Clinical proteomics in lung diseases

Waldburg, N.; Kähne, Thilo; Reisenauer, Anita; Röcken, Christoph; Welte, Tobias; Bühling, Frank

doi:10.1016/j.prp.2004.02.006

Cited by 20 publications

(14 citation statements)

References 48 publications

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“…Proteomics is complementary to gene microarray and by use of high-resolution 2-dimentional electrophoresis allows the detection of multiple proteins in fluids, cells and tissues [293]. This could show patterns of protein expression that relate to specific phenotypes of COPD and may identify new or more appropriate targets, particularly in subsets of patients.…”

Section: Proteomicsmentioning

confidence: 99%

COPD: current therapeutic interventions and future approaches

Barnes¹

2005

European Respiratory Journal

232

143

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Although long-acting bronchodilators have been an important advance for the management of chronic obstructive pulmonary disease (COPD), these drugs do not deal with the underlying inflammatory process. No currently available treatments reduce the progression of COPD or suppress the inflammation in small airways and lung parenchyma. Several new treatments that target the inflammatory process are now in clinical development. Some therapies, such as chemokine antagonists, are directed against the influx of inflammatory cells into the airways and lung parenchyma that occurs in COPD, whereas others target inflammatory cytokines such as tumour necrosis factor-a.Broad spectrum anti-inflammatory drugs are now in phase III development for COPD, and include phosphodiesterase-4 inhibitors. Other drugs that inhibit cell signalling include inhibitors of p38 mitogen-activated protein kinase, nuclear factor-kB and phosphoinositide-3 kinase-c. More specific approaches are to give antioxidants, inhibitors of inducible nitric oxide synthase and leukotriene B 4 antagonists. Other treatments have the potential to combat mucus hypersecretion, and there is also a search for serine proteinase and matrix metalloproteinase inhibitors to prevent lung destruction and the development of emphysema.More research is needed to understand the cellular and molecular mechanisms of chronic obstructive pulmonary disease and to develop biomarkers and monitoring techniques to aid the development of new therapies.

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Section: Proteomicsmentioning

confidence: 99%

COPD: current therapeutic interventions and future approaches

Barnes¹

2005

European Respiratory Journal

232

143

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“…Both of the two main types of lamins that can be discerned (A and B) are intermediate filament proteins. Whereas B-type lamins are ubiquitously expressed in all animal cells, the expression of A-type lamins is low or absent in cells with a low degree of differentiation and/or in highly proliferating cells (42,43). A-type lamins have been associated with several genetic disorders.…”

Section: Structural Proteinsmentioning

confidence: 99%

Impact of Low and High Tidal Volumes on the Rat Alveolar Epithelial Type II Cell Proteome

Hirsch¹,

Hansen²,

Sapru³

et al. 2007

Am J Respir Crit Care Med

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Rationale: Mechanical ventilation with high tidal volumes leads to increased permeability, generation of inflammatory mediators, and damage to alveolar epithelial cells (ATII). Objectives: To identify changes in the ATII proteome after two different ventilation strategies in rats. Methods: Rats (n ϭ 6) were ventilated for 5 hours with high-and low tidal volumes (VTs) (high VT: 20 ml/kg; low VT: 6 ml/kg). Pooled nonventilated rats served as control animals. ATII cells were isolated and lysed, and proteins were tryptically cleaved into peptides. Cellular protein content was evaluated by peptide labeling of the ventilated groups with 18 O. Samples were fractionated by cation exchange chromatography and identified using electrospray tandem mass spectrometry. Proteins identified by 15 or more peptides were statistically compared using t tests corrected for the false discovery rate. Measurements and Main Results: High VT resulted in a significant increase in airspace neutrophils without an increase in extravascular lung water. Compared with low-VT samples, high-VT samples showed a 32% decrease in the inositol 1,4,5-trisphosphate 3 receptor (p Ͻ 0.01), a 34% decrease in Na ϩ , K ϩ -ATPase (p Ͻ 0.01), and a significantly decreased content in ATP synthase chains. Even low-VT samples displayed significant changes, including a 66% decrease in heat shock protein 90-␤ (p Ͻ 0.01) and a 67% increase in mitochondrial pyruvate carboxylase (p Ͻ 0.01). Significant differences were found in membrane, acute phase, structural, and mitochondrial proteins. Conclusions: After short-term exposure to high-VT ventilation, significant reductions in membrane receptors, ion channel proteins, enzymes of the mitochondrial energy system, and structural proteins in ATII cells were present. The data supports the two-hit concept that an unfavorable ventilatory strategy may make the lung more vulnerable to an additional insult.Keywords: acute lung injury; alveolar epithelium; corticosterone Acute lung injury is a major cause of morbidity (1) and mortality, and mechanical ventilation is critical to survival of most patients with acute lung injury. However, mechanical ventilation with high tidal volumes (Vts) is known to have deleterious side effects. The importance of ventilator-induced lung injury caused by mechanical ventilation has been established by several experimental and clinical studies (2, 3). Avoidance of excessive Vts Mechanical ventilation with high tidal volumes leads to increased permeability, generation of inflammatory mediators, and damage to alveolar epithelial cells that may contribute to ventilator-induced lung injury. What This Study Adds to the FieldUsing a proteomic approach, significant reductions of key proteins in alveolar type II cells from rats were identified after short-term positive-pressure ventilation.during mechanical ventilation reduces the risk of ventilatorinduced injury, and application of a lower Vt strategy to ventilate patients with acute respiratory distress syndrome has been shown to lead to a greater than 2...

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“…Specifically, the IPA KB detailed roles including collagen fibrillogenesis (dermatopontin (DPT; Q07507)), protein elongation (ribosomal protein L7, -L8, (RPL7; P18124, RPL8; P62917)) and chemotaxis (peptidylprolyl isomerase A (cyclophilin A)(PPIA; P62937)). Three of the molecules have been previously described in relation to asthma, fibrosis and inflammation, including annexin 5A (ANXA5; P08758) [25], lamin A/C (LMNA;P02545) [26,27] and PPIA [28], indicating the sensitivity of the method and clinical relevance of the samples.…”

Section: Resultsmentioning

confidence: 99%

Network analysis of quantitative proteomics on asthmatic bronchi: effects of inhaled glucocorticoid treatment

et al. 2011

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BackgroundProteomic studies of respiratory disorders have the potential to identify protein biomarkers for diagnosis and disease monitoring. Utilisation of sensitive quantitative proteomic methods creates opportunities to determine individual patient proteomes. The aim of the current study was to determine if quantitative proteomics of bronchial biopsies from asthmatics can distinguish relevant biological functions and whether inhaled glucocorticoid treatment affects these functions.MethodsEndobronchial biopsies were taken from untreated asthmatic patients (n = 12) and healthy controls (n = 3). Asthmatic patients were randomised to double blind treatment with either placebo or budesonide (800 μg daily for 3 months) and new biopsies were obtained. Proteins extracted from the biopsies were digested and analysed using isobaric tags for relative and absolute quantitation combined with a nanoLC-LTQ Orbitrap mass spectrometer. Spectra obtained were used to identify and quantify proteins. Pathways analysis was performed using Ingenuity Pathway Analysis to identify significant biological pathways in asthma and determine how the expression of these pathways was changed by treatment.ResultsMore than 1800 proteins were identified and quantified in the bronchial biopsies of subjects. The pathway analysis revealed acute phase response signalling, cell-to-cell signalling and tissue development associations with proteins expressed in asthmatics compared to controls. The functions and pathways associated with placebo and budesonide treatment showed distinct differences, including the decreased association with acute phase proteins as a result of budesonide treatment compared to placebo.ConclusionsProteomic analysis of bronchial biopsy material can be used to identify and quantify proteins using highly sensitive technologies, without the need for pooling of samples from several patients. Distinct pathophysiological features of asthma can be identified using this approach and the expression of these features is changed by inhaled glucocorticoid treatment. Quantitative proteomics may be applied to identify mechanisms of disease that may assist in the accurate and timely diagnosis of asthma.Trial registrationClinicalTrials.gov registration NCT01378039

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Clinical proteomics in lung diseases

Cited by 20 publications

References 48 publications

COPD: current therapeutic interventions and future approaches

COPD: current therapeutic interventions and future approaches

Impact of Low and High Tidal Volumes on the Rat Alveolar Epithelial Type II Cell Proteome

Network analysis of quantitative proteomics on asthmatic bronchi: effects of inhaled glucocorticoid treatment

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