The Challenges of Chronic Obstructive Pulmonary Diseases (COPD)—A Perspective

Abstract

Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory disease, primarily caused by cigarette smoke, which will soon become the third leading cause of death globally. Despite the importance of the problem, our real understanding of the biological underpinnings of COPD remains incomplete. Consequently, our first-line therapies, while helpful, are not yet as effective as they need to be. In this review, we will focus on these challenges and more, including the role of impaired tissue repair and adaptive immunity in disease pathogenesis, determining who may be at risk, describing COPD phenotypes and potential biomarkers. New ideas for chronic disease management and prevention of exacerbations will also be discussed. While much remains to be accomplished, meeting these challenges will bring rewards because what we learn will have implications for the understanding and treatment of chronic inflammatory diseases beyond COPD.

• Chronic Obstructive Pulmonary Disease
• COPD
• Emphysema
• Chronic bronchitis
• Inflammation

COPD—What Is It?

In the United States chronic obstructive pulmonary disease (COPD) is the 4th leading cause of morbidity and mortality, it affects as many as 24 million people, and it costs up to 32 billion per year [1&2]. Moreover, COPD is poised to become the 3rd leading cause of mortality globally by 2020 [[3]]. In short, COPD is among the most important diseases of our lifetime and the lifetimes of our children, yet it is severely underdiagnosed, undertreated, and incompletely understood.

Of the available therapies only oxygen [4&5] and lung volume reduction surgery (LVRS) [[6]] decrease mortality in COPD, reflecting our poor understanding of its molecular and cellular underpinnings. This statement is not meant to say that we have not made progress, or that our therapies are not valuable. To the contrary, long-acting β2-agonists, anti-cholinergics, and inhaled corticosteroids have proven to be quite efficient at decreasing dyspnea, improving quality of life, and decreasing exacerbation rates [[1]][7-10], and they should be aggressively prescribed; but they only scratch the surface of what COPD therapies can and should accomplish.

Even in 2004 debate continues on how COPD should be defined, diagnosed, and treated. This stems largely from the recognition that COPD is not a single entity; rather, it has multiple pulmonary and systemic effects [[11]]. Recently, Gordon Snider brought these issues into focus in his “Nosology for Our Day” [[12]]. He compared the definitions of COPD provided by the American Thoracic Society [[7]], the European Respiratory Society [[8]], the British Thoracic Society [[9]], and the Global Initiative for Chronic Obstructive Lung Disease (GOLD) [[1]][[10]], and ultimately suggested this definition: “COPD is a disease state characterized by incompletely reversible, progressive airflow obstruction that is associated with inflammation in the lungs due to prolonged exposure to tobacco smoke and other noxious particles and gases.”

Dr. Snider noted that all four expert panels made essentially the same key points:

1. Fixed airflow obstruction is a cardinal feature of COPD.

2. Limited reversibility of airflow obstruction in response to bronchodilator drugs is common in COPD, and absenceof such reversibility does not preclude bronchodilator treatment.

3. Asthma with complete reversal of airflow obstruction is not included within the definition of COPD.

4. Chronic airway obstruction due to other diagnosable conditions such as cystic fibrosis and obliterative bronchiolitis is not included in the definition of COPD.

5. Tobacco smoking is the major, but not the only, risk factor for COPD.

6. The cause of the fixed airflow obstruction in COPD is the presence in the lungs of bronchiolitis or small airway disease, and emphysema, which are present in a variable mix among patients.

In this perspective we highlight a few aspects of COPD mainly as they emerge from the publications in years 2003 and 2004. This, we believe, illustrates that COPD research is again gaining momentum. The spectrum of investigative activities is wide—as it must be—reaching from attempts to distinguish the airway inflammation in asthma from that in COPD [[13]], to the assessment of long-term success of rehabilitation [[14]], to mitochondrial function analysis of inspiratory muscles [[15]]. The purpose of this perspective is context and concepts—not completeness. For current management of COPD we refer you to several excellent reviews [[1]][[10]][16-18].

Pathobiology of COPD

COPD affects the entire lung, including the large and small airways, alveoli, vasculature, and the pleura; so truly it is a whole-lung disease [[1]][19&20]. But, in thinking about COPD, we should not limit ourselves to the lung. COPD is also a systemic disorder that affects the cardiovascular system (e.g., atherosclerosis) [21-26], the musculoskeletal system (e.g., osteoporosis and muscle dysfunction) [27&28], the central nervous system [[29]], and the endocrine system [[30]]—all in a smoking-independent manner.

Cigarette smoke initiates COPD in 80–90% of cases through intense oxidant stress, but cigarettes are not the only risk factors; others include fine organic and inorganic dusts, air pollution, impaired lung development, HIV seropositivity, and genetic factors such as α1-antitrypsin deficiency [[1]] Cigarette smoke causes oxidant damage to the exposed epithelial surface, which initiates an inflammatory response. The cellular components involved include epithelium, macrophages, neutrophils, eosinophils, mast cells, dendritic cells, T and B lymphocytes, and natural killer cells [31&32]. This vigorous inflammatory response is thought to cause tissue damage primarily by releasing proteases (e.g., neutrophil elastase, matrix metalloproteinases [MMP]), cytokines (e.g., TNF-, IFN-γ, IL-1β, and IL-6) and chemokines (e.g., IL-8) [[32]]. Inflammatory cells also release free radicals that cause further oxidant/anti-oxidant imbalance. An important finding that should not go unmentioned is that the inflammatory response induced by cigarette smoke remains persistent, despite smoking cessation [33-36], suggesting that homeostasis has become permanently unbalanced. Ultimately, chronic inflammation results in airway remodeling characterized by goblet cell hyperplasia, mucus hypersecretion, ciliary dysfunction, airway fibrosis and narrowing [[1]][19&20].

COPD—Unmet Needs

An expert panel assembled by the National Heart, Lung, and Blood Institute (NHLBI) recently focused on needs and opportunities in COPD; they concluded that “chronic obstructive pulmonary disease is a common condition and one difficult to manage. Available treatments other than smoking cessation, are only minimally effective and the knowledge basis for clinical decision making is limited” [[37]]. The expert panel recognized 14 high-priority, clinical questions that remain unanswered, and recommended that future research be conducted to:

1. Establish a multi-center clinical research network to perform multiple, short-term clinical trials of treatments in patients with moderate-to-severe COPD.

2. Develop standards for the classification and staging of COPD.

3. Characterize the development and severity of COPD using measures and biomarkers that relate to current concepts of pathogenesis.

4. Create a system for the standardized collection, processing, and distribution of lung tissue specimens and associated clinical and laboratory data.

5. Evaluate indications for long-term oxygen therapy for patients with COPD.

Clearly, COPD has now been recognized as the huge, global health problem that it is. This NHLBI Workshop Summary [[37]], should be required reading for both scientists and clinicians alike, who are involved in understanding and treating COPD. Indeed, at the time of this writing two of the above research aims have begun. A multi-center COPD Clinical Research Network has been established by NHLBI, and measures are being taken to encourage the development and validation of novel biomarkers of disease and disease activity. In addition, the National Institutes of health has established a COPD Lung Tissue Repository. We will take this opportunity to highlight several of the unmet needs that were identified in the NHLBI Workshop Summary [[37]] and to expand on a number of questions that we believe are likely to be critical to understanding the pathobiology of COPD, and to the development of effective, next-generation therapies.

Assessment of Risk

The most important burning question is why do only 15–20% of cigarette smokers develop emphysema? Because factors must exist that distinguish the host that is susceptible to cigarette smoke from the lifetime smoker who is not, any serious preventive strategy will have to start with theunraveling of genetic and environmental susceptibility factors, and their role in the pathobiology of COPD. Although cigarette smoking is risk factor number one, the association of HIV-infection with emphysema in non-smokers and accelerated emphysema in smokers [38-40], or the rare occurrence of emphysema in patients with hypersensitivity pneumonitis [[41]], indicates that there are other unexplored risk factors.

Latent adenoviral infections have increasingly been suggested as initiators or enhancers of airway inflammation in COPD [[42]]. Adenoviruses persist in airway epithelial cells following acute infection [[43]]. In guinea pigs, latent adenoviral infection increased the acute inflammatory response to cigarette smoke [[44]], and over 13 weeks of smoke exposure latent adenoviruses increased both inflammation and emphysema [[45]]. In patients with emphysema, cigarette smoke amplified the inflammatory response in a manner directly related to the degree of latent adenoviral infection [[35]]. Most recently, Ogawa and colleagues demonstrated that latent adenoviral infection also increased growth factors relevant to airway remodeling in COPD [[46]]. Moreover, because latent adenoviruses can induce steroid resistance [[42]], they may contribute to the inability of inhaled steroids to prevent the long-term decline in lung function in COPD [[47]].

There is now evidence that Pneumocystis jiroveci (formerly Pneumocystis carinii) may also contribute to progressive loss of lung function in COPD [[48]]. Morris and colleagues demonstrated that 36.7% of GOLD stage IV patients were colonized with Pneumocystis; this translated into a smoking-adjusted odds ratio of 21 in favor of colonization for GOLD stage IV, compared to less severe GOLD stages. This is an intriguing association, because HIV-infected subjects with Pneumocystis also have accelerated declines in lung function that are indistinguishable from COPD [[49]], and as stated above, appear to be highly susceptible to emphysema [38-40].

Several studies have shown an inconsistent relationship between diabetes mellitus and decreased lung function [50-53]. Recently, Walter and colleagues took a fresh look at this issue by evaluating lung function, diabetes mellitus, and glycemic state in 3254 members of the Framingham Heart Study Offspring Cohort [[54]]. They found that either a diagnosis of diabetes or higher glycemic states were associated with lower lung function, and that this relationship was stronger among ever-smokers than non-smokers. These investigators found that the FEV₁ was 139 ml lower in smokers with diabetes, compared to smokers without diabetes. They raised the possibility that diabetes may increase the susceptibility to the adverse of effects of tobacco smoking, and they proposed that this association might offer insights into the pathogenesis of both COPD and diabetes. Possibly, diabetes and hyperglycemia augment inflammatory responses [[54]] and oxidative stress [[55]] in the lung.

Investigations into the risk factors responsible for the development and progression of COPD are only just beginning. The NHLBI Workshop Summary articulated the situation best when they said, “our understanding of the pathogenesis of COPD, especially as it relates to the variable risk of disease among those exposed, remains quite limited. Risk factors other than tobacco smoking likely contribute to the pathogenesis of COPD, although little is known about these” [[37]].

The Role of the Immune System and Tissue Repair Mechanisms in COPD Pathogenesis

The immune response to cigarette smoke is a powerful force in the development and maintenance of COPD. Up to now most research has focused on the role of the innate immune response, which includes the epithelial cell barrier, intra-epithelial lymphocytes, neutrophils, monocytes, and macrophages [[42]]. These cells are the first-line defense against tissue injury or microorganisms. The collectins, including mannose binding protein, surfactant protein A, and surfactant protein D are innate immune opsonins that interact with pathogen-associated molecular patterns on micro-organisms, ultimately orchestrating their recognition, phagocytosis and destruction by phagocytes. Collectins also perform a related function in the removal of dying, apoptotic cells and on regulation of inflammation [[56]], which may have some bearing on the pathogenesis of COPD [57-60].

In contrast to the innate immune system, the adaptive immune system has largely been ignored; despite the fact that COPD is characterized by increased antigen-presenting dendritic cells, T and B lymphocytes, and bronchus-associated lymphatic tissue [[19]][[42]]. Recently, Agusti and colleagues proposed the hypothesis that, “an acquired immune response to newly created or altered epitopes is an essential component in the pathogenesis of COPD,” and thus suggesting that there is an autoimmune component to COPD. Cigarette smoke might create new antigens through oxidation, or expose hidden antigens by delaying removal of apoptotic cells. In support of this hypothesis, apoptotic cells appear to be increased in COPD [[57]], and the ability of macrophages to ingest these cells may be impaired [[61]]. Since intestinal bacteria are known to be a source of new antigens in rheumatoid arthritis, Agusti and colleagues suggested that airway bacterial colonization may be exerting a similar effect in COPD. Finally, latent viruses in airway epithelium may also be a source of antigens that could drive cytolytic CD8+ T-cell recognition and epithelial destruction [[31]][[62]]. This is an enticing hypothesis that could potentially help explain the 40–50% of COPD exacerbations not caused by infections.

In COPD, inflammation is enhanced and is relatively steroid resistant [[63]]. Barnes and colleagues recently proposed a novel hypothesis; they suggested that enhanced inflammation and corticosteroid resistance may be due to oxidant-mediated inactivation of histone deacetylase-2 [[63]]. Transcription of inflammatory mediator genes is regulated by several nuclear transcription factors, such as NFκB and AP1. These transcription factors bind to a co-activator complex, which has intrinsic histone transacetylase activity. Acetylationof core chromosomal histones causes DNA to unwind and allows RNA polymerase to bind and initiate transcription. Therefore, regulation of histone acetylation is a key step in controlling the inflammatory response. Because cigarette smoke (likely through oxidant stress) decreases histone deacetylase expression, increases inflammatory cytokines, and suppresses the anti-inflammatory effect of corticosteroids [[64]], Dr. Barnes proposed that histone deacetylase inactivation may be an important mechanism underlying the dysregulated inflammation of COPD [[63]].

Could the normal homeostatic balance of alveolar cell life, death, and replacement be disrupted in COPD? We believe that this is a possibility because increased numbers of apoptotic cells are present in the lungs of emphysema patients [65&66] and in the sputum of chronic bronchitis patients [[57]]. Animal models also support this possibility, because factors that increase endothelial [[67]] or epithelial cell [[68]] apoptosis can directly cause emphysema. We propose that homeostatic imbalance of alveoli could come from: 1) overwhelming endothelial or epithelial death, 2) decreased clearance of damaged/dead cells, or 3) decreased proliferation of epithelial or endothelial cells. Cigarette smoke may initiate and maintain homeostatic imbalance by inducing apoptosis of alveolar structural cells and by decreasing their removal.

This model raises the question of whether epithelial or endothelial regeneration is the key element in maintaining parenchymal homeostasis—or whether both are critical. If indeed epithelial and/or endothelial regeneration is key and impaired in COPD, then which growth and maintenance factors are involved? Are stem cells involved? Are bone marrow-derived cells involved [[69]]? Increased and persistent generation or supply of apoptosis inducers may lead to selection of apoptosis resistant cells, which could be a source of early neoplasia.

The ultimate outcome from impaired tissue repair may be either tissue loss (emphysema) or fibrosis (scar). Hogg and colleagues recently looked for small airways inflammation and fibrosis in tissues taken during the National Emphysema Treatment Trial [[6]] and early GOLD-stage COPD patients [[19]]. As GOLD stage increased, small airways demonstrated increased innate and adaptive immune cells, structural narrowing and fibrosis, thus confirming the importance of small airways, and the role of fibrosis, in the pathogenesis of COPD.

Phenotyping

It has become increasingly clear that distinguishing among various COPD phenotypes is essential; this is especially true because the heterogeneity of COPD forces clinical trials to be large in order to achieve adequate power. COPD patients may have pulmonary hypertension [[70]], chronic hypoxemia [[4]], sleep disordered breathing and nocturnal hypoxemia [[71]], nutritional deficiency/low body mass index [[72]], or exercise impairment [[73]]; and these may all impact survival. These are only a few of the manifestations, or co-morbidities, associated with COPD that may separate useful patterns, or phenotypes, and allow us to better prognosticate, or to tailor our therapies.

Bart Celli has taken a giant step forward in the development and validation of a multi-dimensional, disease-stratifying algorithm that depends on the combination of well-described COPD phenotypes that impact on survival [[74]]. The BODE index combines body-mass index (B), the degree of airflow obstruction (O), dyspnea (D), and exercise capacity (E) to accurately predict death from any cause, or respiratory causes, among patients with COPD. The allure of this index is that it uses simple, cheap, reproducible measurements that could be completed in any setting. The success of the BODE index likely stems from the combination of parameters that assess the systemic, pulmonary, and neurologic effects of COPD. Because at similar FEV₁ values, higher BODE scores portend a worse prognosis, it appears to be describing clinically relevant subsets of patients. One could foresee the BODE index contributing to the decision-making process for lung transplantation [[75]]. It will also be interesting to see whether the BODE index can be used to predict efficacy in clinical trials. In other words, if a new therapy changes the BODE index, will that translate into a change in prognosis? Time and validation will hopefully answer these questions.

Maximum exercise capacity alone may help define a unique subset of COPD patients in a clinically meaningful way. Oga and colleagues evaluated the maximum oxygen consumption, and health status, of a group of COPD patients and related this to mortality. These investigators established a link between diminished exercise capacity and higher mortality, which was independent of FEV₁ or age [[76]].

In COPD, the degree of pulmonary hypertension is likely grossly underestimated, because the evaluation of the patients is typically based on resting hemodynamics; it does not take into account pulmonary hypertension as it develops during exercise and sleep [[70]]. Therapeutically, long-term oxygen treatment has been shown to be the only treatment, which slows down the progression of pulmonary hypertension in chronic obstructive pulmonary disease although the structural abnormalities of the pulmonary vessels remain unaffected [[77]]. Whether endothelial cell dysfunction, a hallmark of pulmonary hypertensive disease in COPD, is affected by oxygen treatment is unknown.

Biomarkers

As we move toward a better understanding of the underlying pathobiology of COPD, and its varied clinical manifestations, we will better be able to identify and validate effective biomarkers. To be useful, biomarkers will need to predict underlying disease susceptibility, progression, or propensity for exacerbation, and they will need to be available and cheap.

Exhaled breath and breath condensate are potential sources of disease information that are currently being investigated, mainly for markers of inflammation (e.g., cytokines and leukotrienes) and oxidative stress (e.g., NO, CO, ethane, andisoprostane) [[78]]. The main advantage to these methods is that they are non-invasive.

Gene polymorphisms and their relation to COPD are also being investigated. Guo and colleagues described several smoking-dependent and -independent surfactant protein polymorphisms that were associated with COPD [[58]]. Yang and colleagues found that mannose binding lectin polymorphisms in COPD patients were associated with more frequent hospitalizations for respiratory infections.

The balance of inflammatory [79&80] and anti-inflammatory [[81]] mediators is also being examined. One recent study by Sinn and colleagues [[82]] showed that as little as two weeks of inhaled fluticasone could decrease C-reactive protein by 50% and suggested that this may have an effect on improving cardiovascular outcome in COPD [[26]]. For that matter, could other therapies that decrease C-reactive protein (e.g., aspirin and statins) affect outcomes in COPD patients? Finally, because vascular endothelial growth factor is decreased in the lungs of patients with emphysema [[66]], it may also turn out to be a valuable biomarker.

Strategies for Exacerbation Management and Prevention

The NHLBI Workshop Summary clearly conveyed our current situation in regard to exacerbation management when they said, “acute exacerbations of COPD are the major battlefront of the physician's war on this disease, and the arsenal is ineffective.” Caring for patients with COPD is costly. Sixty-four percent of the direct costs of COPD care are for hospitalizations and emergency department visits [[83]]. Long-acting β2-agonists, anti-cholinergics and inhaled corticosteroids all decrease exacerbation rates, yet they are grossly underprescribed [[1]][[17]]. The prohibitive cost of caring for these patients and their morbidity should convince us that we must do better.

A recent study from the Netherlands demonstrated that oral N-acetylcysteine decreased the risk of re-hospitalization for a COPD exacerbation by 30% [[84]]. These data were also interesting because there was a dose relationship, such that the risk for re-hospitalization was most reduced in the groups that received 400 mg per day or greater. In contrast, treatment with oral prednisone resulted in a marginally diminished relapse rate at 30 days after the initial COPD exacerbation [[85]]. The optimal treatment of COPD, and COPD exacerbations, remains to be discovered. The treatment of patients with COPD with inhaled steroids has been assessed as highly effective by some investigators [[1]][[10]][[17]], yet the interpretation of these studies has now been criticized [[86]].

Strategies for Chronic Disease Management

Results of a multi-center study were recently presented by the National Emphysema Treatment Trial Research Group [[6]]. The data showed that patients with predominantly upper-lobe emphysema and a low maximal work load had a greater probability of survival, improvement in exercise capacity, and improvement in symptoms if they underwent LVRS, compared to medical therapy alone. As expected, LVRS is not the answer for all patients with severe emphysema, although discrete subgroups of patients will certainly benefit from this treatment.

FORTE (Feasibility of Retinoic Acid in Treatment of Emphysema) has been a multi-center, randomized, double-blinded, placebo-controlled clinical trial funded by the NHLBI looking at the effect of different retinoic acid derivatives on the progression of emphysema [[87]]. A substantial amount of preclinical data supported the notion that retinoic acid derivatives may promote alveolar growth and resolution of emphysema [88&89], and a phase 1 clinical trial demonstrated safety [[90]]. FORTE ended in 2003 and preliminary results were presented at the 2004 American Thoracic Society International Meeting. One hundred and forty-eight emphysema patients were randomized to receive 6 months of all-trans-retinoic acid in high-dose (1 mg/kg twice per day) and low-dose (0.5 mg/kg twice per day), 13-cis retinoic acid (1 mg/kg per day), or placebo. Unfortunately, none of the retinoic acid preparations, or doses, tested had any effect on the natural course of emphysema. Even though the results of this trial appear to be negative (final publication pending) it is a very important step in the right direction; that is attempts to promote disease stabilization or reversal.

Insights Derived from New Animal Models

Recent experimental data derived from novel animal models have broadened our concepts of mechanisms, which may be involved in the development of emphysema. Among these models, alveolar cell apoptosis seems to be a recurring theme. Kasahara and colleagues originally demonstrated that rats, treated with a broad inhibitor of vascular endothelial growth factor receptors, developed emphysema associated with endothelial cell apoptosis [[67]], and that this pattern was echoed in human emphysema [[66]]. Tuder followed up on this work by showing that oxidative stress and apoptosis interact to cause emphysema [[91]]. Aoshiba and colleagues turned the equation around by demonstrating rapid emphysematous airspace enlargement after direct airway instillation of membrane-permeable caspase-3, which resulted in massive epithelial apoptosis [[68]]. Therefore it appears that either endothelial cell or epithelial cell apoptosis can contribute to emphysema development. Massaro and colleagues showed that caloric restriction can induce emphysema and lung apoptosis, and that re-feeding reverses the process [92&93]. Interestingly, starvation in adult humans also leads to emphysema [94-96]. Overall, these data suggest that apoptosis may be an important, common, driving factor underlying emphysema development, and that the time required for alveolar loss and formation may be much faster than originally appreciated.

Regulation of matrix metalloproteinases is also an important determinant of lung homeostasis. Morris and colleagues demonstrated that β6-integrin deficient mice spontaneously develop emphysema through a MMP-12-dependent mechanism [[97]]. The authors were able to connect this mechanism to faulty TGF-β1 activation. They did this by showing that the β6-integrin directly activates latent TGF-β1, which suppresses MMP-12. Thus, β6-integrin deficient mice develop emphysema because of the failure of TGF-β to suppress MMP-12 [[97]]. Choe and colleagues also demonstrated that chronic treatment of adult rats with methylprednisolone causes emphysema associated with MMP-9 activation, caspase-6 activation, and alveolar septal cell apoptosis [[98]].

Conclusion

As we enter the 21st century, we must vigorously pursue a deeper understanding of the biologic underpinnings of COPD in order to accomplish our ultimate therapeutic goals, complete restoration of lung tissue homeostasis. FORTE was the first attempt to achieve this “holy grail,” and doubtless more will follow. These endeavors will truly range from bench to bedside, and even more importantly across scientific disciplines. Collaboration will be essential between pulmonary scientists, developmental biologists, vascular biologists, stem cell biologists, neuroscientists, and more. Should we rise to meet this challenge, our bonus will be a better understanding of the complexities of chronic lung diseases, and how they eventually lead to total body disease, and during this process we will gain invaluable knowledge about the regulation of normal lung homeostasis—in short, a challenge with a windfall.