Proceedings of the American Thoracic Society
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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. ⋯ 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.
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Exacerbations of chronic obstructive pulmonary disease (COPD) are a major cause of morbidity, mortality, and rising health care costs. In addition, they are associated with an accelerated loss of lung function and thus have a direct effect on disease progression. ⋯ Current therapies for COPD exacerbations are of limited effectiveness, and a better understanding of the inflammatory events at exacerbation is required to devise new therapeutic agents. The development of experimental models of exacerbation-for example, the use of experimental rhinovirus infection in humans with COPD-would greatly facilitate studies of exacerbations.
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For critically ill patients, mechanical ventilation is a commonly used life-supporting modality, but ventilation per se could also induce lung injury. Mechanical forces-induced cell damage and inflammatory responses have been considered as one of major mechanisms of ventilator-induced lung injury (VILI). Mechanotransduction related to VILI has been the subject of several recent reviews, which focused on the mechanical force-induced signal cascades. ⋯ Proteins associated with the cytoskeleton could transmit physical forces, and bind with signaling-related enzymes through specific functional domains and motifs. These interactions could lead to activation or inactivation of the enzymes, and subsequently alter the signal transduction processes in the cells. Understanding these mechanisms will help us to develop new strategies for the management of VILI.
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There is growing evidence for systemic inflammation in chronic obstructive pulmonary disease (COPD). Increased circulating levels of inflammatory cytokines and acute phase proteins occur in stable disease, and COPD exacerbations are notably associated with pulmonary and systemic inflammation. Although the course of inflammation is determined by the balance between pro- and antiinflammatory mediators, in COPD most attention has focused on the former. ⋯ Although a relationship between lung and systemic inflammation has been suggested, experimental evidence indicates no direct correlations in the regulation of inflammation in the pulmonary and systemic compartments. Longitudinal studies are needed to unravel the role of systemic inflammation in the course of COPD, to analyze the role of acute exacerbations on the chronicity of inflammation, and to evaluate the response of systemic inflammation to different interventions. Emphasis should be placed on the identification of signaling pathways induced and/or altered in skeletal muscle by inflammation, as muscle wasting is a prominent feature of chronic inflammatory disease conditions and contributes significantly to impaired physical functioning and health status in COPD.
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Current pharmacotherapy for chronic obstructive pulmonary disease (COPD) relieves symptoms and reduces exacerbation through improving airflow limitation. Such drugs do not effectively improve exercise tolerance due in part to pulmonary hypertension associated with severe COPD, nor impact on its increased morbidity and mortality. Exercise intolerance is often improved (temporarily) by lung volume reduction surgery and pulmonary rehabilitation. ⋯ End-stage bronchiolitis and emphysema are likely to limit the effectiveness of bronchodilators and corticosteroids. There are effective treatments for idiopathic and scleroderma pulmonary arterial hypertension, which increase exercise tolerance and improve survival. Because idiopathic and COPD pulmonary hypertension share a common vascular intimal thickening, excess endothelin receptor expression, and plasma endothelin-1, an important therapeutic question to address is whether an oral endothelin-1 antagonist can improve exercise tolerance in severe COPD.