Activin-A overexpression in the murine lung causes pathology that simulates acute respiratory distress syndrome.

Abstract:

RATIONALE:Activin-A is up-regulated in various respiratory disorders. However, its precise role in pulmonary pathophysiology has not been adequately substantiated in vivo. OBJECTIVES:To investigate in vivo the consequences of dysregulated Activin-A expression in the lung and identify key Activin-A-induced processes that contribute to respiratory pathology. METHODS:Activin-A was ectopically expressed in murine lung, and functional, structural, and molecular alterations were extensively analyzed. The validity of Activin-A as a therapeutic target was demonstrated in animals overexpressing Activin-A or treated with intratracheal instillation of LPS. Relevancy to human pathology was substantiated by demonstrating high Activin-A levels in bronchoalveolar lavage (BAL) samples from patients with acute respiratory distress syndrome (ARDS). MEASUREMENTS AND MAIN RESULTS:Overexpression of Activin-A in mouse airways caused pulmonary pathology reminiscent of acute lung injury (ALI)/ARDS. Activin-A triggered a lasting inflammatory response characterized by acute alveolar cell death and hyaline membrane formation, sustained up-regulation of high-mobility group box 1, development of systemic hypercoagulant state, reduction of surfactant proteins SpC, SpB, and SpA, decline of lung compliance, transient fibrosis, and eventually emphysema. Therapeutic neutralization of Activin-A attenuated the ALI/ARDS-like pathology induced either by ectopic expression of Activin-A or by intratracheal instillation of LPS. In line with the similarity of the Activin-A-induced phenotype to human ARDS, selective up-regulation of Activin-A was found in BAL of patients with ARDS. CONCLUSIONS:Our studies demonstrate for the first time in vivo the pathogenic consequences of deregulated Activin-A expression in the lung, document novel aspects of Activin-A biology that provide mechanistic explanation for the observed phenotype, link Activin-A to ALI/ARDS pathophysiology, and provide the rationale for therapeutic targeting of Activin-A in these disorders.

authors

Apostolou E,Stavropoulos A,Sountoulidis A,Xirakia C,Giaglis S,Protopapadakis E,Ritis K,Mentzelopoulos S,Pasternack A,Foster M,Ritvos O,Tzelepis GE,Andreakos E,Sideras P

doi

10.1164/rccm.201105-0784OC

subject

Has Abstract

pub_date

2012-02-15 00:00:00

pages

382-91

issue

4

eissn

1073-449X

issn

1535-4970

pii

201105-0784OC

journal_volume

185

pub_type

杂志文章
  • Helper T cell type 1 and 2 cytokines regulate C-C chemokine expression in mouse pleural mesothelial cells.

    abstract::The recruitment of leukocytes to an area of injury or inflammation site is one of the most fundamental host defenses. Pulmonary tuberculosis is characterized by granulomatous inflammation with an extensive infiltration of mononuclear cells. In tuberculous pleurisy pleural mesothelial cells are exposed to mycobacteria ...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.159.5.9810011

    authors: Mohammed KA,Nasreen N,Ward MJ,Antony VB

    更新日期:1999-05-01 00:00:00

  • Localization of insulin-like growth factor-I in lung tissues of patients with fibroproliferative acute respiratory distress syndrome.

    abstract::Insulin-like growth factor-I (IGF-I) is elevated in human fibrotic lung diseases and in animal models of pulmonary fibrosis, implicating IGF-I in the pathogenesis of fibrotic lung disease. We questioned whether IGF-I protein levels were enhanced in fibroproliferative acute respiratory distress syndrome (FP-ARDS). Seri...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.2201012

    authors: Krein PM,Sabatini PJ,Tinmouth W,Green FH,Winston BW

    更新日期:2003-01-01 00:00:00

  • Morning levels of C-reactive protein in children with obstructive sleep-disordered breathing.

    abstract::Obstructive sleep-disordered breathing is associated with cardiovascular disease in adults, and elevated C-reactive protein (CRP) has been proposed as a link between the two disorders. We hypothesized that children with sleep-disordered breathing have higher CRP values than do control subjects. CRP was measured in 39 ...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.200407-928OC

    authors: Kaditis AG,Alexopoulos EI,Kalampouka E,Kostadima E,Germenis A,Zintzaras E,Gourgoulianis K

    更新日期:2005-02-01 00:00:00

  • Nutritional status and mortality in chronic obstructive pulmonary disease.

    abstract::The role of nutritional status in the prognosis of subjects with severe chronic obstructive pulmonary disease was studied in a cohort of Canadian men and women followed for 3 to 5 yr. A total of 348 subjects who were recruited for a study of negative pressure ventilation were evaluated for lung function and body weigh...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.153.3.8630580

    authors: Gray-Donald K,Gibbons L,Shapiro SH,Macklem PT,Martin JG

    更新日期:1996-03-01 00:00:00

  • Computed tomography findings in acute exacerbation of idiopathic pulmonary fibrosis.

    abstract:RATIONALE:The serial computed tomography findings and prognosis of the acute exacerbation of idiopathic pulmonary fibrosis (IPF) are not yet well defined in a larger number of cases. OBJECTIVES:To evaluate the parenchymal abnormalities and prognosis using high-resolution computed tomography (HRCT) in acute exacerbatio...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.200709-1365OC

    authors: Akira M,Kozuka T,Yamamoto S,Sakatani M

    更新日期:2008-08-15 00:00:00

  • Micro-Computed Tomography Comparison of Preterminal Bronchioles in Centrilobular and Panlobular Emphysema.

    abstract:RATIONALE:Very little is known about airways that are too small to be visible on thoracic multidetector computed tomography but larger than the terminal bronchioles. OBJECTIVES:To examine the structure of preterminal bronchioles located one generation proximal to terminal bronchioles in centrilobular and panlobular em...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.201602-0278OC

    authors: Tanabe N,Vasilescu DM,McDonough JE,Kinose D,Suzuki M,Cooper JD,Paré PD,Hogg JC

    更新日期:2017-03-01 00:00:00

  • Bronchoalveolar lavage alterations in pulmonary embolism.

    abstract::The objective of this study was to determine quantitative and qualitative surfactant alterations, proteins, and platelet activating factor (PAF) in bronchoalveolar lavage (BAL) fluid from patients with pulmonary thromboembolism (PTE) with respect to ventilated patients without PTE. Patients with PTE underwent BAL at t...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.158.5.9802036

    authors: Nakos G,Kitsiouli EI,Lekka ME

    更新日期:1998-11-01 00:00:00

  • Interleukin 5 is protective during sepsis in an eosinophil-independent manner.

    abstract:RATIONALE:The immune response in sepsis is characterized by overt immune dysfunction. Studies indicate immunostimulation represents a viable therapy for patients. One study suggests a potentially protective role for interleukin 5 (IL-5) in sepsis; however, the loss of eosinophils in this disease presents a paradox. OB...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.201201-0134OC

    authors: Linch SN,Danielson ET,Kelly AM,Tamakawa RA,Lee JJ,Gold JA

    更新日期:2012-08-01 00:00:00

  • Leukocyte activation and flow behavior in rat skeletal muscle in sepsis.

    abstract::In animal models of endotoxemia, sepsis is associated with the accumulation of leukocytes and altered microvascular perfusion. In order to test the hypothesis that bacterial sepsis upregulates leukocyte-endothelial adhesion, we used intravital microscopy to examine the flow behavior of leukocytes in the postcapillary ...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.157.1.9609012

    authors: Piper RD,Pitt-Hyde ML,Anderson LA,Sibbald WJ,Potter RF

    更新日期:1998-01-01 00:00:00

  • Transfusion-related acute lung injury in the critically ill: prospective nested case-control study.

    abstract:RATIONALE:Acute lung injury (ALI) that develops 6 hours after transfusion (TRALI) is the leading cause of transfusion-related mortality. Several transfusion characteristics have been postulated as risk factors for TRALI, but the evidence is limited to retrospective studies. OBJECTIVES:To compare patient and transfusio...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.200702-271OC

    authors: Gajic O,Rana R,Winters JL,Yilmaz M,Mendez JL,Rickman OB,O'Byrne MM,Evenson LK,Malinchoc M,DeGoey SR,Afessa B,Hubmayr RD,Moore SB

    更新日期:2007-11-01 00:00:00

  • Characterization of a single nucleotide polymorphism in the lipopolysaccharide binding protein and its association with sepsis.

    abstract::We sought to characterize polymorphisms in the proximal coding region of the lipopolysaccharide binding protein gene and to determine whether a previously reported variant was associated with sepsis complicated by organ failure or shock after trauma. We used multiple analytical methods, including pyrosequencing, restr...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.200209-1064OC

    authors: Barber RC,O'Keefe GE

    更新日期:2003-05-15 00:00:00

  • CC chemokine receptor gene polymorphisms in Czech patients with pulmonary sarcoidosis.

    abstract::Genes for the chemokine receptors CCR5 and CCR2 are characterized by polymorphisms resulting in a nonfunctional receptor expression. Ligands for CCR2 and CCR5 (chemokines monocyte chemotactic protein-1 [MCP-1] and RANTES) are implicated in the pathogenesis of sarcoidosis. We have, therefore, analyzed polymorphisms of ...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.162.3.2001022

    authors: Petrek M,Drábek J,Kolek V,Zlámal J,Welsh KI,Bunce M,Weigl E,Du Bois R

    更新日期:2000-09-01 00:00:00

  • Exhaled 8-isoprostane as an in vivo biomarker of lung oxidative stress in patients with COPD and healthy smokers.

    abstract::Most of the studies linking chronic obstructive pulmonary disease (COPD) with oxidative stress are in vitro, using invasive techniques, or measuring systemic oxidative stress. The aim of this study was to quantify oxidative stress in the lungs in patients with COPD and in healthy smokers, as reflected by 8-isoprostane...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.162.3.2001063

    authors: Montuschi P,Collins JV,Ciabattoni G,Lazzeri N,Corradi M,Kharitonov SA,Barnes PJ

    更新日期:2000-09-01 00:00:00

  • Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program.

    abstract:RATIONALE:The Severe Asthma Research Program cohort includes subjects with persistent asthma who have undergone detailed phenotypic characterization. Previous univariate methods compared features of mild, moderate, and severe asthma. OBJECTIVES:To identify novel asthma phenotypes using an unsupervised hierarchical clu...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.200906-0896OC

    authors: Moore WC,Meyers DA,Wenzel SE,Teague WG,Li H,Li X,D'Agostino R Jr,Castro M,Curran-Everett D,Fitzpatrick AM,Gaston B,Jarjour NN,Sorkness R,Calhoun WJ,Chung KF,Comhair SA,Dweik RA,Israel E,Peters SP,Busse WW,Erzurum

    更新日期:2010-02-15 00:00:00

  • Exhaustive treadmill exercise does not reduce twitch transdiaphragmatic pressure in patients with COPD.

    abstract::Reduced diaphragm contractility has been described in normal subjects after whole body endurance exercise, and it indicates low frequency fatigue (LFF); it is unknown whether LFF is of clinical importance. We therefore studied the effect of treadmill exercise to exhaustion on diaphragm contractility in six patients wi...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.152.3.7663810

    authors: Polkey MI,Kyroussis D,Keilty SE,Hamnegard CH,Mills GH,Green M,Moxham J

    更新日期:1995-09-01 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

  • The bactericidal activity of moxifloxacin in patients with pulmonary tuberculosis.

    abstract::Patients in whom acid-fast bacilli smear-positive pulmonary tuberculosis was newly diagnosed were randomized to receive 400 mg moxifloxacin, 300 mg isonaizid, or 600 mg rifampin daily for 5 days. Sixteen-hour overnight sputa collections were made for the 2 days before and for 5 days of monotherapy. Bactericidal activi...

    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/rccm.200305-682OC

    authors: Gosling RD,Uiso LO,Sam NE,Bongard E,Kanduma EG,Nyindo M,Morris RW,Gillespie SH

    更新日期:2003-12-01 00:00:00

  • Macronutrients during pregnancy and life-threatening respiratory syncytial virus infections in children.

    abstract:RATIONALE:Respiratory syncytial virus (RSV) is an important cause of hospitalization and death in infants worldwide. Most RSV deaths occur in developing countries, where burden and risk factors for life-threatening illness are unclear. OBJECTIVES:We defined the burden of life-threatening (O(2) saturation [O(2) sat] ≤ ...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.201301-0016OC

    authors: Ferolla FM,Hijano DR,Acosta PL,Rodríguez A,Dueñas K,Sancilio A,Barboza E,Caría A,Gago GF,Almeida RE,Castro L,Pozzolo C,Martínez MV,Grimaldi LA,Rebec B,Calvo M,Henrichsen J,Nocito C,González M,Barbero G,Losada JV,

    更新日期:2013-05-01 00:00:00

  • Multicenter Comparison of Lung and Oral Microbiomes of HIV-infected and HIV-uninfected Individuals.

    abstract:RATIONALE:Improved understanding of the lung microbiome in HIV-infected individuals could lead to better strategies for diagnosis, therapy, and prophylaxis of HIV-associated pneumonias. Differences in the oral and lung microbiomes in HIV-infected and HIV-uninfected individuals are not well defined. Whether highly activ...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章,多中心研究

    doi:10.1164/rccm.201501-0128OC

    authors: Beck JM,Schloss PD,Venkataraman A,Twigg H 3rd,Jablonski KA,Bushman FD,Campbell TB,Charlson ES,Collman RG,Crothers K,Curtis JL,Drews KL,Flores SC,Fontenot AP,Foulkes MA,Frank I,Ghedin E,Huang L,Lynch SV,Morris A,Pa

    更新日期:2015-12-01 00:00:00

  • Evaluation of continuous positive airway pressure therapy on renin-angiotensin system activity in obstructive sleep apnea.

    abstract:RATIONALE:Obstructive sleep apnea (OSA) has been associated with kidney function loss, which may be related to changes in the renin-angiotensin system (RAS). OBJECTIVES:We sought to determine the effect of continuous positive airway pressure (CPAP) of patients with OSA on renal hemodynamics at baseline and in response...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 临床试验,杂志文章

    doi:10.1164/rccm.201403-0526OC

    authors: Nicholl DD,Hanly PJ,Poulin MJ,Handley GB,Hemmelgarn BR,Sola DY,Ahmed SB

    更新日期:2014-09-01 00:00:00

  • Airway inflammation in childhood asthma.

    abstract::Airway pathology has been extensively investigated in adulthood asthma, whereas only few studies examined bronchial biopsies in childhood asthma. To evaluate the airway pathology in children with asthma, we analyzed bronchial biopsies obtained from 23 children undergoing bronchoscopy for clinical indications other tha...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.200305-650OC

    authors: Barbato A,Turato G,Baraldo S,Bazzan E,Calabrese F,Tura M,Zuin R,Beghe B,Maestrelli P,Fabbri LM,Saetta M

    更新日期:2003-10-01 00:00:00

  • Pivotal role of anionic phospholipids in determining dynamic behavior of lung surfactant.

    abstract::Phosphatidylglycerol (PG) and phosphatidylinositol (PI) are anionic phospholipids (APLs) present in lung surfactant of virtually all species studied, although their specific contribution to function is unknown. This study examines how APLs influence surfactant monolayer stability and adsorption under static and dynami...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.161.3.9903048

    authors: Ingenito EP,Mora R,Mark L

    更新日期:2000-03-01 00:00:00

  • Comparison of an interferon-gamma release assay with tuberculin skin testing in HIV-infected individuals.

    abstract:RATIONALE:Although interferon (IFN)-gamma release assays are approved for the diagnosis of latent tuberculosis infection (LTBI), limited data exist regarding their performance in HIV infection. OBJECTIVES:To compare tuberculin skin test (TST) results to the commercial IFN-gamma release assay QuantiFERON-TB Gold In-Tub...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 临床试验,杂志文章

    doi:10.1164/rccm.200608-1088OC

    authors: Luetkemeyer AF,Charlebois ED,Flores LL,Bangsberg DR,Deeks SG,Martin JN,Havlir DV

    更新日期:2007-04-01 00:00:00

  • Endothelin-1 receptor density, distribution, and function in human isolated asthmatic airways.

    abstract::The potent bronchoconstrictor and mitogenic actions of the peptide endothelin-1 (ET-1) on airway smooth muscle may contribute significantly to the bronchial obstruction observed in asthma. However, the status of the receptor-effector systems that mediate these actions of ET-1 in asthmatic airways is currently unknown....

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.152.5.7582310

    authors: Goldie RG,Henry PJ,Knott PG,Self GJ,Luttmann MA,Hay DW

    更新日期:1995-11-01 00:00:00

  • Nasal mask pressure waveform and inspiratory muscle rest during nasal assisted ventilation.

    abstract::In mechanically ventilated patients, pressure and flow tracings can be used to assess respiratory pump muscle activity or rest. When the ventilation is delivered through an endotracheal tube, the respiratory system can be considered a one-compartment model, and activation of the respiratory muscles results in deformat...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.155.6.9196120

    authors: Jounieaux V,Parreira VF,Delguste P,Aubert G,Rodenstein DO

    更新日期:1997-06-01 00:00:00

  • Muscle size and cardiorespiratory response to exercise in cystic fibrosis.

    abstract::The mechanism responsible for diminished exercise performance in cystic fibrosis (CF) is not clear. We hypothesized that reduced muscle size, rather than an intrinsic muscle defect, was the primary factor in such diminished exercise performance. Twenty-two subjects with CF (14 females and eight males, aged 6.5 to 17.7...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.162.5.2003057

    authors: Moser C,Tirakitsoontorn P,Nussbaum E,Newcomb R,Cooper DM

    更新日期:2000-11-01 00:00:00

  • Exhaled nitric oxide decreases during exercise-induced bronchoconstriction in children with asthma.

    abstract::Nitric oxide (NO) produced in the airways can be either detrimental or protective to the host. To investigate the role of NO in the pathogenesis of exercise-induced bronchoconstriction (EIB), we measured exhaled NO (ENO) after exercise challenge in 39 asthmatic and six normal children. FEV(1) and ENO were measured bef...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.164.10.2009105

    authors: Terada A,Fujisawa T,Togashi K,Miyazaki T,Katsumata H,Atsuta J,Iguchi K,Kamiya H,Togari H

    更新日期:2001-11-15 00:00:00

  • Active detection of chronic obstructive pulmonary disease and asthma in the general population. Results and economic consequences of the DIMCA program.

    abstract::The aim of this prospective study was to detect subjects in the general population with objective signs of chronic obstructive pulmonary disease (COPD) or asthma at an early stage. This was done by means of a two-stage protocol involving screening and a subsequent 2-yr monitoring of all subjects with positive results ...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/ajrccm.158.6.9709003

    authors: van den Boom G,van Schayck CP,van Möllen MP,Tirimanna PR,den Otter JJ,van Grunsven PM,Buitendijk MJ,van Herwaarden CL,van Weel C

    更新日期:1998-12-01 00:00:00

  • Changing demographics, epidemiology, and survival of incident pulmonary arterial hypertension: results from the pulmonary hypertension registry of the United Kingdom and Ireland.

    abstract:RATIONALE:Incident pulmonary arterial hypertension was underrepresented in most pulmonary hypertension registries and may have a different disease profile to prevalent disease. OBJECTIVES:To determine the characteristics and outcome of a purely incident, treatment-naive cohort of idiopathic, heritable, and anorexigen-...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章

    doi:10.1164/rccm.201203-0383OC

    authors: Ling Y,Johnson MK,Kiely DG,Condliffe R,Elliot CA,Gibbs JS,Howard LS,Pepke-Zaba J,Sheares KK,Corris PA,Fisher AJ,Lordan JL,Gaine S,Coghlan JG,Wort SJ,Gatzoulis MA,Peacock AJ

    更新日期:2012-10-15 00:00:00

  • The effect of insurance status on mortality and procedural use in critically ill patients.

    abstract:RATIONALE:Lack of health insurance maybe an independent risk factor for mortality and differential treatment in critical illness. OBJECTIVES:To determine whether uninsured critically ill patients had differences in 30-day mortality and critical care service use compared with those with private insurance and to determi...

    journal_title:American journal of respiratory and critical care medicine

    pub_type: 杂志文章,多中心研究

    doi:10.1164/rccm.201101-0089OC

    authors: Lyon SM,Benson NM,Cooke CR,Iwashyna TJ,Ratcliffe SJ,Kahn JM

    更新日期:2011-10-01 00:00:00