Peroxisome proliferator-activated receptor gamma is expressed in airways and inhibits features of airway remodeling in a mouse asthma model.
BACKGROUND
Allergic asthma is associated with persistent functional and structural changes in the airways and involves many different cell types. Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily, is predominantly expressed in adipose tissue and plays a major role in regulating adipocyte differentiation and glucose metabolism. Recently, PPAR-gamma has been shown to play an important role in the control of inflammatory responses, including within the lung, acting on both immune and nonimmune cells.


OBJECTIVE
Our aim was to assess the anti-inflammatory potential of a PPAR-gamma agonist locally delivered by means of nebulization.


METHODS
We used a mouse model of asthma induced by sensitization and airway challenge with ovalbumin. Ciglitazone, a PPAR-gamma agonist, was administered by means of nebulization alone at the time of antigen challenge or by means of gavage and nebulization. Treatments with both ciglitazone and GW9662, a specific antagonist, were also performed to verify that ciglitazone's effects were mediated through PPAR-gamma activation.


RESULTS
Our results show that PPAR-gamma is mainly expressed in airway epithelium on antigen sensitization. Treatment with ciglitazone reduced PPAR-gamma levels in the lung, whereas combined treatment with GW9662 abrogated this inhibition. Importantly, nebulization with ciglitazone decreased airway hyperresponsiveness, basement membrane thickness, mucus production, collagen deposition, and TGF-beta synthesis. A significant correlation was also found between airway hyperresponsiveness, basement membrane thickness, and TGF-beta levels.


CONCLUSIONS
These results demonstrate that inhaled agonistic ligands of PPAR-gamma might have new therapeutic potential for airway asthmatic inflammation.
Honda
Kohei
K
INSERM U547-IFR17, Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 245, 59019 Lille Cedex, France.
Marquillies
Philippe
P
Capron
Monique
M
Dombrowicz
David
D
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D007150:Immunohistochemistry; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009330:Nebulizers and Vaporizers; D010047:Ovalbumin / Q000276:immunology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000627:therapeutic use; D014132:Trachea / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D018927:Anti-Asthmatic Agents; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D010047:Ovalbumin; C039671:ciglitazone