Inflammatory Mechanisms in Chronic Obstructive Pulmonary Disease

Barnes, Peter J.

doi:10.1002/9783527692156.ch45

Cited by 4 publications

(5 citation statements)

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“…This insensitivity to GCs is associated with a reduction in histone deacetylase-2 (HDAC2) activity, and in line with COPD clinical severity (Barnes, Ito & Adcock, 2004;Footitt et al, 2016;Ito et al, 2005). Excessive inflammation, together with enhanced oxidative stress is an important mechanism for this decrease in HDAC-2 activity in patients with COPD (Barnes, 2016;Footitt et al, 2016). Restoration of GC sensitivity is postulated as a novel approach for COPD management (Marwick, Adcock & Chung, 2010;Mitani, Ito, Vuppusetty, Barnes & Mercado, 2016).…”

Section: Introductionmentioning

confidence: 93%

The impacts of anti-inflammatory phosphodiesterase inhibitors on a murine model of chronic pulmonary inflammation

Zheng

Zhang

Zhou

2020

Preprint

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Chronic obstructive pulmonary disease (COPD) often tends to respond poorly to glucocorticoid (GC) therapy. Reduced Histone deacetylase-2 (HDAC-2) activity is an important mechanism behind this GC insensitivity. In this study, we investigated the effects of three phosphodiesterase inhibitors (PDEIs), with anti-inflammatory propensity, on cigarette smoke (CS) induced pulmonary inflammation and HDAC-2 activity. Male C57BL/6 mice were exposed to cigarette smoke (CS) over the course of 30 weeks. Administration of the PDEIs commenced from the 29th week and followed a schedule of once daily treatments, 5 days a week, for 2 weeks. Roflumilast (ROF) was administered intragastrically (5 mg•kg-1), while pentoxifylline (PTX) (10 mg•kg-1) and theophylline (THEO) (10 mg•kg-1) were administered intraperitoneally, either alone or in combination with a GC (triamcinolone acetonide or TRI, 5 mg•kg-1, i.m., single injection). Lung morphometry, as well as the activity of HDAC-2, pro-inflammatory cytokines and reactive oxygen species (ROS) were assessed at the end of the 30 week course. CS exposure was associated with a reduction in HDAC-2 activity and the up-regulation of ROS expression. PTX, ROF and THEO administration led to the partial restoration of HDAC-2 activity, however combining TRI to any of these PDEIs did not synergistically augment this effect. The restoration of HDAC-2 activity was favorably associated with the reduction of ROS expression.Inactivation of HDAC-2 due to long-term CS exposure is closely related to exaggerated oxidative stress, and this reduced HDAC-2 activity could partially be restored through the use of PDEIs. This finding provides a potential novel approach for further clinical research.

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Section: Introductionmentioning

confidence: 93%

The impacts of anti-inflammatory phosphodiesterase inhibitors on a murine model of chronic pulmonary inflammation

Zheng

Zhang

Zhou

2020

Preprint

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“…Studies have shown that the alveolar macrophages and neutrophils of smokers and COPD patients can release a large number of proteases and cytokines to increase the expression level and activity of MMP-9. MMP-9 not only causes ECM destruction but also degrades α1 antitrypsin and makes the balance of proteaseantitrypsin imbalance, resulting in pulmonary matrix damage and lung dysplasia [38,39]. In mouse colorectal cancer models, neutrophil-secreted MMP-9 activates latent TGFβ in the ECM by degrading the ECM, increasing the level of TGFβ in the tumor microenvironment, and thereby inhibiting antitumor T cell response [40].…”

Section: Matrix Metalloproteinasesmentioning

confidence: 99%

Interplay between Extracellular Matrix and Neutrophils in Diseases

Zhu

Huang

et al. 2021

Journal of Immunology Research

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The extracellular matrix (ECM) is a highly dynamic and complex network structure, which exists in almost all tissues and is the microenvironment that cells rely on for survival. ECM interacts with cells to regulate diverse functions, including differentiation, proliferation, and migration. Neutrophils are the most abundant immune cells in circulation and play key roles in orchestrating a complex series of events during inflammation. Neutrophils can also mediate ECM remodeling by providing specific matrix-remodeling enzymes (such as neutrophil elastase and metalloproteinases), generating neutrophil extracellular traps, and releasing exosomes. In turn, ECM can remodel the inflammatory microenvironment by regulating the function of neutrophils, which drives disease progression. Both the presence of ECM and the interplay between neutrophils and their extracellular matrices are considered an important and outstanding mechanistic aspect of inflammation. In this review, the importance of ECM will be considered, together with the discussion of recent advances in understanding the underlying mechanisms of the intricate interplay between ECM and neutrophils. A better comprehension of immune cell-matrix reciprocal dependence has exciting implications for the development of new therapeutic options for neutrophil-associated infectious and inflammatory diseases.

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“…24,25 The inflammation in COPD is localized predominantly to peripheral airways and lung parenchyma. 26 Airways < 2 mm in diameter are more prone to undergo these pathological changes and thus to be occluded by mucus, inflammatory infiltrates, smooth muscle and mucus glands hypertrophy, and airway wall thickening, which involves the epithelium, the smooth muscle, and the adventitia. 27 Compared with healthy individuals, the airway lumen of patients with COPD is rich in neutrophils and macrophages, and greater concentrations of macrophages, Tlymphocytes, and B-lymphocytes have been reported in the airway wall and parenchyma.…”

Section: Pathobiology Of Small Airways In Copdmentioning

confidence: 99%

“…In fact, the activities of HDAC-2, -3, -5, and -8 have all been demonstrated to be reduced in COPD patients, suggesting a role for the inactivation of HDACs in steroid insensitivity in COPD. 23,26,36 Isajevs and coworkers 37 reported that cigarette smoke increased pro-inflammatory cytokines through the activation of nuclear transcription factor-k B and by inhibiting HDAC-2. Nuclear transcription factork B p65 expression was greater in large airways, correlating with an increased number of macrophages, whereas the HDAC-2 expression was mainly decreased in small airways, suggesting its potential role in the development of bronchiolitis.…”

Section: Pathobiology Of Small Airways In Copdmentioning

confidence: 99%