title: The PPARgamma ligand, rosiglitazone, reduces airways hyperresponsiveness in a murine model of allergen-induced inflammation.
abstract: There is considerable interest in the role of peroxisome proliferator activated receptors (PPARs) as ligand-activated transcription factors in the airways. This study examines the effects of a potent synthetic PPARgamma ligand, rosiglitazone (RG), in a murine model of allergen-induced inflammation, to explore its potential regulation of airways inflammation, structure and function. C57BL/6 mice were sensitised with ovalbumin (OVA, 50 microg i.p., days 0, 12) and challenged with aerosolized OVA (1% w v(-1), 30 min day(-1)) for 7 days (days 20-26). Mice were treated with RG (5 mg kg(-1) i.p.) or vehicle during the challenge period. The OVA challenge induced increases in leukocyte number and MMP-2 activity in bronchoalveolar lavage fluid and in goblet cell number in lung tissue obtained on Day 27. RG failed to inhibit inflammatory cell infiltration, MMP-2 activity or goblet cell hyperplasia. Respiratory resistance in response to methacholine (MCh i.v.) was greater in OVA-challenged mice than saline-challenged mice and this airways hyperresponsiveness (AHR) was reduced by RG. However, RG did not affect MCh-induced contraction in isolated guinea-pig tracheal rings, nor did it influence the airway obstruction induced by MCh in saline-challenged mice, so a direct effect on airway obstruction is unlikely. These data suggest that RG modulates AHR in this model, by a mechanism that is also potentially independent of an anti-inflammatory action.
authors.affiliation: Department of Pharmacology, University of Melbourne, Vic., 3010, Australia. janeew@unimelb.edu.au
authors.forename: J E
authors.initials: JE
authors.lastname: Ward
authors.forename: D J
authors.initials: DJ
authors.lastname: Fernandes
authors.forename: C C
authors.initials: CC
authors.lastname: Taylor
authors.forename: J V
authors.initials: JV
authors.lastname: Bonacci
authors.forename: L
authors.initials: L
authors.lastname: Quan
authors.forename: A G
authors.initials: AG
authors.lastname: Stewart
mesh_terms: D000485:Allergens / Q000633:toxicity; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology; D006168:Guinea Pigs; D006965:Hyperplasia; D066298:In Vitro Techniques; D007274:Injections, Intraperitoneal; D008024:Ligands; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects; D010047:Ovalbumin / Q000633:toxicity; D047495:PPAR gamma / Q000819:agonists*; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000517:prevention & control*; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*; D013997:Time Factors; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000485:Allergens; D016085:Bronchoconstrictor Agents; D008024:Ligands; D047495:PPAR gamma; D045162:Thiazolidinediones; D014665:Vasodilator Agents; D000077154:Rosiglitazone; D016210:Methacholine Chloride; D010047:Ovalbumin; D020778:Matrix Metalloproteinase 2; C039671:ciglitazone