The efficacy of simvastatin and pioglitazone in a murine model of chronic asthma

Abstract EN

Background : The pathologic mechanisms involved in bronchial asthma have not yet been completely elucidated.

T-helper-2 (Th2) lymphocytes are thought to play a key role in the initiation and perpetuation of this chronic airway inflammation.

The imbalance between matrix metalloproteinase 9 (MMP-9) and tissue inhibitor of metalloproteinases (TIMP-1) in addition to increased transforming growth factor (TGF)-B may contribute to some of the remodeling features seen in asthma.

Simvastatin has anti-inflammatory properties unrelated to its serum cholesterol-lowering activity.

Pioglitazone, a peroxisome proliferator–activated receptor (PPAR)-B agonist, which is used in treatment of diabetes, plays an important role in the control of inflammatory responses.

The present study aimed to investigate the effects of these drugs on airway inflammation and remodeling in a murine model of chronic asthma.

Methods : Actively sensitized mice with ovalbumin (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 body weight), pioglitazone (10 mg / kg body weight) 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 bronchoalveolar lavage (BAL) fluids on the basis of eosinophil peroxidase (EPO), and Th2 cytokines (IL-4, IL-5).

Airway remodeling markers were evaluated in BAL fluids on the basis of TGF-B, MMP-9 and TIMP-1 concentrations.

Results : Th2 cytokines IL-4 and IL-5 increased significantly in BAL fluid after OVA-challenge of sensitized mice with concomitantly increased migration and activation of leukocytes, 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.

TGF-B levels in BAL fluids were also elevated after OVA challenge.

Both simvastatin and pioglitazone inhibited leukocytic 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 IL-5 in BAL fluid.

Treatment with simvastatin or pioglitazone resulted in reduction of MMP-9 and TIMP-1 levels in BAL fluid.

Although, pioglitazone significantly inhibited the enhanced levels of TGF-B in BAL fluid, simvastatin failed to exert the same effect.

Conclusion : In view of the present results, it could be concluded that both simvastatin and pioglitazone have therapeutic potential in chronic asthma as they can inhibit allergen-induced chronic airway inflammation and remodeling in this murine model of chronic asthma.

It could be also concluded that pioglitazone is relatively more beneficial than simvastatin in ameliorating airway remodeling.