Simvastatin inhibits airway hyperreactivity: implications for the mevalonate pathway and beyond.

Abstract:

RATIONALE:Statin use has been linked to improved lung health in asthma and chronic obstructive pulmonary disease. We hypothesize that statins inhibit allergic airway inflammation and reduce airway hyperreactivity via a mevalonate-dependent mechanism. OBJECTIVES:To determine whether simvastatin attenuates airway inflammation and improves lung physiology by mevalonate pathway inhibition. METHODS:BALB/c mice were sensitized to ovalbumin over 4 weeks and exposed to 1% ovalbumin aerosol over 2 weeks. Simvastatin (40 mg/kg) or simvastatin plus mevalonate (20 mg/kg) was injected intraperitoneally before each ovalbumin exposure. MEASUREMENTS AND MAIN RESULTS:Simvastatin reduced total lung lavage leukocytes, eosinophils, and macrophages (P < 0.05) in the ovalbumin-exposed mice. Cotreatment with mevalonate, in addition to simvastatin, reversed the antiinflammatory effects seen with simvastatin alone (P < 0.05). Lung lavage IL-4, IL-13, and tumor necrosis factor-alpha levels were all reduced by treatment with simvastatin (P < 0.05). Simvastatin treatment before methacholine bronchial challenge increased lung compliance and reduced airway hyperreactivity (P = 0.0001). CONCLUSIONS:Simvastatin attenuates allergic airway inflammation, inhibits key helper T cell type 1 and 2 chemokines, and improves lung physiology in a mouse model of asthma. The mevalonate pathway appears to modulate allergic airway inflammation, while the beneficial effects of simvastatin on lung compliance and airway hyperreactivity may be independent of the mevalonate pathway. Simvastatin and similar agents that modulate the mevalonate pathway may prove to be treatments for inflammatory airway diseases, such as asthma.

authors

Zeki AA,Franzi L,Last J,Kenyon NJ

doi

10.1164/rccm.200901-0018OC

subject

Has Abstract

pub_date

2009-10-15 00:00:00

pages

731-40

issue

8

eissn

1073-449X

issn

1535-4970

pii

200901-0018OC

journal_volume

180

pub_type

杂志文章
  • Remotely Monitored Therapy and Nitric Oxide Suppression Identifies Nonadherence in Severe Asthma.

    abstract:RATIONALE:Poor adherence is common in difficult-to-control asthma. Distinguishing patients with difficult-to-control asthma who respond to inhaled corticosteroids (ICS) from refractory asthma is an important clinical challenge. OBJECTIVES:Suppression of fractional exhaled nitric oxide (FeNO) with directly observed ICS...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.201806-1182OC

    authors: Heaney LG,Busby J,Bradding P,Chaudhuri R,Mansur AH,Niven R,Pavord ID,Lindsay JT,Costello RW,Medical Research Council UK Refractory Asthma Stratification Programme (RASP-UK).

    更新日期:2019-02-15 00:00:00

  • Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America.

    abstract::Background: This document provides evidence-based clinical practice guidelines on the management of adult patients with community-acquired pneumonia.Methods: A multidisciplinary panel conducted pragmatic systematic reviews of the relevant research and applied Grading of Recommendations, Assessment, Development, and Ev...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章,实务指引

    doi:10.1164/rccm.201908-1581ST

    authors: Metlay JP,Waterer GW,Long AC,Anzueto A,Brozek J,Crothers K,Cooley LA,Dean NC,Fine MJ,Flanders SA,Griffin MR,Metersky ML,Musher DM,Restrepo MI,Whitney CG

    更新日期:2019-10-01 00:00:00

  • Diaphragm recruitment during nonrespiratory activities.

    abstract::We previously found that weight lifters could generate greater inspiratory pressures and had more diaphragm mass than control subjects. We postulated that the weight-lifting activity itself provided a strength-training stimulus to the diaphragm. To evaluate the extent to which the diaphragm is recruited during strenuo...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.162.2.9908059

    authors: Al-Bilbeisi F,McCOOL FD

    更新日期:2000-08-01 00:00:00

  • Tidal breathing analysis as a measure of airway obstruction in children three years of age and older.

    abstract::This study was designed to evaluate the value and applicability of tidal breathing pattern analysis to assess airflow obstruction in young children. The time needed to reach maximal tidal expiratory flow (TME) divided by total expiratory time (TE) was measured in 228 healthy children 3 to 11 yr of age, 64 patients wit...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.153.4.8616550

    authors: van der Ent CK,Brackel HJ,van der Laag J,Bogaard JM

    更新日期:1996-04-01 00:00:00

  • Daily telemonitoring of exhaled nitric oxide and symptoms in the treatment of childhood asthma.

    abstract:RATIONALE:Asthma treatment might improve when inhaled steroids are titrated on airway inflammation. Fractional exhaled nitric oxide (FeNO0.05), a marker of eosinophilic airway inflammation, can be measured at home. OBJECTIVES:We assessed daily FeNO0.05 telemonitoring in the management of childhood asthma. METHODS:Chi...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章,多中心研究,随机对照试验

    doi:10.1164/rccm.200807-1010OC

    authors: de Jongste JC,Carraro S,Hop WC,CHARISM Study Group.,Baraldi E

    更新日期:2009-01-15 00:00:00

  • Elevated serum levels of mucin-associated antigen in patients with acute respiratory distress syndrome.

    abstract::Increased serum levels of mucin-associated antigen have been previously demonstrated in patients with cystic fibrosis (CF) and interstitial pneumonia, and in lung-transplant recipients. The present study assessed the serum airway mucin levels in patients with acute respiratory distress syndrome (ARDS). An enzyme-linke...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.156.5.9701061

    authors: Shih JY,Yang SC,Yu CJ,Wu HD,Liaw YS,Wu R,Yang PC

    更新日期:1997-11-01 00:00:00

  • A birth cohort study of subjects at risk of atopy: twenty-two-year follow-up of wheeze and atopic status.

    abstract::This study describes the natural history of atopic and wheezy disorders from birth to adult life in a cohort at risk of atopy. One hundred subjects born in Poole, England, were selected at birth in 1976 on the basis that at least one parent was atopic. Subjects were examined annually in the preschool years, and at the...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.165.2.2104032

    authors: Rhodes HL,Thomas P,Sporik R,Holgate ST,Cogswell JJ

    更新日期:2002-01-15 00:00:00

  • Predictors of successful extubation in neurosurgical patients.

    abstract::A respiratory therapist-driven weaning protocol incorporating daily screens, spontaneous breathing trials (SBT), and prompts to caregivers has been associated with superior outcomes in mechanically ventilated medical patients. To determine the effectiveness of this approach in neurosurgical (NSY) patients, we conducte...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1164/ajrccm.163.3.2003060

    authors: Namen AM,Ely EW,Tatter SB,Case LD,Lucia MA,Smith A,Landry S,Wilson JA,Glazier SS,Branch CL,Kelly DL,Bowton DL,Haponik EF

    更新日期:2001-03-01 00:00:00

  • In vitro performance characteristics of high-frequency oscillatory ventilators.

    abstract::This study aimed to examine the performance characteristics of four high-frequency oscillatory-type ventilators, using an in vitro model of the intubated neonatal respiratory system. Each ventilator was examined across its operative range of settings and at varying model lung compliance (C) and resistance. The oscilla...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.164.6.2005008

    authors: Pillow JJ,Wilkinson MH,Neil HL,Ramsden CA

    更新日期:2001-09-15 00:00:00

  • Procedural skills of practicing pulmonologists. A national survey of 1,000 members of the American College of Physicians.

    abstract::We surveyed pulmonologists to determine which procedures they do in practice, where they learned the procedures, and how much training they recommend to attain and maintain clinical competence in each. We mailed a survey to a random sample of 1,000 members of the American College of Physicians who were identified as p...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.151.2.7842180

    authors: Tape TG,Blank LL,Wigton RS

    更新日期:1995-02-01 00:00:00

  • Tumor necrosis factor-alpha and angiostatin are mediators of endothelial cytotoxicity in bronchoalveolar lavages of patients with acute respiratory distress syndrome.

    abstract::Acute respiratory distress syndrome (ARDS) is characterized by an extensive alveolar capillary leak, permitting contact between intra-alveolar factors and the endothelium. To investigate whether factors contained in the alveolar milieu induce cell death in human lung microvascular endothelial cells, we exposed these c...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.2109004

    authors: Hamacher J,Lucas R,Lijnen HR,Buschke S,Dunant Y,Wendel A,Grau GE,Suter PM,Ricou B

    更新日期:2002-09-01 00:00:00

  • Chlamydophila pneumoniae and Mycoplasma pneumoniae: a role in asthma pathogenesis?

    abstract::The potential role of atypical bacterial infection in the pathogenesis of asthma is a subject of continuing debate. There is an increasing body of literature concerning the association between the atypical bacteria Chlamydophila pneumoniae and Mycoplasma pneumoniae and asthma pathogenesis; however, many studies invest...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章,评审

    doi:10.1164/rccm.200412-1743PP

    authors: Johnston SL,Martin RJ

    更新日期:2005-11-01 00:00:00

  • Inhibition of c-Jun N-terminal kinase limits lipopolysaccharide-induced pulmonary neutrophil influx.

    abstract::The influx of neutrophils into the lung is a sentinel event in LPS-induced acute lung inflammation. Previous studies have shown that systemic inhibition of p38 decreases LPS-induced neutrophil influx into the alveolar space but has no effect on pulmonary parenchymal neutrophil accumulation or on microvascular leak, in...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.200406-712OC

    authors: Arndt PG,Young SK,Lieber JG,Fessler MB,Nick JA,Worthen GS

    更新日期:2005-05-01 00:00:00

  • Skeletal muscle oxidative capacity, fiber type, and metabolites after lung transplantation.

    abstract::Lung transplant (LTx) recipients have a low peak work rate, peak oxygen consumption (V O2peak), and early lactate threshold on incremental exercise. We hypothesized that LTx recipients have reduced oxidative function and altered fiber type proportion in peripheral skeletal muscle. Seven stable LTx recipients and seven...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.160.1.9805092

    authors: Wang XN,Williams TJ,McKenna MJ,Li JL,Fraser SF,Side EA,Snell GI,Walters EH,Carey MF

    更新日期:1999-07-01 00:00:00

  • Effects of sex and of gene variants in constitutive nitric oxide synthases on exhaled nitric oxide.

    abstract::Genetic factors may contribute to the variability of exhaled nitric oxide in healthy individuals. We studied exhaled nitric oxide and genetic variants in both neuronal and endothelial nitric oxide synthases in 105 healthy nonsmoking and smoking subjects. Genomic DNA was screened for a repeat polymorphism in intron 20 ...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.200211-1342OC

    authors: Grasemann H,Storm van's Gravesande K,Buscher R,Drazen JM,Ratjen F

    更新日期:2003-04-15 00:00:00

  • Increased prevalence of post-traumatic stress disorder symptoms in critical care nurses.

    abstract:RATIONALE:Intensive care unit (ICU) nurses work in a demanding environment where they are repetitively exposed to traumatic situations and stressful events. The psychological effects on nurses as a result of working in the ICU are relatively unknown. OBJECTIVE:To determine whether there is an increased prevalence of p...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.200606-735OC

    authors: Mealer ML,Shelton A,Berg B,Rothbaum B,Moss M

    更新日期:2007-04-01 00:00:00

  • The role of immunoglobulin E in allergy and asthma.

    abstract::It has been nearly a century since the first suggestion that a soluble factor in plasma or serum might be responsible for the symptoms of allergic disease and asthma, and more than 30 yr since immunoglobulin E (IgE) was identified as the key molecule in mediating what are now described as type 1 hypersensitivity react...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章,评审

    doi:10.1164/ajrccm.164.supplement_1.2103024

    authors: Platts-Mills TA

    更新日期:2001-10-15 00:00:00

  • The effect of the absence of abdominal muscles on pulmonary function and exercise.

    abstract::In order to determine the long-term sequelae of prune belly syndrome (PBS) and whether the absence of abdominal wall musculature impairs exercise performance we studied nine patients 6 to 31 yr of age with PBS. Conventional spirometry, lung volumes, DLCO, and respiratory muscle strength were measured. A progressive 1-...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.153.4.8616560

    authors: Ewig JM,Griscom NT,Wohl ME

    更新日期:1996-04-01 00:00:00

  • Reference values for dynamic responses to incremental cycle ergometry in males and females aged 20 to 80.

    abstract::Interpretation of incremental cardiopulmonary exercise tests (CPET) might be enhanced by considering the simultaneous rates of change of certain key variables, e.g., Delta oxygen uptake/Delta work rate (Delta VO(2)/Delta WR), Delta heart rate/Delta VO(2) (Delta HR/Delta VO(2)), Delta ventilation/Delta carbon dioxide p...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.164.8.2103007

    authors: Neder JA,Nery LE,Peres C,Whipp BJ

    更新日期:2001-10-15 00:00:00

  • Lung cancer and cryptogenic fibrosing alveolitis. A population-based cohort study.

    abstract::Cryptogenic fibrosing alveolitis has been reported to be associated with an increased risk of lung cancer. However, it has recently become apparent that cigarette smoking may be a risk factor for cryptogenic fibrosing alveolitis as well as for lung cancer, and so may confound the association between these conditions. ...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.161.1.9906062

    authors: Hubbard R,Venn A,Lewis S,Britton J

    更新日期:2000-01-01 00:00:00

  • A candidate gene study of obstructive sleep apnea in European Americans and African Americans.

    abstract:RATIONALE:Obstructive sleep apnea (OSA) is hypothesized to be influenced by genes within pathways involved with obesity, craniofacial development, inflammation, and ventilatory control. OBJECTIVES:We conducted the first candidate gene study of OSA using family data from European Americans and African Americans, select...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.201002-0192OC

    authors: Larkin EK,Patel SR,Goodloe RJ,Li Y,Zhu X,Gray-McGuire C,Adams MD,Redline S

    更新日期:2010-10-01 00:00:00

  • Maximal oxygen uptake and severity of disease in lymphangioleiomyomatosis.

    abstract::Lymphangioleiomyomatosis (LAM), a disease that occurs primarily in women, is characterized by cystic lung lesions causing respiratory failure, which may require lung transplantation. Lung diffusion (DLCO) and/or FEV1 are decreased, but frequently not in parallel with each other. Because cardiopulmonary exercise testin...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.200206-593OC

    authors: Taveira-DaSilva AM,Stylianou MP,Hedin CJ,Kristof AS,Avila NA,Rabel A,Travis WD,Moss J

    更新日期:2003-12-15 00:00:00

  • Dilatation of the constricted human airway by tidal expansion of lung parenchyma.

    abstract:RATIONALE:In the normal lung, breathing and deep inspirations potently antagonize bronchoconstriction, but in the asthmatic lung this salutary effect is substantially attenuated or even reversed. To explain these findings, the prevailing hypothesis focuses on contracting airway smooth muscle and posits a nonlinear dyna...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.201202-0368OC

    authors: Lavoie TL,Krishnan R,Siegel HR,Maston ED,Fredberg JJ,Solway J,Dowell ML

    更新日期:2012-08-01 00:00:00

  • Lung alkaline phosphatase as a marker of fibrosis in chronic interstitial disorders.

    abstract::Alkaline phosphatase (ALP) in lung lavage fluids is a marker of tissue damage and type II cell proliferation. Type II pneumocytes are extensively involved in fibrosis. The aim of our study was to verify whether local ALP activity can be held as a marker of fibrosis in chronic interstitial lung disorders. ALP was deter...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.155.1.9001320

    authors: Capelli A,Lusuardi M,Cerutti CG,Donner CF

    更新日期:1997-01-01 00:00:00

  • Acute effects of exercise on cognition in patients with chronic obstructive pulmonary disease.

    abstract::Prior data indicate positive effects of long-term exercise interventions for cognitive functioning among patients with chronic obstructive pulmonary disease (COPD), but no prior studies have examined acute effects of individual bouts of exercise among patients with COPD. This study evaluated acute effects of exercise ...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 临床试验,杂志文章,随机对照试验

    doi:10.1164/ajrccm.164.9.2104137

    authors: Emery CF,Honn VJ,Frid DJ,Lebowitz KR,Diaz PT

    更新日期:2001-11-01 00:00:00

  • Compartmentalized IL-8 and elastase release within the human lung in unilateral pneumonia.

    abstract::Because interleukin 8 (IL-8) is a potent neutrophil chemotactic and activating cytokine, we investigated IL-8 production in relation to neutrophil migration and elastase release in the human lung during unilateral community-acquired pneumonia (CAP). In 17 patients, the local response in the involved lung was compared ...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.153.1.8542140

    authors: Boutten A,Dehoux MS,Seta N,Ostinelli J,Venembre P,Crestani B,Dombret MC,Durand G,Aubier M

    更新日期:1996-01-01 00:00:00

  • Persistent endothelial dysfunction in humans after diesel exhaust inhalation.

    abstract:RATIONALE:Exposure to combustion-derived air pollution is associated with an early (1-2 h) and sustained (24 h) rise in cardiovascular morbidity and mortality. We have previously demonstrated that inhalation of diesel exhaust causes an immediate (within 2 h) impairment of vascular and endothelial function in humans. O...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章,随机对照试验

    doi:10.1164/rccm.200606-872OC

    authors: Törnqvist H,Mills NL,Gonzalez M,Miller MR,Robinson SD,Megson IL,Macnee W,Donaldson K,Söderberg S,Newby DE,Sandström T,Blomberg A

    更新日期:2007-08-15 00:00:00

  • House dust endotoxin and wheeze in the first year of life.

    abstract::We examined endotoxin exposure and wheezing episodes during the first year of life in a birth cohort of 499 infants with one or both parents having a history of asthma or allergy. We measured endotoxin in settled dust from the baby's bed, bedroom floor, family room, and kitchen floor within the first 3 mo after birth....

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.163.2.2002088

    authors: Park JH,Gold DR,Spiegelman DL,Burge HA,Milton DK

    更新日期:2001-02-01 00:00:00

  • Reactive oxygen species regulate neutrophil recruitment and survival in pneumococcal pneumonia.

    abstract:RATIONALE:The role of NADPH oxidase activation in pneumonia is complex because reactive oxygen species contribute to both microbial killing and regulation of the acute pulmonary infiltrate. The relative importance of each role remains poorly defined in community-acquired pneumonia. OBJECTIVES:We evaluated the contribu...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.200707-990OC

    authors: Marriott HM,Jackson LE,Wilkinson TS,Simpson AJ,Mitchell TJ,Buttle DJ,Cross SS,Ince PG,Hellewell PG,Whyte MK,Dockrell DH

    更新日期:2008-04-15 00:00:00

  • Rhinovirus disrupts the barrier function of polarized airway epithelial cells.

    abstract:RATIONALE:Secondary bacterial infection following rhinovirus (RV) infection has been recognized in chronic obstructive pulmonary disease. OBJECTIVES:We sought to understand mechanisms by which RV infection facilitates secondary bacterial infection. METHODS:Primary human airway epithelial cells grown at air-liquid int...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.200801-136OC

    authors: Sajjan U,Wang Q,Zhao Y,Gruenert DC,Hershenson MB

    更新日期:2008-12-15 00:00:00