Systemic inflammation and mortality in chronic obstructive pulmonary diseaseThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.

Sin, Don D.; Man, S. F. Paul

doi:10.1139/y06-093

Cited by 90 publications

(17 citation statements)

References 35 publications

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“…Likewise, we presently observed interdependency between the plethysmographically assessed residual volume and LEAD Fontaine stages (p=0.02). Thus, there is mounting evidence that suggests a persistent, largely hypoxia-mediated low-grade systemic inflammation in COPD that enhances endothelial dysfunction as a direct precursor of atherosclerosis [25]. The inflammatory cascade that initially arises from exposure to noxious substances, mainly tobacco smoke, accelerates atherogenesis at all stages by formation, destabilisation and rupture of plaque as well as by platelet activation and clotting that lead to atheroma formation and atherothrombosis [2, 26].…”

Section: Discussionmentioning

confidence: 99%

Lower extremity and carotid artery disease in COPD

et al. 2016

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In view of their common chronic inflammatory process, we sought to determine the linkage between peripheral artery disease and chronic obstructive pulmonary disease (COPD).107 COPD patients (mean±sd age 64.6±10.4 years, 52.2% male) and 22 control smokers without previously diagnosed peripheral artery disease underwent standardised angiological examination for lower extremity artery disease (LEAD) and carotid artery disease.LEAD was significantly more prevalent in COPD patients than in controls (80.4% versus 54.5%, p=0.002). Among COPD patients, 57.0%, 12.2%, 10.3% and 0.9% were found to be in Fontaine stages I, IIA, IIB and III, respectively. As with carotid artery disease, its frequency increased from 36.4% in controls to 58.9% in COPD patients (p=0.003). Carotid plaque burden, LEAD Fontaine degrees as well as pulse wave index and ankle–brachial index manifested significant impairment over percentage predicted forced expiratory volume in 1 s (FEV1 % pred) (p=0.02, p<0.001, p=0.01 and p<0.001, respectively). Multivariate analysis revealed that COPD Global Initiative for Chronic Obstructive Lung Disease status was the strongest independent predictor for the presence of plaque in lower extremity arteries (odds ratio 1.63, 95% CI 1.19–2.25, p=0.003) and carotids (odds ratio 1.66, 95% CI 1.14–2.44, p=0.009).As compared with control smokers, peripheral artery disease is diagnosed in a sizeable proportion of COPD patients and exhibits significant distributive differences over FEV1 % pred that exceed the susceptibility conferred by common cardiovascular stressors.

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Section: Discussionmentioning

confidence: 99%

Lower extremity and carotid artery disease in COPD

et al. 2016

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“…COPD primarily affects lungs; however, it now recognised a disease with organ-specific characteristics and systemic manifestations such as chronic inflammation [53]–[55]. We have analysed the expression of two of the most important pro-inflammatory cytokines, IL-6 and CXCL8, that are elevated in plasma, BAL fluids and sputum of COPD patients and whose expression correlates with disease severity [56]–[58].…”

Section: Discussionmentioning

confidence: 99%

Brd4 Is Essential for IL-1β-Induced Inflammation in Human Airway Epithelial Cells

et al. 2014

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BackgroundChronic inflammation and oxidative stress are key features of chronic obstructive pulmonary disease (COPD). Oxidative stress enhances COPD inflammation under the control of the pro-inflammatory redox-sensitive transcription factor nuclear factor-kappaB (NF-κB). Histone acetylation plays a critical role in chronic inflammation and bromodomain and extra terminal (BET) proteins act as “readers” of acetylated histones. Therefore, we examined the role of BET proteins in particular Brd2 and Brd4 and their inhibitors (JQ1 and PFI-1) in oxidative stress- enhanced inflammation in human bronchial epithelial cells.MethodsHuman primary epithelial (NHBE) cells and BEAS-2B cell lines were stimulated with IL-1β (inflammatory stimulus) in the presence or absence of H2O2 (oxidative stress) and the effect of pre-treatment with bromodomain inhibitors (JQ1 and PFI-1) was investigated. Pro-inflammatory mediators (CXCL8 and IL-6) were measured by ELISA and transcripts by RT-PCR. H3 and H4 acetylation and recruitment of p65 and Brd4 to the native IL-8 and IL-6 promoters was investigated using chromatin immunoprecipitation (ChIP). The impact of Brd2 and Brd4 siRNA knockdown on inflammatory mediators was also investigated.ResultH2O2 enhanced IL1β-induced IL-6 and CXCL8 expression in NHBE and BEAS-2B cells whereas H2O2 alone did not have any affect. H3 acetylation at the IL-6 and IL-8 promoters was associated with recruitment of p65 and Brd4 proteins. Although p65 acetylation was increased this was not directly targeted by Brd4. The BET inhibitors JQ1 and PFI-1 significantly reduced IL-6 and CXCL8 expression whereas no effect was seen with the inactive enantiomer JQ1(-). Brd4, but not Brd2, knockdown markedly reduced IL-6 and CXCL8 release. JQ1 also inhibited p65 and Brd4 recruitment to the IL-6 and IL-8 promoters.ConclusionOxidative stress enhanced IL1β-induced IL-6 and CXCL8 expression was significantly reduced by Brd4 inhibition. Brd4 plays an important role in the regulation of inflammatory genes and provides a potential novel anti-inflammatory target.

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“…COPD is currently a leading cause of morbidity and mortality worldwide whose prevalence and burden are projected to increase due to smoke exposure and the changing age structure of the world population, particularly in women [1,3]. COPD is characterized by a chronic inflammation of the lower airway and, importantly, the presence of COPD increases the risk of lung cancer up to 4.5-fold among long-term smokers [4,5,6,7,8,9]. COPD is by far the greatest risk factor for lung cancer amongst smokers and is found in 50–90% of patients with lung cancer [10].…”

Section: Introductionmentioning

confidence: 99%

Chronic Obstructive Pulmonary Disease and Lung Cancer: New Molecular Insights

2011

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Both chronic obstructive pulmonary disease (COPD) and lung cancer are major causes of death worldwide. In most cases this reflects cigarette smoke exposure which is able to induce an inflammatory response in the airways of smokers. Indeed, COPD is characterized by lower airway inflammation, and importantly, the presence of COPD is by far the greatest risk factor for lung cancer amongst smokers. Cigarette smoke induces the release of many inflammatory mediators and growth factors including TGF-β, EGFR, IL-1, IL-8 and G-CSF through oxidative stress pathways and this inflammation may persist for decades after smoking cessation. Mucus production is also increased by these inflammatory mediators, further linking airway inflammation to an important mechanism of lung cancer. A greater understanding of the molecular and cellular pathobiology that distinguishes smokers with lung cancer from smokers with and without COPD is needed to unravel the complex molecular interactions between COPD and lung cancer. By understanding the common signalling pathways involved in COPD and lung cancer the hope is that treatments will be developed that not only treat the underlying disease process in COPD, but also reduce the currently high risk of developing lung cancer in these patients.

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Systemic inflammation and mortality in chronic obstructive pulmonary diseaseThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.

Cited by 90 publications

References 35 publications

Lower extremity and carotid artery disease in COPD

Lower extremity and carotid artery disease in COPD

Brd4 Is Essential for IL-1β-Induced Inflammation in Human Airway Epithelial Cells

Chronic Obstructive Pulmonary Disease and Lung Cancer: New Molecular Insights

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