Chest
Neutrophils and the Pathogenesis of COPD
Section snippets
The Neutrophil
α1-AT is a serum inhibitor of serine proteinases, although it also provides an effective antiproteinase screen in the alveolar region2 and, by inference, in the lung interstitium. Studies in vivo have shown that two serine proteinases, elastase and proteinase-3, which are released by neutrophils,3,4 can induce in animals pathologic changes that resemble human emphysema. Furthermore, neutrophil sequestration in the pulmonary circulation also will lead to the development of emphysema in dogs.5
Neutrophil Differentiation and Migration
The neutrophil originates in the bone marrow where it differentiates over a period of 7 to 10 days from promyeloblast to a mature cell. During this period, the neutrophil manufactures its full complement of NE and proteinase-3, and stores the enzymes within the primary or azurophil granules. The enzyme genes are “switched on” early during differentiation at the promyelocyte stage and are “switched off” at the myelocyte stage.11 Thereafter, there is no further production of these enzymes. The
Neutrophils in COPD
The neutrophil is a short-lived and transient cell. In the lung it is usually (in the absence of pneumonia or interstitial lung disease) recruited from the circulation to the airways. Its passage through the interstitial space is a rapid event, and neutrophils are usually found in the circulation or the airways. Nevertheless, pathology studies13 have identified an increased number of neutrophils in the bronchial tissue of some patients with COPD and have shown that this relates to the severity
Susceptibility
Only a proportion of smokers develop significant airflow obstruction, suggesting an interaction between genetic and environmental factors. It is clearly possible to explain the development of emphysema in patients with α1-AT deficiency because of a defective protective antiproteinase screen within the lung. However, as intimated previously, the majority of patients with COPD and emphysema appear to have normal circulating concentrations, and therefore lung concentrations of, α1-AT. Previous
Role of Neutrophils in Exacerbations
Exacerbations of COPD are episodes in which the patient's symptoms worsen for several days, requiring therapeutic intervention.30 Although neutrophils respond to bacterial infections in all tissues, and represent an important component of secondary host defenses, their role during such episodes is uncertain. Some exacerbations of COPD are undoubtedly related to bacteria, and careful controlled studies31 and meta-analyses32 of antibiotic therapy have indicated an advantage to such interventions,
Summary
In conclusion, the neutrophil can play a central role in many of the features of COPD. The neutrophil contains the only cell products that have been shown directly to cause all of the pathologic features of COPD. It is likely, therefore, that even in the absence of α1-AT deficiency, the size and extent of neutrophil traffic is of major pathogenic importance. Understanding the mechanisms involved should lead to the design of appropriate therapeutic strategies. The site of neutrophil recruitment
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