Abstract:
RATIONALE:Pulmonary Alveolar Proteinosis (PAP) patients exhibit an acquired deficiency of biologically active granulocyte-macrophage colony stimulating factor (GM-CSF) attributable to GM-CSF specific autoantibodies. PAP alveolar macrophages are foamy, lipid-filled cells with impaired surfactant clearance and markedly reduced expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPARγ) and the PPARγ-regulated ATP binding cassette (ABC) lipid transporter, ABCG1. An open label proof of concept Phase II clinical trial was conducted in PAP patients using rituximab, a chimeric murine-human monoclonal antibody directed against B lymphocyte specific antigen CD20. Rituximab treatment decreased anti-GM-CSF antibody levels in bronchoalveolar lavage (BAL) fluid, and 7/9 patients completing the trial demonstrated clinical improvement as measured by arterial blood oxygenation. OBJECTIVES:This study sought to determine whether rituximab therapy would restore lipid metabolism in PAP alveolar macrophages. METHODS:BAL samples were collected from patients pre- and 6-months post-rituximab infusion for evaluation of mRNA and lipid changes. RESULTS:Mean PPARγ and ABCG1 mRNA expression increased 2.8 and 5.3-fold respectively (p ≤ 0.05) after treatment. Lysosomal phospholipase A2 (LPLA2) (a key enzyme in surfactant degradation) mRNA expression was severely deficient in PAP patients pre-treatment but increased 2.8-fold post-treatment. In supplemental animal studies, LPLA2 deficiency was verified in GM-CSF KO mice but was not present in macrophage-specific PPARγ KO mice compared to wild-type controls. Oil Red O intensity of PAP alveolar macrophages decreased after treatment, indicating reduced intracellular lipid while extracellular free cholesterol increased in BAL fluid. Furthermore, total protein and Surfactant protein A were significantly decreased in the BAL fluid post therapy. CONCLUSIONS:Reduction in GM-CSF autoantibodies by rituximab therapy improves alveolar macrophage lipid metabolism by increasing lipid transport and surfactant catabolism. Mechanisms may involve GM-CSF stimulation of alveolar macrophage ABCG1 and LPLA2 activities by distinct pathways.
journal_name
Respir Resjournal_title
Respiratory researchauthors
Malur A,Kavuru MS,Marshall I,Barna BP,Huizar I,Karnekar R,Thomassen MJdoi
10.1186/1465-9921-13-46subject
Has Abstractpub_date
2012-06-14 00:00:00pages
46eissn
1465-9921issn
1465-993Xpii
1465-9921-13-46journal_volume
13pub_type
临床试验,杂志文章abstract:BACKGROUND:Prior microrheologic assessments of selected, microlitre plugs of cystic fibrosis (CF) sputum suggest no intrinsic rheologic abnormality. However, such analyses may not be representative of CF sputum as a whole. We therefore reassessed this question using whole sputum macrorheology. Additionally, we wished t...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-10-63
更新日期:2009-07-06 00:00:00
abstract:BACKGROUND:Genetic variation may underlie phenotypic variation in chronic obstructive pulmonary disease (COPD) in subjects with and without alpha 1 antitrypsin deficiency (AATD). Genotype specific sub-phenotypes are likely and may underlie the poor replication of previous genetic studies. This study investigated subjec...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-9-52
更新日期:2008-07-11 00:00:00
abstract::Respiratory diseases including asthma and chronic obstructive pulmonary disease (COPD) are characterised by excessive and persistent inflammation. Current treatments are often inadequate for symptom and disease control, and hence new therapies are warranted. Recent emerging research has implicated dyslipidaemia in pul...
journal_title:Respiratory research
pub_type: 杂志文章,评审
doi:10.1186/s12931-017-0526-9
更新日期:2017-02-28 00:00:00
abstract::The role of autoimmunity targeting epithelial antigens in asthma has been suggested, in particular in non-atopic and severe asthma. Periplakin, a desmosomal component, is involved in epithelial cohesion and intracellular signaling. We detected anti-periplakin IgG antibodies in 47/260 (18 %) patients with asthma, with ...
journal_title:Respiratory research
pub_type: 信件
doi:10.1186/s12931-016-0441-5
更新日期:2016-10-07 00:00:00
abstract:BACKGROUND:Airway absorption and bioavailability of inhaled corticosteroids (ICSs) may be influenced by differences in pharmacokinetic properties such as lipophilicity and patient characteristics such as lung function. This study aimed to further investigate and clarify the distribution of budesonide and fluticasone in...
journal_title:Respiratory research
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1186/1465-9921-10-104
更新日期:2009-10-31 00:00:00
abstract:BACKGROUND:The coexistence of COPD and asthma is widely recognized but has not been well described. This study characterizes clinical features, spirometry, and chest CT scans of smoking subjects with both COPD and asthma. METHODS:We performed a cross-sectional study comparing subjects with COPD and asthma to subjects ...
journal_title:Respiratory research
pub_type: 临床试验,杂志文章,多中心研究
doi:10.1186/1465-9921-12-127
更新日期:2011-09-27 00:00:00
abstract:BACKGROUND:Tracheal epithelial cells are anchored to a dynamic basement membrane that contains a variety of extracellular matrix proteins including collagens and laminins. During development, wound repair and disease of the airway epithelium, significant changes in extracellular matrix proteins may directly affect cell...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-7-105
更新日期:2006-08-02 00:00:00
abstract::The hygiene hypothesis states that childhood asthma develops as a result of decreased exposure to infectious agents during infancy and early childhood. This results in the persistence of the neonatal T helper lymphocyte 2 immunophenotype, thereby predisposing the child to atopic disease. While multiple studies support...
journal_title:Respiratory research
pub_type: 杂志文章,评审
doi:10.1186/rr81
更新日期:2001-01-01 00:00:00
abstract:BACKGROUND:Acute respiratory distress syndrome (ARDS) can have various causes. The study objective was to investigate whether different pathophysiologic models of ARDS would show different respiratory, cardiovascular and inflammatory outcomes. METHODS:We performed a prospective, randomized study in 27 ventilated ewes ...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-020-01475-0
更新日期:2020-08-08 00:00:00
abstract:BACKGROUND:To identify COPD associated gene susceptibility and lung function in a longitudinal cohort including COPD and subjects who were at risk for developing COPD, and to replicate this in two cross-sectional and longitudinal populations in Chinese Han population. METHODS:Three cohorts were recruited in this study...
journal_title:Respiratory research
pub_type: 杂志文章,多中心研究
doi:10.1186/s12931-015-0209-3
更新日期:2015-04-18 00:00:00
abstract:BACKGROUND:β2 receptor agonists induce airway smooth muscle relaxation by increasing intracellular cAMP production. PKA is the traditional downstream signaling pathway of cAMP. Exchange protein directly activated by cAMP (Epac) was identified as another important signaling molecule of cAMP recently. The role of Epac in...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-019-1260-2
更新日期:2019-12-18 00:00:00
abstract:BACKGROUND:Human beta-defensin-4 (hBD-4), a new member of the beta-defensin family, was discovered by an analysis of the genomic sequence. The objective of this study was to clarify hBD-4 expression in human lung tissue, along with the inducible expression in response to infectious stimuli, localization, and antimicrob...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-6-130
更新日期:2005-11-04 00:00:00
abstract:BACKGROUND:Acute respiratory distress syndrome (ARDS) is a severe form of lung injury characterized by damage to the epithelial barrier with subsequent pulmonary edema and hypoxic respiratory failure. ARDS is a significant medical problem in intensive care units with associated high care costs. There are many potential...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-018-0856-2
更新日期:2018-08-22 00:00:00
abstract:BACKGROUND:Identifying genetic determinants for lung function is important in providing insight into the pathophysiology of asthma. Signal transducer and activator of transcription 3 is a transcription factor latent in the cytoplasm; the gene (STAT3) is activated by a wide range of cytokines, and may play a role in lun...
journal_title:Respiratory research
pub_type: 杂志文章,随机对照试验
doi:10.1186/1465-9921-6-52
更新日期:2005-06-03 00:00:00
abstract::The molecular mechanisms of Idiopathic Pulmonary Fibrosis (IPF) remain elusive. Transforming Growth Factor beta 1(TGF-beta1) is a key effector cytokine in the development of lung fibrosis. We used microarray and computational biology strategies to identify genes whose expression is significantly altered in alveolar ep...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-7-114
更新日期:2006-09-01 00:00:00
abstract:BACKGROUND:Dual bronchodilator therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD). There are limited data on effects of a combination of two long-acting bronchodilators on lung function including body plethysmography. METHODS:This multicentre, randomised, double-blind, si...
journal_title:Respiratory research
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1186/s12931-016-0498-1
更新日期:2017-01-11 00:00:00
abstract:BACKGROUND:Inhaled furosemide offers a potentially novel treatment for dyspnoea, which may reflect modulation of pulmonary stretch receptor feedback to the brain. Specificity of relief is unclear because different neural pathways may account for different components of clinical dyspnoea. Our objective was to evaluate i...
journal_title:Respiratory research
pub_type: 杂志文章,随机对照试验
doi:10.1186/s12931-018-0886-9
更新日期:2018-09-20 00:00:00
abstract:OBJECTIVE:To investigate the differences in the proportions of BMPR2 mutations in familial hereditary pulmonary arterial hypertension (HPAH) and idiopathic pulmonary arterial hypertension (IPAH) between males and females and the relationship between BMPR2 mutation and PAH severity. METHODS:A computer was used to searc...
journal_title:Respiratory research
pub_type: 杂志文章,meta分析
doi:10.1186/s12931-020-1309-2
更新日期:2020-02-06 00:00:00
abstract::Over the past decade there has been a significant shift to the use of murine models for investigations into the molecular basis of respiratory diseases, including asthma and chronic obstructive pulmonary disease. These models offer the exciting prospect of dissecting the complex interaction between cytokines, chemokin...
journal_title:Respiratory research
pub_type: 杂志文章,评审
doi:10.1186/rr17
更新日期:2000-01-01 00:00:00
abstract:BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease course. The recent advancement of antifibrotic therapy has increased the need for reliable and specific biomarkers. This study aimed to assess alveolar epithelial biomarkers as predictors for the efficacy of the anti...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-020-01582-y
更新日期:2020-11-30 00:00:00
abstract:: ...
journal_title:Respiratory research
pub_type:
doi:10.1186/s12931-018-0930-9
更新日期:2018-12-20 00:00:00
abstract:BACKGROUND:Recent research has suggested that the Th1 and Th2 chemokine/cytokine axis contributes to the development of chronic hypersensitivity pneumonitis (HP). Acute exacerbations (AE) are significant factors in the prognosis of chronic HP. Little is known, however, about these biomarkers in association with AE in c...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-14-57
更新日期:2013-05-25 00:00:00
abstract:BACKGROUND:Little is known about the factors associated with CT-quantified emphysema progression in heavy smokers. The objective of this study was to investigate the effect of length of smoking cessation and clinical / demographical factors on the rate of emphysema progression and FEV1-decline in male heavy smokers. M...
journal_title:Respiratory research
pub_type: 杂志文章,随机对照试验
doi:10.1186/1465-9921-14-55
更新日期:2013-05-20 00:00:00
abstract:BACKGROUND:Surfactant protein D (SP-D) and Mannose Binding Lectin (MBL) are collectins that have opsonic and immunoregulatory functions, are found in lung fluid and interact with the human immunodeficiency virus (HIV). We compared collectin levels in lung fluid and serum from HIV infected and normal subjects to determi...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-8-42
更新日期:2007-06-13 00:00:00
abstract:BACKGROUND:Generally, structural destruction of lung parenchyma, such as pulmonary emphysema, is considered to be related to the low diagnostic yields and high complication rates of lung biopsies of peripheral lung lesions. Currently, little is known about the clinical outcomes of using endobronchial ultrasound with a ...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-019-1149-0
更新日期:2019-08-06 00:00:00
abstract:BACKGROUND:An imbalance in the generation of pro-inflammatory leukotrienes, and counter-regulatory lipoxins is present in severe asthma. We measured leukotriene B4 (LTB4), and lipoxin A4 (LXA4) production by alveolar macrophages (AMs) and studied the impact of corticosteroids. METHODS:AMs obtained by fiberoptic bronch...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-11-71
更新日期:2010-06-07 00:00:00
abstract:BACKGROUND:The aim of the study is to examine the effect of limited and prolonged hyperoxia on neonatal rat lung. This is done by examining the morphologic changes of apoptosis, the expression of ceramide, an important mediator of apoptosis, the expression of inflammatory mediators represented by IL-1beta and the expre...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-7-100
更新日期:2006-07-26 00:00:00
abstract::The aim was to compare the diagnosis of COPD among smokers according to different international guidelines and to compare the outcome when using slow (SVC) and forced vital capacity (FVC). In order to find current smokers a questionnaire was sent to persons who had been on sick leave for more than two weeks. Those who...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/1465-9921-8-89
更新日期:2007-12-04 00:00:00
abstract:BACKGROUND:It has been confirmed that NF-κB p65 signaling pathway is involved in the regulation of alveolar hypercoagulation and fibrinolysis inhibition in acute respiratory distress syndrome (ARDS). Whether SN50, a NF-κB cell permeable inhibitor, could attenuate alveolar hypercoagulation and fibrinolysis inhibition in...
journal_title:Respiratory research
pub_type: 杂志文章
doi:10.1186/s12931-020-01372-6
更新日期:2020-05-27 00:00:00
abstract:BACKGROUND:There is considerable heterogeneity in the rate of lung function decline in chronic obstructive pulmonary disease (COPD), the determinants of which are largely unknown. Observational studies in COPD indicate that low body mass index (BMI) is associated with worse outcomes, and overweight/obesity has a protec...
journal_title:Respiratory research
pub_type: 杂志文章,meta分析
doi:10.1186/s12931-019-1209-5
更新日期:2019-10-29 00:00:00