ABSTRACT
Background: The pathologic mechanisms involved in bronchial asthma have not yet been completely elucidated. Th2 lymphocytes are thought to play a key role in the initiation and perpetuation of this chronic airway inflammation. 0n the other hand, the imbalances between MMP-9 and TIMP-I in addition to increased TGF-beta may contribute to some of the remodeling features seen in asthma. Simvastatin has anti-inflammatory properties unrelated to their serum cholesterol=lowering activity. PPAR-gamma agonist, which is used in treatment of diabetes, plays an important role in the control of inflammatory responses. So we sought to investigate the effects of these drugs on airway inflammation and remodeling in a murine model of chronic asthma
Methods: Actively sensitized mice with OVA were challenged with OVA or saline aerosols for 30 min/day, 3 days/week for 6 weeks. During the OVA-challenge period, mice were divided into 3 groups and treated with either simvastatin [40 mg/kg], pioglitazone [10 mg/kg] or saline orally. The saline challenged mice were treated with placebo [saline] and served as additional controls. At the end of the challenge period, animals were sacrificed and the serum was analyzed for total IgE. Airway inflammation was assessed in BAL fluids on the basis of EPO and Th2 cytokines [IL-4, IL-5]. Airway remodeling markers were evaluated in BAL fluids on the basis of TGF-beta, MMP-9 and TIMP-I concentrations
Results: Th2 cytokines IL-4 and 5 increased significantly in BAL fluid after OVA-challenge of sensitized mice with concomitantly increased migration and activation of leucocytes, namely eosinophils to bronchial tissues. The serum total IgE levels were also increased. OVA-challenge resulted also in increased MMP-9 and TIMP-1 concentrations in BAL fluid with more pronounced increase of TIMP-1. TGF-beta levels in BAL fluids were also elevated after OVA challenge. Both simvastatin and pioglitazone inhibited leucocytic and specifically eosinophilic infiltration and activation in the airways. However, the level of total serum IgE did not significantly change. Both drugs inhibited secretion of IL-4 and lL-5 in BAL fluid. Treatment with simvastatin or pioglitazone resulted in reduction of MMP-9 and TIMP-I levels in BALfluid with more pronounced effect on TIMP. Although pioglitazone significantly inhibited the enhanced levels of TGF-beta in lung lavagefluid, simvastatin failed to exert the same ejfect
Conclusion: We can conclude that although both of the tested drugs can inhibit allergen induced chronic airway inflammation, pioglitazone is relatively more beneficial in ameliorating airway wall remodeling in this murine model of chronic asthma