Different Modulation of Decorin Production by Lung Fibroblasts from Patients with Mild and Severe Emphysema

Noordhoek, Jacobien A.; Postma, Dirkje S.; Chong, Luis L.; Menkema, Lorian; Kauffman, Henk F.; Timens, Wim; Straaten, Jeanette F.M. van; Geld, Ymke M. van der

doi:10.1081/copd-200050678

Cited by 54 publications

(48 citation statements)

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“…Loss of decorin in the lung may contribute to loosening of the collagen fibre network and higher levels of active transforming growth factor-b. As we have shown that decorin is consistently reduced in its presence and production in COPD [33,34,43], it will be of interest to evaluate whether a humoral autoimmune response may be involved. The next step is to also perform ELISPOT analysis on lung tissue to find out whether these anti-decorin IgG antibody-producing cells are also prominent in the lungs of COPD patients.…”

Section: Discussionmentioning

confidence: 99%

Differential switching to IgG and IgA in active smoking COPD patients and healthy controls

et al. 2012

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Several studies have demonstrated the presence of B-cell follicles and autoantibodies in chronic obstructive pulmonary disease (COPD). It is unclear against which antigens this B-cell response is directed and whether it contributes to development or worsening of disease.We assessed different B-cell subsets in blood and lung tissue from COPD patients and controls, and compared differences in B-cell responsiveness to stimulation with lung-specific antigens.Active smoking induced an adaptive immune response with relatively high levels of (classswitched) memory B-cells in blood and immunoglobulin (Ig)G memory B-cells in the lung. COPD smokers showed more switching to IgG, whereas healthy smokers switched more to IgA. COPD patients had higher levels of memory B-cells in the lung and stimulation with lung-specific antigens induced higher numbers of anti-decorin antibody-producing cells in COPD patients compared with healthy controls.Differential switching to IgG and IgA indicates that the adaptive immune response to smoke differs between COPD patients and healthy controls. A higher level of memory B-cells in the lungs of COPD patients may reflect an antigen-specific immune response, which could be directed against decorin, as suggested by the induction of anti-decorin antibody-producing cells in response to antigen-specific stimulation in COPD patients.

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Section: Discussionmentioning

confidence: 99%

Differential switching to IgG and IgA in active smoking COPD patients and healthy controls

et al. 2012

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“…Fibroblast cultures were established from parenchymal lung tissue by an explant technique as previously described [24]. Isolated cells were characterized as fibroblasts by morphological appearance and expression pattern of specific proteins as described previously [24,25].…”

Section: Methodsmentioning

confidence: 99%

A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK

et al. 2012

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BackgroundChronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time.MethodsIn order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions × 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans.ResultsWe identified 127 genes whose expression levels were significantly associated with regional emphysema severity while controlling for gene expression differences between individuals. Genes increasing in expression with increasing emphysematous destruction included those involved in inflammation, such as the B-cell receptor signaling pathway, while genes decreasing in expression were enriched in tissue repair processes, including the transforming growth factor beta (TGFβ) pathway, actin organization, and integrin signaling. We found concordant differential expression of these emphysema severity-associated genes in four cross-sectional studies of COPD. Using the Connectivity Map, we identified GHK as a compound that can reverse the gene-expression signature associated with emphysematous destruction and induce expression patterns consistent with TGFβ pathway activation. Treatment of human fibroblasts with GHK recapitulated TGFβ-induced gene-expression patterns, led to the organization of the actin cytoskeleton, and elevated the expression of integrin β1. Furthermore, addition of GHK or TGFβ restored collagen I contraction and remodeling by fibroblasts derived from COPD lungs compared to fibroblasts from former smokers without COPD.ConclusionsThese results demonstrate that gene-expression changes associated with regional emphysema severity within an individual's lung can provide insights into emphysema pathogenesis and identify novel therapeutic opportunities for this deadly disease. They also suggest the need for additional studies to examine the mechanisms by which TGFβ and GHK each reverse the gene-expression signature of emphysematous destruction and the effects of this reversal on disease progression.

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“…In the past, it has been demonstrated that decorin and biglycan, two important proteoglycans of the ECM, show a diminished presence in lung tissue of COPD patients [12,13]. In addition, isolated fibroblasts of stage IV COPD patients showed strongly reduced decorin production under the influence of TGF-b stimulation [14]. Other ECM components, such as elastin and collagens, are also differentially expressed in lung tissue of COPD patients [15].…”

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“…Other ECM components, such as elastin and collagens, are also differentially expressed in lung tissue of COPD patients [15]. This led the current authors to hypothesise that the TGF-b-Smad pathway is altered in COPD patients and could serve as an explanation for the defective tissue repair observed in COPD [14].…”

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Altered expression of the Smad signalling pathway: implications for COPD pathogenesis

Zandvoort¹,

Postma²,

Jonker³

et al. 2006

European Respiratory Journal

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Pulmonary emphysema, as a feature of chronic obstructive pulmonary disease (COPD), is characterised by destruction of alveolar tissue. The present authors previously demonstrated reduced decorin expression in the peribronchial area of COPD patients, reflecting an altered extracellular matrix (ECM) modulation. Decorin transcription is regulated by the transforming growth factor (TGF)-b-Smad pathway, the key intracellular signal route for initiation of ECM component gene transcription. Whether this pathway is aberrantly expressed in COPD is not known.An immunohistochemical study was performed to compare protein expression of TGF-b 1 and TGF-b receptors, Smad 2, 3, 4 and 7, and decorin in lung tissue of Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II and IV COPD patients and controls.Epithelial expression of the inhibitory Smad 7 was significantly lower in patients with GOLD stages II and IV than in controls, with other Smad protein expressions being similar in the groups. The expression of TGF-b 1 and TGF-b receptor type I was significantly lower in stage II patients. Decorin staining of the adventitia and alveolar walls was significantly reduced in COPD stage IV.In conclusion, the transforming growth factor-b-Smad pathway is aberrantly expressed in chronic obstructive pulmonary disease patients, implying an abnormal tissue repair ultimately resulting in reduced decorin production. The results of the present study contribute to better understanding of the pathogenesis of emphysema and the airway fibrosis observed in chronic obstructive pulmonary disease patients.

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Different Modulation of Decorin Production by Lung Fibroblasts from Patients with Mild and Severe Emphysema

Cited by 54 publications

References 30 publications

Differential switching to IgG and IgA in active smoking COPD patients and healthy controls

Differential switching to IgG and IgA in active smoking COPD patients and healthy controls

A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK

Altered expression of the Smad signalling pathway: implications for COPD pathogenesis

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