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1 Respiratory and Inflammation Research Area, AstraZeneca, London, United Kingdom; 2 Developmental Biology and Regenerative Medicine Program, Saban Research Institute, Childrens Hospital Los Angeles, Keck School of Medicine and School of Dentistry, University of Southern California, Los Angeles, California; and 3 Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska
Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, 985910 Nebraska Medical Center, Omaha, NE 68198-5910. E-mail: srennard{at}unmc.edu
ABSTRACT
To advance our ability to effect earlier diagnosis, prevent, and possibly restore healthy lung function in patients with chronic obstructive pulmonary disease (COPD) may require novel thinking. One avenue to explore is the concept of COPD as a trans-generational disease. Early development and COPD may be related first by failure of normal growth development leading to an increased risk of disease, and second by recapitulation of some developmental pathways that may be key to lung repair after injury. While we should be mindful that "aging" may not be only thought of as "late" development in a COPD context, the aging process in the lung is probably fundamentally different from emphysema. However, injury of the aging lung may result in emphysema. Finally, taking a more holistic view of COPD, aging and development in extrapulmonary contexts (e.g., musculoskeletal or immune systems) may also impact on COPD initiation and progression. Addressing the impact of development and the aging process on the natural history of the disease, both in men and in women, may open up research avenues that will drive new advances in disease classification, diagnosis, prognosis, and therapy for this chronic debilitating lung disease.
Key Words: chronic obstructive pulmonary disease • lung development • aging • respiratory disease
The goal of any multidisciplinary conference is to push the limits of current thinking to define new hypotheses. This is based on the concept that insight gained in one area may stimulate new thinking in another. Our current understanding of the natural course of chronic obstructive pulmonary disease (COPD) is based on a prospective epidemiologic study of early stage COPD in men (1), wherein "13% of smokers got a diagnosis of COPD," while the majority of smokers develop disease to a variable extent. The "Fletcher and Peto Curve" that resulted from these studies was later modified by Burrows (2): the concept emerged that maximal lung function attained in young adulthood is a major determinant of lung function later on in life, akin to bone density and the occurrence of osteoporosis in the aged. However, COPD is a heterogeneous disease. It is a collection of "signatures" with a common diagnosis. At diagnosis, one cannot distinguish between natural histories, and herein lies the crux of a fundamental problem—how do you study the importance of development and aging in a disease that mainly occurs later in life given the length of observation required? In addition, COPD affects more than just the lung; there is increasing acceptance of the concept that systemic inflammation can lead to damage in other target organs and tissues (3). It might also be that defects in other tissues may contribute to COPD (e.g., the immune or musculoskeletal systems). There are many measures that are altered in COPD, such as inflammatory cells assessed in sputum or bronchoalveolar lavage. However, these measures are very heterogeneous within the COPD population. While this may reflect heterogeneity in pathogenesis, this remains to be fully delineated.
It is well established that there are benefits to smoking cessation (4), and if one quits early enough, one can get back to a "normal" aging trajectory: symptoms improve and cardiovascular issues diminish, leading to a substantial effect on subsequent mortality. On the other hand, quitting later in the disease has considerably smaller benefits on loss of lung function (5), and inflammation in the lung persists.
Different aspects of COPD may be related differently to the aging process. For example, emphysema versus the peribronchiolar fibrotic lesion that occurs in small airways disease both may compromise FEV1. However, they may have strikingly different relationships to age. Thus to advance disease classification and earlier diagnosis, as well as to identify treatment regimes that prevent and possibly restore healthy lung function, requires a full understanding of the varied aspects of the natural history of the disease. Unfortunately, there is much needed in this regard. We believe that the lateral thinking of COPD as a transgenerational disease contributes to this need. This article will not resolve the complex issues of how development and aging impact COPD, but instead endeavors to emphasize the three key questions addressed in the 2009 Lund COPD Symposium.
WHAT IS THE RELEVANCE OF THE MECHANISMS OF LUNG DEVELOPMENT AND CHILDHOOD EXPOSURES IN PREDISPOSING TO COPD?
The lung performs diverse functions in addition to gas exchange such as air humidification, detoxification, and clearance of environmental particles and does this through the balanced action of the ciliated, secretory, and neuroendocrine cells that line the airways. How these different cell types originate and are orchestrated from lung progenitor cells is not yet understood.
Recent developmental biology research has highlighted the importance of signaling pathways such as Notch (6, 7) on lung cell growth and differentiation. Their impact on basic cellular processes such as the expansion of progenitor cells or critical lung growth factors such as FGF10 (8) have relevance to the structure (e.g., epithelial branching) and function of the adult lung. The heterogeneity observed histopathologically in COPD may arise from a reparative process that attempts to compartmentalize the injury response. Viewed another way, does the string evolutionary pressure to get alveolar repair done rapidly, override doing it right? How does the size and shape of the lung impact incidence and distribution of COPD pathologies within the lung? What is the impact of genetic polymorphisms in developmental pathway genes on the development and repair processes? Subtle defects in the orchestration of these developmental and repair processes may contribute to heterogeneity in vital capacity and lung function decline, as inferred from the "Fletcher and Peto Curve" (1) as well as the more recent Framingham Offspring analysis (5).
Further understanding of the cellular and molecular process involved in lung development could serve as candidate biomarkers or genetic determinates of the disease. Molecular regulators originally associated with the developmental processes in lung may be recapitulated in adult disease, perhaps as part of pathologic responses to injury, or as part of the chronic inflammatory state induced by smoking. To this end, analysis of the airway transcriptome has shown substantial differences in the expression of Notch components associated with smoking and COPD (9). Thus, elucidation of the molecular mechanisms of development may identify novel druggable targets for therapeutic intervention.
Understanding lung development also could be critical to helping repair and/or regeneration of lung tissue. It may also illuminate the processes leading to epithelial hyperplasia that might presage lung cancer. Human clinical trials of adult mesenchymal stem cells in patients with COPD are currently underway (10). Although preliminary, interim analysis has not contravened the primary goal of safety, there was as yet no obvious improvement in pulmonary function. Failure to observe any improvement could be due to the relatively short length of the evaluation period (6 mo not being long enough), or to the fact that the cells may be receiving incorrect spatial and temporal signals. It might be envisioned that better understanding of the molecular signals could identify further points for optimization of this therapeutic modulation.
In addition, recent studies have identified lung self-renewal cells from subjects undergoing lung biopsy (11). It is possible that aberrant activity of these cells might be associated with improper repair (e.g., fibrosis seen in patients with COPD). Alternatively, a subpopulation of these activated stem/progenitor cells in damaged lungs could indicate a first step toward lung cancer (12). However, in situ modulation of these potentially pluripotent cells possibly could be used to drive regeneration as observed in retinal cells from human pluripotent stem cells (13) or modulate improper growth as observed of cancer stem cells (14).
Important lessons may also be learned and applied to COPD from study of the newborn such as those premature infants with bronchopulmonary dysplasia (BPD) (15), of young children (16), or perhaps patients with acute respiratory distress syndrome (ARDS) (17). Lesions in neonates who have BPD resemble those seen in adult COPD. Interestingly, these lesions are reversible to some extent in BPD (18). Improved understanding of alveolarization and septation mechanisms, as well as early lung development are likely to be helpful. It is these processes that presumably contribute to post-pneumectomy lung growth (19). Moreover, patients with ARDS often get substantial recovery of lung structure and function (20). The mechanisms for this, however, are largely unknown.
Early environmental factors may also impact eventual adult lung function (e.g., maternal health before conception, maternal nutrition lung [21], and childhood exposure to environmental pollutants [22–24]). Could this type of information be used to construct an algorithm to predict or identify those at risk for earlier onset of COPD or faster progression when there are additional risk factors (e.g., smoking)?
WHAT IS THE IMPORTANCE OF AGING OF THE LUNG, IMMUNE SYSTEM, AND MUSCULOSKELETAL SYSTEM ON INITIATION, PROGRESSION, OR TREATMENT STRATEGIES FOR COPD?
The presence of respiratory symptoms at baseline and/or a respiratory diagnosis during follow-up appears to identify a group of susceptible smokers (5), suggesting that it may not be what COPD does to the lung, but rather what the lung does back to the insult of smoking that is important. The lung's response may be dependent on many variables, including its cellular population, genetic predisposition, and environmental exposures, principally including but not limited to smoking. One further variable may be aging, not only of the lung but also of other tissues that have an indirect role on lung function such as the immune system and skeletal muscle.
Much of our knowledge about the aging lung and relationship to lung dysfunction comes from study of animal models of accelerated aging, such as the senescence accelerated mouse (25), or the Klotho (26) mouse. However, these are not truly representative of the human patient with emphysema. Nevertheless, clues have emerged from this work that point to the importance of accelerated aging in enhancing susceptibly to COPD, although accelerated aging per se does not result in COPD. The results suggest that intrinsic effects of aging and extrinsic effects of the environment are interrelated, although we lack clarity about the effect of "abnormal" aging on COPD initiation and progression. In addition, it is uncertain whether normal aging should be separated from disease. We also do not know why the effect of smoking or other particulate matter on lung function is greater in the aged than the young lung. Finally, whether we can meaningfully apply what we understand from aging to the diagnosis of COPD is far from certain.
Senescent aging may also impact the reparative capacity of the lung. Preliminary information suggests that in the lung self-renewing (i.e., progenitor) cell density may be lower in material from patients with COPD (27), while the effect of aging is not yet known. The significance of this to lung function decline in patients with COPD is not yet known, nor are the processes that contribute to this decrease. Although it is reasonable to suggest that the interaction between cells and matrix may be important and the impact of lung damage to the matrix may lead to apoptosis, other factors such as telomere shortening, oxidative stress, and epigenetic alterations may also contribute. For instance, differences in embryonic muscle progenitor cell and adult satellite cells have been observed (28). However, it is not known whether lung progenitor/stem cells may also become senescent. To this end it might be useful to evaluate whether accelerated lung aging can enhance susceptibility to COPD, or accelerate disease progression in subjects with COPD. Investigation of accelerated human models of aging (e.g., Downs syndrome) could give us clues that can lead to improved repair of the lung. It is especially interesting to note that in Downs syndrome accelerated aging may be due to faults in stem cells (29). Such evaluation may give information about whether senescence can compromise repair or exacerbate emphysema in the patient with COPD. Finally, it may be possible that how the lung develops may also influence the senescence of lung cells later in life.
Aging in other systems may also impact the patient with COPD. For instance, bacterial and viral infections are the major contributors to exacerbations in patients with COPD. The ability of the immune system to respond to pathogens is diminished in both the young and the elderly (30), with immune responses beginning to decline at around 50 years of age, possibly due to immunosenescence (31). The reduction in the adaptive immune function is compensated for by an up-regulation of innate immunity that in turn leads to a proinflammatory state. Such a series of events in the elderly may favor COPD. However, little is known about the impact of an aging immune system on the incidence or severity of the clinical manifestations in COPD, nor what role this may play in smokers versus nonsmokers. In addition, there is lack of clarity on which of the many immunomodulatory cells contribute the most to this age-related response. In the future, targeted therapies to rejuvenate the aging immune system may help to treat or could even help prevent COPD.
During aging, there is a also gradual decrease in the ability to maintain skeletal muscle function and mass. However, whether this has any bearing on COPD is not known, nor whether the muscles of the diaphragm and those involved in mobility are similarly affected. The latter may be especially important in patients with moderate to severe COPD who experience rapidly developing fatigue in response to physical exercise. Many aspects of skeletal muscle dysfunction in COPD have been identified, including the role of systemic inflammation, oxidative stress, and fiber type switching (32). However, from an aging perspective, a combination of the gradual failure in the satellite cells, which help to regenerate skeletal muscle fibers, and a decrease in sensitivity to or the availability of critical secreted growth factors, which are necessary to maintain muscle mass and satellite cell survival, should be considered (28).
HOW DOES OUR UNDERSTANDING OF LUNG DEVELOPMENT AND AGING AFFECT THE RESEARCH AGENDA FOR COPD?
The current research agenda for COPD largely stems from three mostly separate lines of investigation: clinical trials aimed at registering or supporting new therapies for COPD, epidemiologic studies, and investigation of underlying pathogenetic and physiologic mechanisms. Use of a relatively simple and inclusive disease definition that uses airflow, assessed as FEV1 to both define and stage disease, has generally facilitated enrolment in clinical and epidemiologic studies. This approach makes evaluation of the heterogeneous nature of COPD difficult and has underestimated the extrapulmonary manifestations that are often of prime clinical importance. These approaches are manifest in the Fletcher-Peto diagram, which describes the "Natural History" of COPD entirely in terms of FEV1 (1).
It is now clear that many clinical features of COPD relate poorly to FEV1. These should probably be regarded as separate features of the disease, and the complete description of a patient with COPD would require their evaluation. The number of independent measures required to describe a patient with COPD remains undetermined. However, attempts to define the number of variables required to describe patients with COPD using limited databases have suggested that as many as six variables may be required (33).
Multicomponent indices have been suggested as a strategy to assess parameters in addition to the FEV1. The BODE index, for example, combines airflow, body habitus, dyspnea, and walking distance into a single parameter (34). The resulting index is a better prognostic indicator than any of the components. While this has utility for prognosis, and possibly in assessing response to therapy, it is likely that the components of an index such as BODE progress independently. Separate measures of progression and natural history will, therefore, be required.
Finally, the growing body of literature that supports the involvement of childhood exposures on the initiation and possible progression of COPD supports the need for collecting longitudinal data on lung function from childhood. Although the impact of such information might not be observed for years, such knowledge may in the future be able to generate algorithms to enable better prediction of who might get the disease.
Advances in understanding the physiology and pathophysiology of COPD have a different tradition. Often these studies are conducted on small numbers of subjects who are evaluated in highly specific ways. These investigations have revealed a large number of pathophysiologic mechanisms. These include induction of inflammation, oxidant and proteolytic damage, and disruption of repair and maintenance programs that are mediated by a large and rapidly growing number of cells and biochemical moieties. As a result, these basic studies have identified a very large number of targets for potential therapeutic intervention. Translational studies have supported many of these targets, but have also highlighted the variable expression of mediators within the COPD population, and thus the heterogeneity of the disease.
Studies of the cell biology of the lung have, of necessity, evaluated cells available. Thus, the populations of cells in the lung that are self-renewing have only recently begun to be identified. Further research on these cells may catalyze the development of therapies for lung repair and regeneration.
With regard to heterogeneity, the basic and clinical studies have reached common ground. Several large studies are in progress, which are designed to describe COPD heterogeneity and to relate clinical heterogeneity to objective measures. These studies will test the concept that a more "information-intense" approach, together with the necessary use of diagnostic studies, will be identify more uniform patient populations. Such subgroups may be particularly appropriate for novel therapeutic approaches.
The current symposium highlighted two areas for this developing research agenda. First, developmental pathways that lead to the formation of lung structures are often, in varying degree, activated in the response to lung injury. Targeting these pathways, therefore, is a strategy that could either slow the loss or restore lung function in COPD. In addition, it is clear that the lung in the aged is not the same as the lung in the young adult. While senile lung is not emphysema, it is likely that some aspects of COPD develop most prominently in the aging lung. The pathophysiologic mechanisms in the aged lung are likely to be different in many ways from the mechanisms that have been delineated in younger patients and in young animals. Studies of the aged, together with studies of COPD development during aging, therefore, should be key items on the COPD research agenda.
This agenda should also include the collection of clinical data in greater detail and diversity than has been accomplished to date. It should address longitudinal changes in inflammation and immunity, in particular mechanisms to down-regulate inflammation, which is likely to shed light on extrapulmonary disease relationships. In addition, the role of tissue repair processes, the role of progenitor cells, and the ability to manipulate repair and remodeling (either by altering developmental programs or by replacing cellular populations) should be pursued.
FOOTNOTES
Conflict of Interest Statement: R.A.M. has received reimbursement for employment with AstraZeneca ($100,001 or more). She also has stock ownership or options, and financial interests in AstraZeneca ($100,001 or more). Her spouse/life partner has also declared stock ownership or options in AstraZeneca ($10,001–$50,000). D.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.I.R. notes that he had tobacco industry funding. Specifically, he has received funding from the tobacco industry for studies relating to harm reduction and to the impact of tobacco smoke on stem cells. He has also consulted with RJ Reynolds without personal fee on the topic of harm reduction. He received funding from RJ Reynolds ($100,001 or more) to evaluate the effect of a harm reduction product in normal smokers (1996) and in subjects with chronic bronchitis (1999) and to assess the effect of smoking cessation on lower respiratory tract inflammation (2000); participated in a Philip Morris ($100,001 or more) multicenter study to assess biomarkers of smoke exposure (2002); received funding for a clinical trial from the Institute for Science and Health (2005) ($100,001 or more), which receives support from the tobacco industry, to evaluate biomarkers in exhaled breath associated with smoking cessation and reduction. This study was supplemented with funding from Lorillard ($100,001 or more) and RJ Reynolds. He received a grant from the Philip Morris External Research Program (2005) to assess the impact of cigarette smoking on circulating stem cells in the mouse. He consulted with RJ Reynolds on the topic of harm reduction until 2007, but did not receive personal remuneration for this. There are no active tobacco industry–funded projects. All ties with tobacco industry companies and entities supported by tobacco companies were terminated in 2007. He has also received funding from noncommercial entities such as NHLBI ($100,001 or more) and NIEHS ($100,001 or more).
(Received in original form August 31, 2009; accepted in final form August 31, 2009)
REFERENCES
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