Anti-inflammatory mechanism of simvastatin in mouse allergic asthma model
Introduction
Statins, such as atorvastatin, cerivastatin, fluvastatin, pravastatin, lovastatin, and simvastatin, are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase in cholesterol biosynthesis and have numerous beneficial pleiotropic effects. Because they are known to reduce atherogenesis and cardiovascular morbidity, they have also been used as cholesterol lowering agents in coronary artery disease (Albert et al., 2001, Joukhadar et al., 2001, Shepherd et al., 1995). It has also been reported that statins have anti-inflammatory property independent of plasma cholesterol lowering (Crisby et al., 2001, Joukhadar et al., 2001, Sparrow et al., 2001) and immunomodulatory activities (Takemoto and Liao, 2001).
Although the mechanism underlying the anti-inflammatory action of statins is not known, it may involve the inhibition of a variety of inflammatory intermediate substances called isoprenoids, which are formed during the endogenous biosynthesis of cholesterol. Statins inhibit the interaction between cellular adhesion molecules, such as lymphocyte function-associated antigen (LFA)-1, and intracellular adhesion molecule (ICAM)-1 (Weitz-Schmidt et al., 2001). More recently, it has been reported that simvastatin reduces the secretion of inflammatory cytokines, but does not alter serum total IgE or ovalbumin-specific IgG1 and IgG2a levels in allergic asthma mouse model (McKay et al., 2004).
Allergic asthma is a chronic inflammatory disease of the lung characterized by reversible obstruction of airway hyperresponsiveness, infiltration of inflammatory cells into lung tissues, mucus overproduction (Kon and Kay, 1999), the over-expressions of Th2-mediated cytokines including interleukin (IL)-4, IL-5, IL-13 and tumor necrosis factor (TNF)-α, and chemokines such as eotaxin and RANTES in the airways of allergic asthmatics (Berkman et al., 1996, Zimmermann et al., 2003). It has been increasing in prevalence, morbidity, and mortality over the last two decades (Umetsu et al., 2002). Despite the prevalence of this disease, its source and mechanism remain unclear. It has also been reported that inflammatory and structural cells contribute to the increased bronchoconstriction chronically, to airway remodeling. Current asthma therapy does not inhibit these features satisfactorily. Recently, Rho family kinases as a potential drug target were introduced because of increasing evidences which have a central role for this pathway in acute and chronic airway hyperresponsiveness (Blease, 2005, Gosens et al., 2006). These Rho family kinases regulate mitogen-activated protein (MAP) kinases (Hall et al., 2001) and many functions of leukocytes (Ridley, 2001).
As the pathophysiological mechanism mitigating the effects of simvastatin on asthma is not known, we aimed to investigate whether simvastatin reduces ovalbumin-specific allergic asthma symptoms in mice, and to investigate the inhibitory mechanism of simvastatin in ovalbumin-specific allergic asthma.
Section snippets
Sensitization, challenge and experimental protocol
Specific pathogen free female BALB/c mice, 6–8 weeks of age were divided into four groups (8 mice/group). Control, mice sensitized and nebulized with phosphate buffered saline (PBS, negative control); general sensitized mice, mice sensitized with ovalbumin and nebulized with PBS (general sensitization); ovalbumin-challenged mice, mice sensitized and nebulized with ovalbumin (local challenge); simvastatin treatment, ovalbumin-challenged mice treated with simvastatin. Hereafter, we used these
Ovalbumin-specific serum IgE levels
Antigen-specific Th2 responses are known to induce antigen-specific IgE antibody production. Therefore, we examined whether simvastatin influenced ovalbumin-specific IgE production in allergic asthma mouse model using ELISA. Serum ovalbumin-specific IgE levels were elevated in general sensitized mice (156.8 ± 1.27 ng/ml) and ovalbumin-challenged mice (203.0 ± 11.00 ng/ml) versus control mice (0.5 ± 0.23 ng/ml). Simvastatin (150.6 ± 2.39 ng/ml) treated mice showed ovalbumin-specific IgE antibody
Discussion
It is important to understand the pathogenesis of allergic asthma because it is one of the most common diseases encountered in the clinic, and because the mortality associated with allergic asthma has increased worldwide over the last two decades (Umetsu et al., 2002). However, the mechanisms involved have not been completely elucidated. Moreover, there are difficulties in the drug development process because of the limited understanding of molecular pathogenesis of allergic asthma. Therefore,
Acknowledgments
This work was funded by Samsung biomedical Research Institute, Sungkyunkwan University School of Medicine (Grant no. #SBRI S-M 200106).
References (46)
- et al.
Potential drug targets: small GTPases that regulate leukocyte function
Tips
(1999) - et al.
Synergistic up-regulation of metalloproteinase-9 by growth factors and inflammatory cytokines: an absolute requirement for transcription factor NF-κB
FEBS Lett.
(1998) - et al.
The effect of marimastat, a metalloprotease inhibitor, on allergen-induced asthmatic hyper-reactivity
Toxicol. Appl. Pharmacol.
(2005) - et al.
CD40 and OX40 ligand are increased on stimulated asthmatic airway smooth muscle
J. Allergy Clin. Immunol.
(2005) - et al.
Transduction of a dominant-negative H-Ras into human eosinophils attenuates extracellular signal-regulated kinase activation interleukin-5-mediated cell viability
Blood
(2001) - et al.
Extracellular matrix proteins modulate asthmatic airway smooth muscle cell proliferation via an autocrine mechanism
J. Allergy Clin. Immunol.
(2004) - et al.
A comparison of airway and serum matrix metalloproteinase-9 activity among normal subjects, asthmatic patients, and patients with asthmatic mucus hypersecretion
Chest
(2005) - et al.
Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme
Cell
(2000) Rho family proteins: coordinating cell responses
Trends Cell Biol.
(2001)- et al.
Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study
J. Am. Med. Assoc.
(2001)
Cross-linking CD40 on B cells rapidly activates nuclear factor-κB
J. Immunol.
Expression of RANTES mRNA and protein in airways of patients with mild asthma
Am. J. Respir. Crit. Care Med.
Targeting kinases in asthma
Expert Opin. Investig. Drugs
Correlation between nuclear factor-κB activity in bronchial brushing samples and lung dysfunction in an animal model of asthma
Am. J. Respir. Crit. Care Med.
Pravastatin treatment increases collagen content and decreases lipid content, inflammation, metalloproteinases, and cell death in human carotid plaques: implications for plaque stabilization
Circulation
Induction of activation-induced cytidine deaminase gene expression by IL-4 and CD40 ligation is dependent on STAT6 and NFκB
Int. Immunol.
Flt-3 ligand reverses late allergic response and airway hyper-responsiveness in a mouse model of allergic inflammation
J. Immunol.
Interleukin-4 is required to generate and sustain in vivo IgE responses
J. Immunol.
NF-κB and Rel proteins: evolutionarily conserved mediators of immune responses
Annu. Rev. Immunol.
Rho-kinase as a drug target for the treatment of airway hyperresponsiveness in asthma
Mini Rev. Med. Chem.
NF-κB and Rel: participants in a multiform transcriptional regulatory system
Int. Rev. Cyt.
Rac2, a hematopoiesis-specific Rho GTPase, specifically regulates mast cell protease gene expression in bone marrow-derived mast cells
Mol. Cell. Biol.
Perflubron reduces lung inflammation in respiratory syncytial virus infection by inhibition chemokine expression and nuclear factor-κB activation
Am. J. Respir. Crit. Care Med.
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