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The Relationship Between Asthma and COPD^*

Lessons From Transgenic Mice

^* From the Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT.

Correspondence to: Jack Elias, MD, Chief, Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520; e-mail: jack.elias{at}yale.edu

	Abstract

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 
Asthma is characterized by eosinophilic and mononuclear cell infiltration, mucous metaplasia, airway remodeling, reversible airflow obstruction, and airway hyperresponsiveness. COPD is typified by nonreversible or incompletely reversible airway obstruction, often accompanied by mucous metaplasia and alveolar destruction. There is considerable overlap in pathogenesis and clinical features between the conditions. However, asthma and COPD may be distinguished by their respective cytokine profiles. Studies in transgenic mice have illuminated the roles of the T helper (Th) 1-mediated cytokine interferon- in COPD, supporting the British hypothesis, and the Th2-mediated cytokine interleukin-13 in asthma, supporting the Dutch hypothesis. COPD and asthma may represent disease states along a continuum, with varying degrees of each disease often present in the same patient.

Key Words: airway remodeling • alveolar remodeling • COPD • cytokine • Dutch hypothesis • interleukin • transgenic • tumor necrosis factor

	Introduction

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 
The ability of asthma to cause episodic coughing, wheezing, and shortness of breath has been recognized since antiquity. In accord with the medical importance of asthma, students of human biology have worked diligently to define and characterize this disorder. As a result of these efforts, our concept of asthma pathogenesis has evolved from the prior assumption that asthma is caused by an intrinsic abnormality in airway smooth muscle to our present conceptualization that asthma is a chronic inflammatory disorder of the airway. Inherent in this conceptualization is the belief that a dysregulated T helper cell (Th) type 2 inflammatory response is responsible for the eosinophilic and mononuclear cell infiltration, mucous metaplasia, airway remodeling, reversible airflow obstruction, and airways hyperresponsiveness (AHR) that are seen in asthma patients and that characterize asthma.

COPD is a composite term that is used to describe a variety of diseases including chronic bronchitis and emphysema. Like asthma, COPD is characterized by a variable airflow obstruction, can be seen with AHR, and manifests as episodic shortness of breath, dyspnea, and wheezing. In contrast to asthma, however, the airways obstruction in COPD is classically irreversible or incompletely reversible, and the mucous metaplasia of chronic bronchitis and the alveolar destruction of emphysema cause a chronic, progressive loss of lung function.¹ The protease-antiprotease hypothesis has dominated pathogenetic thinking about COPD over the past 40 years. It proposes that there is a balance between proteases such as matrix metalloproteases (MMPs), cathepsins and serine proteases, and antiproteases, such as tissue inhibitors of metalloproteases, cystatins, ₁-antitrypsin, and secretory leukocyte proteinase inhibitor. In the healthy lung, an antiprotease shield is believed to predominate, preventing proteolytic parenchymal injury. Emphysema is proposed to occur when there is an increase in proteases or a decrease in antiproteases, a process that can be initiated by oxidant lung injury and/or lung inflammation.¹

The relationship between asthma and COPD has been speculated on and investigated. What is called the British hypothesis has held scientific and clinical sway in recent years. It proposes that asthma and COPD are distinct entities that are generated by distinct mechanisms. A variety of lines of evidence have been cited to support this idea. For example, it has long been contended that, in contrast to COPD, the airways obstruction in asthma is totally or largely reversible and that asthmatic patients do not experience progressive loss of lung function. However, some studies²³ have highlighted asthmatic populations with rapid rates of lung function loss and irreversible airflow obstruction. In addition, patients with COPD with reversible airways obstruction also have been documented.⁴ The differences between asthma and COPD in inflammation, airway remodeling, alveolar remodeling, and cytokine production are not as disease-specific as they once were thought to be. Each is reviewed below.

	Inflammation

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 
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 neutrophils are prominent findings in BAL fluids from patients with COPD.¹ However, a number of studies have blurred the clarity of these distinctions. These studies demonstrated that alveolar inflammation can be seen in the asthmatic lung⁵ and that neutrophilia is a common finding in tissues and biological fluids in patients with severe asthma.⁶ It is now appreciated that tissue eosinophilia is a common finding in COPD patients, especially in those with acute disease exacerbations.⁷ Notably, these COPD patients respond more vigorously to therapy with steroids than do patients without these eosinophil findings.⁴

	Airway Remodeling

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 
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 been well-described.³⁸ Although less attention has been directed at blood vessel alterations in this disorder, a number of investigations have noted an increase in blood vessel number and an increase in vessel leakiness and mural edema.⁹¹⁰

Studies of the airways of patients with COPD have focused, to a great extent, on the mucous metaplasia, goblet cell hyperplasia, and mucous gland enlargement that are characteristic of chronic bronchitis. Although epithelial alterations that are more specific for COPD (ie, atrophy, focal squamous metaplasia, and ciliary abnormalities) also have been described, the mucous responses in patients with chronic bronchitis and asthma are similar in many ways.³ Many studies of COPD tissues have not highlighted prominent muscle or fibrotic changes in the airway. In fact, standard definitions of COPD frequently point out the lack of overt fibrosis in this disorder. It is now appreciated, however, that an increase in total airway smooth muscle also occurs in COPD patients, most prominently in the small bronchi and bronchioli.³ In addition, dysregulated repair with peribroncheolar fibrosis and mural wall edema also have been recognized in COPD patients.³¹¹

	Alveolar Remodeling

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 
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. Studies^1213141516 of emphysematous human tissues have highlighted alterations that heighten tissue proteolysis, including the enhanced expression of MMPs and cathepsins. However, states of increased elastin degradation and enhanced expression of proteases also have been documented in asthma patients.¹⁷¹⁸ These abnormalities may contribute to the COPD-like alterations in lung compliance (referred to as pseudo-emphysema) that have been described in asthmatic patients.¹⁹

	Cytokine Profiles

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 
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)- 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 has been proposed to contribute to the pathogenesis of COPD. However, studies²²²³ of asthmatic patients also have demonstrated increased levels of TNF, and polymorphisms have been shown to correlate with the presence of asthma in some populations. Most recently, the soluble TNF- receptor, a potent TNF inhibitor, has been demonstrated³ to be an effective therapy for patients with chronic severe asthma.²⁴ In addition, increased levels of IL-4, IL-5, and IL-13 have been documented in COPD patients.

	Epidemiology

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 
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 only 10 to 15% of the variation in FEV₁ in a given patient population. Atopy, increased IgE levels, AHR, eosinophilia, and asthma, however, all have been shown to be risk factors for developing COPD in smokers. Rapid rates of lung function loss have been seen in asthmatic patients who smoke. The latter observations highlight an important, but poorly understood, relationship between atopy, and Th2-like responses and susceptibility to the adverse effects of cigarette exposure.

	Dutch Hypothesis

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 
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 endogenous factors (presumably genetic), including those that contribute to the genesis of AHR and atopy, are responsible for a basic disturbance or constitution that predisposes a person to the development of chronic obstructive lung diseases.

	Lessons From Transgenic Mice

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 
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 cell 10-kd protein promoter is frequently used to target gene expression because it is selectively expressed by the Clara cells that make up 40% of the epithelium of the murine airway. To generate transgenic mice, male and female mice are allowed to mate, and the fertilized eggs are washed out of the female’s oviduct. The desired DNA construct is then directly microinjected into the pronuclei of these eggs, and the eggs are placed in the uterus of a pseudopregnant mouse. A pseudopregnant mouse is a female mouse that has been mated with a vasectomized male mouse. She is behaving, from a hormonal perspective, as if she is pregnant, and does get pregnant when the fertilized eggs are deposited in her uterus. She subsequently carries to term, delivering a litter of pups, some of which have the transgene integrated into their genome. These mice are differentiated from one another by extracting DNA from tail biopsies and determining whether the transgene is present by Southern or polymerase chain reaction analysis. Thus, an outstanding experimental system is established in which one can compare the phenotypes of mice born to the same mother, on the same day, that are exposed to the same environment and differ only in the genes that have been inserted. Because it has been proposed that asthma and COPD are mediated by Th2 and Th1 responses, respectively, this transgenic approach was used to express the Th2 cytokine IL-13 and the prototypic Th1 cytokine IFN-. The results that were obtained are outlined below.

	IL-13 OE Transgenic Mice

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 
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 appropriately sized alveoli as the result of a postnatal growth and septation process. Thus, enlarged alveoli in a transgenic mouse could be caused by a transgene that either induces a destructive response in a normally formed lung or blocks lung development. To differentiate between these options, we developed OE transgenic mice in which IL-13 gene expression could be externally regulated. This allowed us to express IL-13 selectively in the fully formed lung and to see whether IL-13 still caused alveolar alterations. In these experiments, IL-13 caused alveolar enlargement when expressed in a fully formed lung. This demonstrates that IL-13 induces an emphysema-like tissue response.²⁹

One of the advantages of these models is that they allow investigators to dissect the pathways that mediate tissue pathology. Studies of the IL-13 transgenic mice have revealed a number of mechanisms that are particularly relevant to the pathogenesis of asthma and COPD. These studies demonstrate that IL-13 generates airway fibrosis by inducing and activating TGF-ß₁.³⁰³¹ In accord with the belief that emphysema is the result of proteolytic tissue injury, IL-13 was shown to induce the expression of a variety of MMPs and cathepsins. Interventions that have blocked MMPs or cathepsins markedly ameliorated the IL-13-induced emphysematous response.²⁹ Enhanced levels of adenosine have been documented in fluids and tissues from patients with asthma and COPD, and aerosol adenosine challenge elicits bronchospasm in these patients but not in control subjects. IL-13 has been shown³² to be a potent stimulator of adenosine accumulation and a potent inhibitor of adenosine deaminase.

These studies demonstrate that IL-13, a gene that has been intimately implicated in the pathogenesis of asthma, also has the ability to induce an alveolar remodeling response that includes significant emphysema. In many ways, the IL-13 OE transgenic mouse represents the molecular validation of the Dutch hypothesis.

	IFN- OE Transgenic Mice

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 
Increased numbers of CD8⁺ cells that produce IFN- have been documented in this disorder. To define the role that IFN- 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- 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 increase in tissue neutrophils and an impressive increase in BAL fluid neutrophils were seen. IFN- did not induce mucous metaplasia. It did, however, cause impressive increases in MMPs and cathepsins, which contributed to the alveolar remodeling in this modeling system. In many ways, the IFN- transgenic mouse is the molecular validation of the British hypothesis.

	Summary

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 
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 persons with a unique form of COPD or patients who happen to have two common diseases (ie, asthma and COPD) simultaneously. It is evident, however, that IL-13 and IFN- individually can activate pathways in the murine lung in vivo that generate syndromes that are compatible with the Dutch and British hypotheses, respectively (Fig 1 ). As a result of these findings, it is reasonable to hypothesize that in these patients there is a continuum between COPD/emphysema and asthma (Fig 2 ). At the asthmatic extreme are patients with normal alveoli, normal pulmonary compliance, and minimal tissue proteolysis and injury. As one moves toward COPD and emphysema, there is a progressive increase in alveolar destruction, compliance, and parenchymal injury and remodeling. Using this concept, it is easy to see how varying degrees of asthma and COPD may overlap in the same individual.

View larger version (22K): [in this window] [in a new window] [Download PPT slide]   Figure 1.. Potential mechanistic heterogeneity in COPD. In transgenic mice, IL-13 and IFN- both cause emphysema. The IL-13 response is associated with mucous metaplasia and eosinophilia, and looks like what one would expect from Dutch hypothesis patients. In contrast, the IFN- response is associated with an increase in neutrophils and lacks mucous metaplasia. It has many of the features one would expect from British hypothesis patients. Both pathways are associated with increases in proteases and decreases in antiproteases. SLPI = secretory leukoprotease inhibitors; AT = antitrypsin.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 2.. Proposed relationship between asthma and emphysema.

	Footnotes

 
Abbreviations: AHR = airways hyperresponsiveness; IFN = interferon; IL = interleukin; MMP = matrix metalloprotease; OE = overexpressed; Th = T helper cell; TNF = tumor necrosis factor

The author has received research grants from Aventis and Millennium, and is a consultant for Aventis and Millennium.

	References

TOP Abstract Introduction Inflammation Airway Remodeling Alveolar Remodeling Cytokine Profiles Epidemiology Dutch Hypothesis Lessons From Transgenic Mice IL-13 OE Transgenic Mice IFN-{gamma} OE Transgenic Mice Summary References

 

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Elias, J. Search for Related Content PubMed PubMed Citation Articles by Elias, J.