, inflammatory cytokine mRNA levels in lung tissue, as well as total lung GSH, Gclc, and Gclm protein levels.
  
  
  RESULTS
  The Gclm heterozygosity was associated with a significant increase in DEP-induced lung inflammation when compared to that of wild type mice.
  
  
  CONCLUSIONS
  This finding indicates that GSH synthesis can mediate DEP-induced lung inflammation and suggests that polymorphisms in Gclm may be an important factor in determining adverse health outcomes in humans following inhalation of PM₂.₅.
authors.affiliation: Department of Environmental and Occupational Health, University of Washington, Seattle, WA 98195, USA.
authors.forename: Chad S
authors.initials: CS
authors.lastname: Weldy
authors.forename: Collin C
authors.initials: CC
authors.lastname: White
authors.forename: Hui-Wen
authors.initials: HW
authors.lastname: Wilkerson
authors.forename: Timothy V
authors.initials: TV
authors.lastname: Larson
authors.forename: James A
authors.initials: JA
authors.lastname: Stewart
authors.forename: Sean E
authors.initials: SE
authors.lastname: Gill
authors.forename: William C
authors.initials: WC
authors.lastname: Parks
authors.forename: Terrance J
authors.initials: TJ
authors.lastname: Kavanagh
mesh_terms: D000393:Air Pollutants / Q000737:chemistry / Q000633:toxicity; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D006579:Heterozygote; D007249:Inflammation / Q000139:chemically induced* / Q000235:genetics; D008171:Lung Diseases / Q000139:chemically induced* / Q000235:genetics*; D008297:Male; D051379:Mice; D052638:Particulate Matter / Q000737:chemistry / Q000633:toxicity*; D021122:Protein Subunits; D001335:Vehicle Emissions / Q000032:analysis*
chemical_list: D000393:Air Pollutants; D052638:Particulate Matter; D021122:Protein Subunits; D001335:Vehicle Emissions; C560749:GCLM protein, mouse; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione