Simvastatin Inhibits Airway Hyperreactivity

Zeki, Amir A.; Franzi, Lisa M.; Kenyon, Nicholas J.

doi:10.1164/rccm.200901-0018oc

Cited by 108 publications

(79 citation statements)

References 51 publications

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“…Inhibitors of the human Mev pathway (statins and bisphosphonates) are used clinically to reduce cholesterol biosynthesis, increase bone density, and decrease cell proliferation in cancer (34). Down-regulation of the human Mev pathway by statins has recently been linked to disruption of replication by hepatitis C virus (35,36) and human immunodeficiency virus (37), enhancement of anticancer drugs (38), and anti-inflammatory effects in the lung and airways (39,40). These findings suggest that DPM-DC inhibitors may find additional uses in the treatment of non-infectious diseases, which obviates the need for selective DPM-DC inhibition.…”

Section: Resultsmentioning

confidence: 99%

Probing Ligand-binding Pockets of the Mevalonate Pathway Enzymes from Streptococcus pneumoniae

Lefurgy

Rodriguez

Park

et al. 2010

Journal of Biological Chemistry

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Diphosphomevalonate (Mev⅐pp) is the founding member of a new class of potential antibiotics targeting the Streptococcus pneumoniae mevalonate (Mev) pathway. We have synthesized a series of Mev⅐pp analogues designed to simultaneously block two steps in this pathway, through allosteric inhibition of mevalonate kinase (MK) and, for five of the analogues, by mechanismbased inactivation of diphosphomevalonate decarboxylase (DPM-DC). The analogue series expands the C 3 -methyl group of Mev⅐pp with hydrocarbons of varying size, shape, and chemical and physical properties. Previously, we established the feasibility of a prodrug strategy in which unphosphorylated Mev analogues could be enzymatically converted to the active Mev⅐pp forms by the endogenous MK and phosphomevalonate kinase. We now report the kinetic parameters for the turnover of non-, mono-, and diphosphorylated analogues as substrates and inhibitors of the three mevalonate pathway enzymes. The inhibition of MK by Mev⅐pp analogues revealed that the allosteric site is selective for compact, electron-rich C 3 -subsitutents. The lack of reactivity of analogues with DPM-DC provided evidence, counter to the existing model, for a decarboxylation transition state that is concerted rather than dissociative. The Mev pathway is composed of three structurally and functionally conserved enzymes that catalyze consecutive steps in a metabolic pathway. The current work reveals that these enzymes exhibit significant differences in specificity toward R-group substitution at C 3 and that these patterns are explained well by changes in the volume of the C 3 R-group-binding pockets of the enzymes.Streptococcus pneumoniae, the primary cause of bacterial meningitis and pneumonia, kills over 4000 people daily worldwide and disproportionately affects children and the elderly (1, 2). Antibiotic resistance is a major problem in fighting this organism, with multiple-drug resistance rates as high as 95% in some regions (3). Although vaccines targeting the 7 or 23 most prevalent strains have shown success in reducing disease incidence in developed countries (4), there is a continual need for new antibiotic strategies to combat unvaccinated strains, which are rapidly filling the biological niches left by the vaccine (5).The mevalonate (Mev) 3 pathway is essential for the survival of S. pneumoniae in lung and serum (6). The bacterium uses this pathway to convert Mev to isopentenyl diphosphate, the "building block" of the isoprenoids: a class of 25,000 unique molecules having a wide range of biological functions. The pathway consists of three GHMP family kinases: Mev kinase (MK), phosphomevalonate kinase (PMK) and diphosphomevalonate decarboxylase (DPM-DC) ( Fig. 1) (7). Mutations that knock out genes in this pathway kill the organism in vivo, suggesting that S. pneumoniae cannot obtain the necessary precursors or downstream products from the host (6). In principle, each of the three enzymes is an antibiotic target, because inhibition of any of them prevents the production of isopentenyl d...

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Section: Resultsmentioning

confidence: 99%

Probing Ligand-binding Pockets of the Mevalonate Pathway Enzymes from Streptococcus pneumoniae

Lefurgy

Rodriguez

Park

et al. 2010

Journal of Biological Chemistry

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“…intraperitoneal (i.p.)) administration of statins for the treatment of allergic asthma demonstrated reduced eosinophilic inflammation, airway mucus production, and airway hyperresponsiveness [31,32,34–38]. The repurposing of statins for the treatment of lung diseases is, therefore, a worthwhile opportunity since there is a growing need to find alternative therapies for the treatment of severe asthma refractory to standard controller therapy, i.e.…”

Section: Introductionmentioning

confidence: 99%

Innovations in asthma therapy: is there a role for inhaled statins?

Zeki

Elbadawi-Sidhu

2018

Expert Review of Respiratory Medicine

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Introduction Asthma manifests as chronic airflow obstruction with persistent inflammation and airway hyperresponsiveness. The immunomodulatory and anti-inflammatory properties of the HMG-CoA reductase (HMGCR) inhibitors (a.k.a. statins), suggest a therapeutic role in chronic inflammatory lung diseases. However, despite positive laboratory investigations and promising epidemiological data, clinical trials using statins for the treatment of asthma have yielded conflicting results. Inadequate statin levels in the airway compartment could explain these findings. Areas covered HMGCR is in the mevalonate (MA) pathway and MA signaling is fundamental to lung biology and asthma. This article will discuss clinical trials of oral statins in asthma, review lab investigations relevant to the systemic versus inhaled administration of statins, address the advantages and disadvantages of inhaled statins, and answer the question: is there a role for inhaled statins in the treatment of asthma? Expert commentary If ongoing investigations show that oral administration of statins has no clear clinical benefits, then repurposing statins for delivery via inhalation is a logical next step. Inhalation of statins bypasses first-pass metabolism by the liver, and therefore, allows for delivery of significantly lower doses to the airways at greater potency. Statins could become the next major class of novel inhalers for the treatment of asthma.

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“…Neutrophil accumulation in the airway results in the expression of proinflammatory cytokines (especially TNF-alpha and interleukins), which are a fundamental part of the pathogenesis. In a recent experimental animal study evaluating the effect of simvastatin on airway inflammation in COPD, decreases in inflammatory markers such as leukocytes, macrophages, eosinophils, TNF-alpha, IL-4, and IL-13 were reported [25]. In another study evaluating the cardiovascular risk of COPD patients, an increase in C-reactive protein (CRP) was found to be related to COPD severity [26].…”

Section: Resultsmentioning

confidence: 99%

Influence of Statin Therapy on Exacerbation Frequency in Patients with Chronic Obstructive Pulmonary Disease

et al. 2017

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OBJECTIVES:Chronic obstructive pulmonary disease (COPD) is an inflammatory disease, in which chronic and systemic inflammation plays an important role. By decreasing neutrophil infiltration and cytokine production, statins have anti-inflammatory mechanisms. MATERIALS AND METHODS:Fifty-seven patients who had diagnosis of chronic obstructive pulmonary disease according to GOLD guideline were included in the study; 20 of them were statin users. Statin users group were patients being under medication with regular simvastatin, atorvastatin or rosuvastatin 20 mg per day for at least the past 1 year. RESULTS:There was statistically no significant difference between patients with or without statin treatment with respect to; age, femalemale ratio, COPD severity level, medication used for COPD, pulmonary function tests results and smoking habits. COPD exacerbation frequency in patients using statins was significantly less than patients not using statins (p<0.05). Patient number with COPD exacerbation, antibiotic treatment and outpatient clinic administration and outpatient clinic administration frequency was significantly lower in statin using patients (p<0.05).CONCLUSION: COPD patients receiving statins have a lower frequency of COPD exacarbations, hospital administration and antibiotic treatment compared to patients not receiving statins. KEYWORDS: Statin, COPD, exacerbations INTRODUCTIONChronic obstructive pulmonary disease (COPD) is an inflammatory disease of the lungs characterized by progressive airway obstruction [1]. Some studies have proposed a significant association between smoking and pulmonary inflammation [2,3]. However, recent studies have shown an increase in systemic inflammatory markers in non-smokers, suggesting a possible association with systemic inflammation rather than solitary pulmonary inflammation [4]. Deterioration in pulmonary functions may result in decreased functional capacity, frequent hospitalization, increase in hospitalization rates, and early mortality [5]. Currently, COPD is the fourth leading cause of mortality worldwide and is projected to be the third by 2020 [6]. The economic burden of the disease is high due to close follow-up requirements, hospitalization due to exacerbations, and long-term treatments of the disease. However, the only available options that increase survival rate are oxygen treatment and smoking cessation [7,8].Chronic and systemic inflammation plays an important role in the pathogenesis of COPD. Statins are a class of drugs that inhibit cholesterol production in the liver by blocking the mevalonate pathway. Currently, these drugs are used in the prevention of cardiovascular diseases. In addition to their cholesterol-lowering effects, recent studies have shown that they also possess immune modulatory and pleiotropic effects [9,10]. Decrease in neutrophil infiltration and cytokine production, blockage of matrix remodelling, and slowdown in endothelial and epithelial integrity and apoptosis are the antiinflammatory mechanisms of statins in COPD patients [11]. Recen...

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Simvastatin Inhibits Airway Hyperreactivity

Cited by 108 publications

References 51 publications

Probing Ligand-binding Pockets of the Mevalonate Pathway Enzymes from Streptococcus pneumoniae

Probing Ligand-binding Pockets of the Mevalonate Pathway Enzymes from Streptococcus pneumoniae

Innovations in asthma therapy: is there a role for inhaled statins?

Influence of Statin Therapy on Exacerbation Frequency in Patients with Chronic Obstructive Pulmonary Disease

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