Pioglitazone is as effective as dexamethasone in a cockroach allergen-induced murine model of asthma.
BACKGROUND
While glucocorticoids are currently the most effective therapy for asthma, associated side effects limit enthusiasm for their use. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activators include the synthetic thiazolidinediones (TZDs) which exhibit anti-inflammatory effects that suggest usefulness in diseases such as asthma. How the ability of TZDs to modulate the asthmatic response compares to that of glucocorticoids remains unclear, however, because these two nuclear receptor agonists have never been studied concurrently. Additionally, effects of PPAR-gamma agonists have never been examined in a model involving an allergen commonly associated with human asthma.


METHODS
We compared the effectiveness of the PPAR-gamma agonist pioglitazone (PIO) to the established effectiveness of a glucocorticoid receptor agonist, dexamethasone (DEX), in a murine model of asthma induced by cockroach allergen (CRA). After sensitization to CRA and airway localization by intranasal instillation of the allergen, Balb/c mice were challenged twice at 48-h intervals with intratracheal CRA. Either PIO (25 mg/kg/d), DEX (1 mg/kg/d), or vehicle was administered throughout the period of airway CRA exposure.


RESULTS
PIO and DEX demonstrated similar abilities to reduce airway hyperresponsiveness, pulmonary recruitment of inflammatory cells, serum IgE, and lung levels of IL-4, IL-5, TNF-alpha, TGF-beta, RANTES, eotaxin, MIP3-alpha, Gob-5, and Muc5-ac. Likewise, intratracheal administration of an adenovirus containing a constitutively active PPAR-gamma expression construct blocked CRA induction of Gob-5 and Muc5-ac.


CONCLUSIONS
Given the potent effectiveness shown by PIO, we conclude that PPAR-gamma agonists deserve investigation as potential therapies for human asthma.
Narala
Venkata R
VR
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109-2200, USA. narala@umich.edu
Ranga
Rajesh
R
Smith
Monica R
MR
Berlin
Aaron A
AA
Standiford
Theodore J
TJ
Lukacs
Nicholas W
NW
Reddy
Raju C
RC
D000485:Allergens / Q000633:toxicity*; D000818:Animals; D052179:Antigens, Plant; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy*; D003907:Dexamethasone / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000627:therapeutic use*
D000485:Allergens; D052179:Antigens, Plant; D045162:Thiazolidinediones; C060835:allergen CRa, cockroach; D003907:Dexamethasone; D000077205:Pioglitazone