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The Relationship Between Asthma and COPD: Lessons From Transgenic Mice
Section snippets
Inflammation
Studies of biopsy specimens from asthmatic airways have demonstrated a CD4+ lymphocyte-rich, eosinophil-rich, and macrophage-rich inflammatory response. This response is classically found in the bronchial tree and is thought not to be present in alveoli. Studies of biopsy and resection specimens from patients with COPD, however, have revealed prominent increases in CD8+ T cells and macrophages. These responses are most prominent around the bronchi and bronchioles and in alveoli. Increases in
Airway Remodeling
There is an increased appreciation that, in addition to inflammation, structural alterations, which are collectively referred to as airway remodeling, are prominent in asthmatic airways.8 The abnormalities that have been noted include mucous metaplasia with increases in goblet cells and submucosal glands, and intermittent mucous plugging.38 Airway fibrosis is most prominent in the lamina reticularis of the airway, and myocyte hypertrophy, myocyte hyperplasia, and myofibroblast hyperplasia have
Alveolar Remodeling
Classically, asthma is thought of as a disease with normal alveoli in which tissue proteolytic responses do not play a significant role in disease pathogenesis. In contrast, alveolar destruction with secondary alveolar enlargement and a decrease in bronchiolar attachments is a characteristic feature of emphysema. Studies1213141516 of emphysematous human tissues have highlighted alterations that heighten tissue proteolysis, including the enhanced expression of MMPs and cathepsins. However,
Cytokine Profiles
As previously noted, Th2-dominated tissue inflammation is believed to play a central role in asthma pathogenesis. Accordingly, exaggerated levels of interleukin (IL)-4, IL-5, IL-9, and IL-13 have been documented in the asthmatic airway.20 In contrast, Th1-dominated responses, including the enhanced production of interferon (IFN)-γ by CD8+ cells, have been documented in COPD patients.21 The enhanced production of IL-8 and tumor necrosis factor (TNF) also has been documented in COPD patients and
Epidemiology
Numerous investigators have attempted to define the relationship between asthma and COPD using epidemiologic approaches. It is clear from these studies that, in Western societies, the vast majority of patients with COPD are or were smokers. This has led some to believe that these disorders can be differentiated based on this historical finding. However, only 10 to 15% of smokers get significant COPD. Moreover, cumulative estimates of cigarette-smoking exposure have been shown to account for
Dutch Hypothesis
Because of the complexities of the relationship between asthma and COPD (as described by Postma and Boezen elsewhere in this Supplement25), an alternative hypothesis, called the Dutch hypothesis, has been proposed and revised over the years.2627 The Dutch hypothesis suggests that COPD and asthma are not distinct entities in selected individuals, and that similar pathogenetic mechanisms may be involved in the pathogenesis of asthma and COPD in some individuals. The hypothesis also proposes that
Lessons From Transgenic Mice
Mice in which genes can be selectively overexpressed (OE) in a given organ (ie, transgenic mice) are being used with increasing frequency to define the effects that a gene has in a specific organ and the mechanisms that may be operative in human disease. To generate a transgenic mouse, a DNA construct is prepared that contains the gene that the investigator wishes to express linked to a promoter that is designed to drive the expression of this gene in the desired organ and/or tissue. The Clara
IL-13 OE Transgenic Mice
When IL-13 was OE in the murine lung, a striking phenotype was noted. Prominent findings included asthma-like eosinophil-rich, macrophage-rich, and lymphocyte-rich inflammation, mucous metaplasia with goblet cell hyperplasia, airway fibrosis, and AHR.28 In contrast to the traditional concept of asthma, however, alveolar enlargement was also readily apparent.28
The normal mouse is not born with true alveoli. Instead, it is born with large sack-like structures and develops a normal number of
IFN-γ OE Transgenic Mice
Increased numbers of CD8+ cells that produce IFN-γ have been documented in this disorder. To define the role that IFN-γ might play in this disorder, we utilized the inducible overexpression transgenic approaches that have been described previously. These studies demonstrate that the transgenic expression of IFN-γ in the murine lung causes impressive pulmonary emphysema.33 Contrary to the response in the IL-13 mouse, tissue eosinophilia and BAL eosinophilia were not noted. Instead, a modest
Summary
The studies noted illustrate the complex relationship between asthma and COPD. It is clear from these studies that there are populations of patients with COPD and asthma that can be readily distinguished from one another based on their physiology, natural history, and/or disease pathogenesis. It is also clear from these studies that there are many patients who appear to have features of both disorders. It is not clear from our human investigations whether these Dutch hypothesis patients are
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The author has received research grants from Aventis and Millennium, and is a consultant for Aventis and Millennium.