Molecular Mechanisms of Inflammation During Exacerbations of Chronic Obstructive Pulmonary Disease

Kersul, Ana; Iglesias, Amanda; Ríos, Ángel; Noguera, Aina; Forteza, Aina; Serra, Enrique; Agustí, Àlvar; Cosío, Borja G.

doi:10.1016/s1579-2129(11)70043-x

Cited by 46 publications

(30 citation statements)

References 37 publications

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“…These findings further supported the cytoprotective effects of carbocisteine against airway inflammation in COPD. Because the exacerbation of COPD has been associated with a substantial release of pro-inflammatory cytokines and chemokines [32,33] , the inhibitory effects of carbocisteine, as confirmed by previous studies and our team, may lend support to interpreting the reduced frequency of exacerbations in COPD.…”

Section: Discussionsupporting

confidence: 72%

Carbocisteine attenuates TNF-α-induced inflammation in human alveolar epithelial cells in vitro through suppressing NF-κB and ERK1/2 MAPK signaling pathways

et al. 2016

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Aim: We previously proven that carbocisteine, a conventional mucolytic drug, remarkably reduced the rate of acute exacerbations and improved the quality of life in the patients with chronic obstructive pulmonary disease. In this study we investigated the mechanisms underlying the anti-inflammatory effects of carbocisteine in human alveolar epithelial cells in vitro. Methods: Human lung adenocarcinoma cell line A549 was treated with TNF-α (10 ng/mL). Carbocisteine was administered either 24 h prior to or after TNF-α exposure. The cytokine release and expression were measured using ELISA and qRT-PCR. Activation of NF-κB was analyzed with Western blotting, immunofluorescence assay and luciferase reporter gene assay. The expression of ERK1/2 MAPK signaling proteins was assessed with Western blotting. Results: Carbocisteine (10, 100, 1000 µmol/L), administered either before or after TNF-α exposure, dose-dependently suppressed TNF-α-induced inflammation in A549 cells, as evidenced by diminished release of IL-6 and IL-8, and diminished mRNA expression of IL-6, IL-8, TNF-α, MCP-1 and MIP-1β. Furthermore, pretreatment with carbocisteine significantly decreased TNF-α-induced phosphorylation of NF-κB p65 and ERK1/2 MAPK, and inhibited the nuclear translocation of p65 subunit in A549 cells. In an NF-κB luciferase reporter system, pretreatment with carbocisteine dose-dependently inhibited TNF-α-induced transcriptional activity of NF-κB. Conclusion: Carbocisteine effectively suppresses TNF-α-induced inflammation in A549 cells via suppressing NF-κB and ERK1/2 MAPK signaling pathways.

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Section: Discussionsupporting

confidence: 72%

Carbocisteine attenuates TNF-α-induced inflammation in human alveolar epithelial cells in vitro through suppressing NF-κB and ERK1/2 MAPK signaling pathways

et al. 2016

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“…Sputum or serum levels of CRP, TNF-α, IL-6, IL-8, IL-1β, IL-10, fibrinogen and total cell counts are significantly increased, compared with stable patients or controls [60,[71][72][73], and this increase often persists after the improvement of lung function [71].…”

Section: Systemic Inflammation and Acd: The Role Of Exacerbationsmentioning

confidence: 98%

Anaemia in chronic obstructive pulmonary disease: an insight into its prevalence and pathophysiology

2014

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Chronic obstructive pulmonary disease (COPD) is a major health problem, with increasing morbidity and mortality. There is a growing literature regarding the extra-pulmonary manifestations of COPD, which can have a significant impact on symptom burden and disease progression. Anaemia is one of the more recently identified co-morbidities, with a prevalence that varies between 4.9% and 38% depending on patient characteristics and the diagnostic criteria used. Systemic inflammation seems to be an important factor for its establishment and repeated bursts of inflammatory mediators during COPD exacerbations could further inhibit erythropoiesis. However, renal impairment, malnutrition, low testosterone levels, growth hormone level abnormalities, oxygen supplementation, theophylline treatment, inhibition of angiotensin-converting enzyme and aging itself are additional factors that could be associated with the development of anaemia. The present review evaluates the published literature on the prevalence and significance of anaemia in COPD. Moreover, it attempts to elucidate the reasons for the high variability reported and investigates the complex pathophysiology underlying the development of anaemia in these patients.

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“…Recent data demonstrate that the airways of smokers have increased SLPI expression and secretion, yet the mechanisms mediating this phenomenon remain unclear (23,29). To examine SLPI levels in respiratory epithelial cells from nonsmokers and smokers, we used an in vitro model of differentiated primary NECs, as previously described (33).…”

Section: Necs From Smokers Have Increased Slpi Expression In Vitro Anmentioning

confidence: 99%

“…As a potential balance to the increased protease expression and activity, recent studies indicate that a key antiprotease secretory leukoprotease inhibitor (SLPI) is elevated in smokers compared with nonsmokers (8). Moreover, in patients with chronic obstructive pulmonary disease (COPD) and in patients with COPD and secondary bacterial infection, SLPI levels are elevated in the respiratory tract (23,29). However, the mechanisms mediating this induction of SLPI in the respiratory tract of smokers and patients with COPD are not known.…”

mentioning

confidence: 99%

Regulation and activity of secretory leukoprotease inhibitor (SLPI) is altered in smokers

Meyer

Bauer

Letang

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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A hallmark of cigarette smoking is a shift in the protease/antiprotease balance, in favor of protease activity. However, it has recently been shown that smokers have increased expression of a key antiprotease, secretory leukoprotease inhibitor (SLPI), yet the mechanisms involved in SLPI transcriptional regulation and functional activity of SLPI remain unclear. We examined SLPI mRNA and protein secretion in differentiated nasal epithelial cells (NECs) and nasal lavage fluid (NLF) from nonsmokers and smokers and demonstrated that SLPI expression is increased in NECs and NLF from smokers. Transcriptional regulation of SLPI expression was confirmed using SLPI promoter reporter assays followed by chromatin immunoprecipitation. The role of STAT1 in regulating SLPI expression was further elucidated using WT and stat1(-/-) mice. Our data demonstrate that STAT1 regulates SLPI transcription in epithelial cells and slpi protein in the lungs of mice. Additionally, we reveal that NECs from smokers have increased STAT1 mRNA/protein expression. Finally, we demonstrate that SLPI contained in the nasal mucosa of smokers is proteolytically cleaved but retains functional activity against neutrophil elastase. These results demonstrate that smoking enhances expression of SLPI in NECs in vitro and in vivo, and that this response is regulated by STAT1. In addition, despite posttranslational cleavage of SLPI, antiprotease activity against neutrophil elastase is enhanced in smokers. Together, our findings show that SLPI regulation and activity is altered in the nasal mucosa of smokers, which could have broad implications in the context of respiratory inflammation and infection.

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Molecular Mechanisms of Inflammation During Exacerbations of Chronic Obstructive Pulmonary Disease

Cited by 46 publications

References 37 publications

Carbocisteine attenuates TNF-α-induced inflammation in human alveolar epithelial cells in vitro through suppressing NF-κB and ERK1/2 MAPK signaling pathways

Carbocisteine attenuates TNF-α-induced inflammation in human alveolar epithelial cells in vitro through suppressing NF-κB and ERK1/2 MAPK signaling pathways

Anaemia in chronic obstructive pulmonary disease: an insight into its prevalence and pathophysiology

Regulation and activity of secretory leukoprotease inhibitor (SLPI) is altered in smokers

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