Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations

Caramori, Gaetano; Romagnoli, Micaela; Casolari, Paolo; Bellettato, Cinzia Maria; Casoni, Gian Luca; Boschetto, Pierà; Chung, Kian Fan; Barnes, Peter J.; Adcock, Ian M.; Ciaccia, A.; Fabbri, Leonardo M.; Papi, Alberto

doi:10.1136/thorax.58.4.348

Cited by 195 publications

(129 citation statements)

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“…Many of the inflammatory mediators that are expressed in COPD are controlled by the transcription factor nuclear factor (NF)-B, which is upregulated in alveolar macrophages in patients with COPD and in airway cells in patients with mild/ moderate COPD in comparison with control nonsmokers (35). Upregulation of NF-B in lung cells in COPD may be a key molecular mechanism involved in the ongoing inflammatory process in the airways.…”

Section: Inflammation In the Lungs In Copdmentioning

confidence: 99%

Pathogenesis of Chronic Obstructive Pulmonary Disease

MacNee¹

2005

Proceedings of the American Thoracic Society

357

220

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The current paradigm for the pathogenesis of chronic obstructive pulmonary disease is that chronic airflow limitation results from an abnormal inflammatory response to inhaled particles and gases in the lung. Airspace inflammation appears to be different in susceptible smokers and involves a predominance of CD8 ؉ T lymphocytes, neutrophils, and macrophages. Studies have characterized inflammation in the peripheral airspaces in different stages of disease severity. Two other processes have received considerable research attention. The first is a protease-antiprotease imbalance, which has been linked to the pathogenesis of emphysema. However, the hypothesis of an increased protease burden associated with functional inhibition of antiproteases has been difficult to prove and is now considered an oversimplification. The second process, oxidative stress, has a role in many of the pathogenic processes of chronic obstructive pulmonary disease and may be one mechanism that enhances the inflammatory response. In addition, it has been proposed that the development of emphysema may involve alveolar cell loss through apoptosis. This mechanism may involve the vascular endothelial growth factor pathway and oxidative stress.Keywords: apoptosis; emphysema; inflammation; oxidative stress; protease-antiprotease imbalance Chronic obstructive pulmonary disease (COPD) is a slowly progressive condition characterized by airflow limitation, which is largely irreversible (1). Cigarette smoking is the main etiologic factor in this condition, far outweighing any of the other risk factors. The pathogenesis of COPD is therefore strongly linked to the effects of cigarette smoke on the lungs. There is a general relationship between the extent of the smoking history and the severity of the airflow limitation; however, there is a huge individual variation. Fletcher and Peto (2), in an 8-yr prospective study of working men in West London, showed that the average decline in FEV 1 in smokers is faster (60 ml/yr) than in nonsmokers (30 ml/yr). However, smokers who develop COPD have an average decline in FEV 1 of greater than 60 ml/yr, and only 15 to 20% of smokers develop clinically significant COPD. It is from these studies that the concept of the susceptible smoker developed. SUBTYPES OF COPD Chronic BronchitisThe cough and sputum production that define chronic bronchitis result from an innate immune response to inhaled toxic particles and gases in cigarette smoke. In chronic bronchitis there is inflammation in the epithelium of the central airways and in the mucus-producing glands (3). This airway inflammation is associ-

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Section: Inflammation In the Lungs In Copdmentioning

confidence: 99%

Pathogenesis of Chronic Obstructive Pulmonary Disease

MacNee¹

2005

Proceedings of the American Thoracic Society

357

220

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“…NF-kB is activated in macrophages and epithelial cells of COPD patients, particularly during exacerbations [207]. NF-kB activation is also implicated in mediating systemic inflammation and may be involved in skeletal muscle weakness in COPD patients [82].…”

Section: Pde4 Inhibitorsmentioning

confidence: 99%

Systemic manifestations and comorbidities of COPD

Barnes¹,

Celli²

2009

European Respiratory Journal

1,465

1,113

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Increasing evidence indicates that chronic obstructive pulmonary disease (COPD) is a complex disease involving more than airflow obstruction. Airflow obstruction has profound effects on cardiac function and gas exchange with systemic consequences. In addition, as COPD results from inflammation and/or alterations in repair mechanisms, the ''spill-over'' of inflammatory mediators into the circulation may result in important systemic manifestations of the disease, such as skeletal muscle wasting and cachexia. Systemic inflammation may also initiate or worsen comorbid diseases, such as ischaemic heart disease, heart failure, osteoporosis, normocytic anaemia, lung cancer, depression and diabetes. Comorbid diseases potentiate the morbidity of COPD, leading to increased hospitalisations, mortality and healthcare costs. Comorbidities complicate the management of COPD and need to be evaluated carefully. Current therapies for comorbid diseases, such as statins and peroxisome proliferator-activated receptor-agonists, may provide unexpected benefits for COPD patients. Treatment of COPD inflammation may concomitantly treat systemic inflammation and associated comorbidities. However, new broad-spectrum anti-inflammatory treatments, such as phosphodiesterase 4 inhibitors, have significant side-effects so it may be necessary to develop inhaled drugs in the future. Another approach is the reversal of corticosteroid resistance, for example with effective antioxidants. More research is needed on COPD comorbidities and their treatment.

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“…In preclinical pharmacology studies, animal models of neutrophil inflammation are routinely used for efficacy measures in an attempt to mimic the disease state in humans. It is known that in COPD patients the percentage of sputum neutrophils are increased with each GOLD stage, are also raised in COPD exacerbations (Caramori et al 2003) (Papi et al 2006), and that neutrophils are involved in the pathogenesis of emphysema through the secretion of proteases and elastases (Cowburn et al 2008) (Sharafkhaneh et al 2008). Taken together, these observations would suggest that sputum neutrophils have the potential to be a biomarker predictor of the degree of airflow obstruction, however the reality is far from clear.…”

Section: Challenges In Copd Clinical Studiesmentioning

confidence: 69%