Increased soluble serum markers caspase‐cleaved cytokeratin‐18, histones, and ST2 indicate apoptotic turnover and chronic immune response in COPD

Hacker, Stefan; Lambers, Christopher; Pollreisz, Andreas; Höetzenecker, Konrad; Lichtenauer, Michael; Mangold, Andreas; Niederpold, Tina; Hacker, A. B.; Láng, György; Dworschak, Martin; Vukovich, Thomas; Gerner, Christopher; Klepetko, Walter; Ankersmit, Hendrik Jan

doi:10.1002/jcla.20348

Cited by 33 publications

(16 citation statements)

References 39 publications

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“…A recent study using a mouse model showed that the expression levels of IL-33 and ST2 were markedly enhanced in the lung tissue after inhalation of cigarette smoke [61]. This observation supports those presented by Hacker et al [62], who reported increased serum levels of soluble ST-2 in COPD patients compared with healthy controls.…”

Section: Discussionsupporting

confidence: 81%

Exacerbating Factors Induce Different Gene Expression Profiles in Peripheral Blood Mononuclear Cells from Asthmatics, Patients with Chronic Obstructive Pulmonary Disease and Healthy Subjects

Pniewska

Sokołowska²,

Kupryś‐Lipińska³

et al. 2014

Int Arch Allergy Immunol

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Background: Despite several common phenotypic features, chronic obstructive pulmonary disease (COPD) and severe asthma differ with regard to their causative factors and pathophysiology. Both diseases may be exacerbated by environmental factors, however, the molecular profiles of disease episodes have not been comprehensively studied. We identified differences in gene and protein expression profiles expressed by peripheral blood mononuclear cells (PBMC) of COPD patients, patients with atopic asthma and healthy subjects when challenged with exacerbating factors in vitro: lipopolysaccharide (LPS), house dust mite (HDM) and cat allergen. Methods: PBMC isolated from patients with severe atopic asthma and COPD, as well as healthy subjects were stimulated with rDer p 1 DG, rFel d 1 DG and LPS. The changes in the expression of 47 genes belonging to five groups (phospholipase A₂, eicosanoids, transcription factors, cytokines and airway remodeling) were studied using TaqMan low density array cards. Immunoblotting was used to study relative protein expression. Results: rDer p 1 significantly up-regulated the expression of PLA2G4A, PLA2G6, PLA2G15, CYSLTR1, LB4R2, PTGS1, PTGS2, FOXP1, GATA3, HDAC2, IREB2, PPARG, STAT4, TSLP and CHI3L1 genes in asthmatics in comparison to healthy subjects. LPS induced significant expression of ANXA1 and LTA4H in asthmatics when compared to COPD patients and healthy subjects. SOX6,STAT4 and IL1RL1 were induced in COPD after LPS stimulation. Analysis of protein expression revealed a pattern similar to mRNA expression. Conclusions: LPS-induced exacerbation of asthma and COPD is characterized by differential expression of selected genes in PBMC. HDM allergen changed the expression profile of inflammatory genes between patients with asthma of atopic origin and healthy controls.

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Section: Discussionsupporting

confidence: 81%

Exacerbating Factors Induce Different Gene Expression Profiles in Peripheral Blood Mononuclear Cells from Asthmatics, Patients with Chronic Obstructive Pulmonary Disease and Healthy Subjects

Pniewska

Sokołowska²,

Kupryś‐Lipińska³

et al. 2014

Int Arch Allergy Immunol

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“…Soluble ST2 receptor is considered anti-inflammatory in animal models,171 and its plasma level is increased in mild/moderate stable COPD compared to control smokers with normal lung function 172. In animal models after exposure to tobacco smoking, the lung expression of IL-33 and ST2 is markedly enhanced and associated with neutrophil and macrophage infiltration and expression of inflammatory cytokines (IL-1β, TNFα, IL-17), chemokines (CCL2), and MUC5AC in the lower airways.…”

Section: Individual Cytokines Involved In the Pathogenesis Of Copdmentioning

confidence: 99%

Cytokine inhibition in the treatment of COPD

Caramori¹,

Adcock²,

Stefano³

et al. 2014

COPD

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Cytokines play an important part in many pathobiological processes of chronic obstructive pulmonary disease (COPD), including the chronic inflammatory process, emphysema, and altered innate immune response. Proinflammatory cytokines of potential importance include tumor necrosis factor (TNF)-α, interferon-γ, interleukin (IL)-1β, IL-6, IL-17, IL-18, IL-32, and thymic stromal lymphopoietin (TSLP), and growth factors such as transforming growth factor-β. The current objectives of COPD treatment are to reduce symptoms, and to prevent and reduce the number of exacerbations. While current treatments achieve these goals to a certain extent, preventing the decline in lung function is not currently achievable. In addition, reversal of corticosteroid insensitivity and control of the fibrotic process while reducing the emphysematous process could also be controlled by specific cytokines. The abnormal pathobiological process of COPD may contribute to these fundamental characteristics of COPD, and therefore targeting cytokines involved may be a fruitful endeavor. Although there has been much work that has implicated various cytokines as potentially playing an important role in COPD, there have been very few studies that have examined the effect of specific cytokine blockade in COPD. The two largest studies that have been reported in the literature involve the use of blocking antibody to TNFα and CXCL8 (IL-8), and neither has provided benefit. Blocking the actions of CXCL8 through its CXCR2 receptor blockade was not successful either. Studies of antibodies against IL-17, IL-18, IL-1β, and TSLP are currently either being undertaken or planned. There is a need to carefully phenotype COPD and discover good biomarkers of drug efficacy for each specific target. Specific groups of COPD patients should be targeted with specific anticytokine therapy if there is evidence of high expression of that cytokine and there are features of the clinical expression of COPD that will respond.

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“…Lambers et al [15 ]recently described that the level of a clonally expanded cytotoxic T cell subset with natural killer-cell features is significantly increased in COPD patients compared to controls. Furthermore, Hacker et al [16,17 ]have shown that increased serum levels of heat shock protein (HSP) 27, HSP70, soluble ST2, caspase-cleaved cytokeratin 18 (ccCK-18) and histones correlate with COPD disease severity.…”

Section: Introductionmentioning

confidence: 99%

Increased Serum Levels of HSP27 as a Marker for Incipient Chronic Obstructive Pulmonary Disease in Young Smokers

Ankersmit

Nickl

Hoeltl³

et al. 2012

Respiration

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Background: Although chronic obstructive pulmonary disease (COPD) is amongst the leading causes of morbidity and mortality, no biomarkers for its early detection are known. We have recently demonstrated that COPD is accompanied by elevated serum heat shock protein (HSP) 27 levels as compared to a control population. Objectives: In an open prospective study, we investigated whether elevated HSP27 levels are associated with the early radiological signs of COPD, i.e. air trapping (AT), emphysema (E) and impaired lung function. Methods: In total, 120 apparently healthy smokers underwent lung function testing and serum sampling. Serum levels of HSP27, phospho-HSP27, CXCR2 chemokines and proteins related to inflammation, tissue remodeling and apoptosis were evaluated by ELISA. Of these 120 subjects, 94 voluntarily underwent a high-resolution computed tomography scan. Results: AT or AT and E were detected in 57.45%. Subjects with AT and E (n = 23) showed significantly higher HSP27 levels than those without any pathology [i.e. nothing abnormal detected (NAD)] (4,618 ± 1,677 vs. 3,282 ± 1,607 pg/ml; p = 0.0081). In a univariate logistic regression model including NAD and AT and E, the area under the curve of HSP27 in the receiver-operating-characteristic curve was 0.724, (0.594–0.854, 95% CI; p = 0.0033). Interestingly, proinflammatory IL-8 was elevated in those subjects with evidence of AT and E compared to those with AT and NAD. Lung function did not correlate with increased HSP27 levels or pathological radiological findings. Conclusions: HSP27 serum levels correlated with the early radiological signs of COPD, whereas lung function did not match with radiological findings or HSP27 serum levels. Serum HSP27 levels may serve as a potential marker to identify the early signs of COPD independent of lung function in young smokers.

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Increased soluble serum markers caspase‐cleaved cytokeratin‐18, histones, and ST2 indicate apoptotic turnover and chronic immune response in COPD

Abstract: Our results indicate a systemic release of apoptosis-specific proteins as markers for increased cellular turnover accompanied by progression of COPD. Furthermore, soluble ST2 seems to have a critical role in the anti-inflammatory regulatory mechanism at early stages of the disease.

Cited by 33 publications

References 39 publications

Exacerbating Factors Induce Different Gene Expression Profiles in Peripheral Blood Mononuclear Cells from Asthmatics, Patients with Chronic Obstructive Pulmonary Disease and Healthy Subjects

Exacerbating Factors Induce Different Gene Expression Profiles in Peripheral Blood Mononuclear Cells from Asthmatics, Patients with Chronic Obstructive Pulmonary Disease and Healthy Subjects

Cytokine inhibition in the treatment of COPD

Increased Serum Levels of HSP27 as a Marker for Incipient Chronic Obstructive Pulmonary Disease in Young Smokers

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