title: The ion channel transient receptor potential melastatin-2 does not play a role in inflammatory mouse models of chronic obstructive pulmonary diseases.
abstract: BACKGROUND
  There is strong evidence that oxidative stress is associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). The transient receptor potential melastatin-2 (TRPM2) is an oxidative stress sensing channel that is expressed in a number of inflammatory cells and therefore it has been suggested that inhibition of TRPM2 could lead to a beneficial effect in COPD patients. In this study, we have investigated the role of TRPM2 in a variety of mouse models of oxidative stress and COPD using TRPM2-deficent mice.
  
  
  METHODS
  Mice were exposed to ozone (3 ppm for 4 h) or lipopolysaccharide (LPS, 0.3 mg/kg, intranasaly). In another model, mice were exposed to tobacco smoke (750 μg/l total wet particulate matter) for 30 min twice a day on three consecutive days. For the exacerbation model, the smoke exposure on the morning of day 3 animals was replaced with intranasal administration of LPS (0.3 mg/kg). Animals were killed 3 and 24 h after the challenge (ozone and LPS model) or 18 h after the last tobacco smoke exposure. In vitro neutrophil chemotaxis and monocyte activation were also studied using cells isolated from wild type and TRPM2-deficient animals. Statistical significance for the in vivo data (P < 0.05) was determined using analysis of variance with Kruskal-Wallis and Dunns multiple comparison test.
  
  
  RESULTS
  In all models studied, no difference in the bronchoalveolar lavage inflammation could be evidenced when comparing wild type and TRPM2-deficient mice. In addition, no difference could be seen in the lung inflammation as assessed by the measurement of various cytokines/chemokines. Similarly in various in vitro cellular activation assays using isolated neutrophils and monocytes no significant differences could be observed when comparing wild type and TRPM2-deficient mice.
  
  
  CONCLUSIONS
  We have shown, in all the models tested, no difference in the development of airway inflammation or cell activation between TRPM2-deficient mice and their wild type counterparts. These results would suggest that inhibiting TRPM2 activity in COPD would have no anti-inflammatory effect.
authors.affiliation: Novartis Institutes for BioMedical Research, Respiratory Diseases Area, Basel, Switzerland.
authors.forename: Liz
authors.initials: L
authors.lastname: Hardaker
authors.forename: Parmjit
authors.initials: P
authors.lastname: Bahra
authors.forename: Benjamin Cochin
authors.initials: BC
authors.lastname: de Billy
authors.forename: Mark
authors.initials: M
authors.lastname: Freeman
authors.forename: Natalia
authors.initials: N
authors.lastname: Kupfer
authors.forename: Daniel
authors.initials: D
authors.lastname: Wyss
authors.forename: Alexandre
authors.initials: A
authors.lastname: Trifilieff
mesh_terms: D000818:Animals; D018845:CD11 Antigens / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D066298:In Vitro Techniques; D007249:Inflammation / Q000503:physiopathology*; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009504:Neutrophils / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D010126:Ozone / Q000009:adverse effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000139:chemically induced / Q000503:physiopathology*; D050053:TRPM Cation Channels / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D014028:Tobacco Smoke Pollution / Q000009:adverse effects
chemical_list: D018845:CD11 Antigens; D008070:Lipopolysaccharides; D050053:TRPM Cation Channels; C544443:TRPM2 protein, mouse; D014028:Tobacco Smoke Pollution; D010126:Ozone