Pathogenesis of Chronic Obstructive Pulmonary Disease

Abstract

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-

Genetic Epidemiology of Cigarette Smoke–Induced Lung Disease

“…Pathways involved in the pathogenesis of COPD and lung cancer include inflammation, extracellular matrix proteolysis, and oxidative stress (38)(39)(40). A number of candidate gene singlenucleotide polymorphisms (SNPs) have been associated with susceptibility to lung cancer and COPD, including those coding for epoxide hydrolase 1 (EPHX1), matrix metalloproteinases, and IL-1b (41)(42)(43)(44)(45).…”

Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate

“…I n tobacco smoking-induced chronic obstructive pulmonary disease (COPD), chronic inflammation of the small airways and the lung parenchyma leads to fixed narrowing of small airways and alveolar wall destruction (emphysema) (1)(2)(3)(4). The chronic inflammatory infiltrate is characterized by augmented numbers of alveolar leukocytes, including both B and T lymphocytes.…”

“…This finding indicates that innate inflammatory cells, such as neutrophils and macrophages, may play an essential role in the pathogenesis of COPD. Massive accumulations of neutrophils are frequently found in the bronchoalveolar lavage fluid (BALF) of patients with both stable and acute exacerbations of COPD (1)(2)(3)(4). The enzymes and reactive oxygen species (ROSs) released by neutrophils can damage the surrounding tissues.…”

“…The enzymes and reactive oxygen species (ROSs) released by neutrophils can damage the surrounding tissues. Therefore, abnormal accumulation of neutrophils in the small airways and alveoli is likely to be a major contributor to the irreversible lung damage seen in tobacco-induced COPD (1)(2)(3)(4).…”

“…We previously established deactivation of the phosphatidylinositol 3,4,5 trisphosphate [PtdIns (3,4,5)P3]/Akt pathway as a causal mediator of neutrophil spontaneous death (12). Akt is a well known cellular survival signal.…”