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American Journal of Respiratory Cell and Molecular Biology. Vol. 28, pp. 551-554, 2003
© 2003 American Thoracic Society
DOI: 10.1165/rcmb.F269

Perspective

Apoptosis and Emphysema

The Missing Link

Rubin M. Tuder, Irina Petrache, Jack A. Elias, Norbert F. Voelkel and Peter M. Henson

Department of Pathology, Division of Cardiopulmonary Pathology, and Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Section of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut; Division of Pulmonary and Critical Care Medicine, and COPD Center, Department of Medicine, University of Colorado School of Medicine, Denver, Colorado; and Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado

Address correspondence to: Rubin M. Tuder, M.D., Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine, 720 Rutland Ave., Ross 519, Baltimore, MD 21205. E-mail: Rtuder{at}JHMI.EDU

Abbreviations: chronic obstructive pulmonary disease, COPD • matrix metalloprotease, MMP • vascular endothelial growth factor, VEGF

Emphysema, which with chronic bronchitis accounts for most of the chronic obstructive pulmonary diseases (COPD), is defined as "a condition of the lung characterized by abnormal, permanent enlargement of airspaces distal to the terminal bronchiole, accompanied by destruction of their walls, with or without obvious fibrosis" (1). The concepts of permanent and destruction are critical in this definition, as they convey the unique and characteristic distinguishing features of a disease process ultimately leading to the disappearance of lung tissue. Over the past 30 years, inflammation and a protease/antiprotease imbalance have been proposed to act as downstream effectors of the lung destruction following chronic cigarette smoking, which accounts for 95% of cases of emphysema. Accordingly, emphysema study designs relied on determining whether a specific experimental approach aimed at exposing animals to chronic cigarette smoke, lung inflammation, or proteolytic destruction of alveolar matrix caused or did not cause emphysema (2).

However, the emphasis on alveolar matrix destruction by the combination of inflammation and excessive proteolysis has failed to fully account for the mechanisms behind the eradication of septal structures (3) and the unique nature of lung destruction as compared with alterations seen in other inflammatory lung diseases. For example, the downstream consequences and the direct injury to alveolar cells by components of cigarette smoke have received much less attention. It is in this context that the contribution of the work of Aoshiba and coworkers should be analyzed (4).

Building on a recent paradigm that highlights the presence of apoptosis in human emphysematous lungs (5–7) (Figure 1) and the causal role of apoptosis in an animal model of emphysema initiated by blockade of vascular endothelial growth factor (VEGF) receptors (8), Aoshiba and colleagues asked whether directly-induced alveolar cell apoptosis suffices to trigger emphysema. By using an amphipathic reagent to transport proteins into bronchial epithelial cells in vivo, Aoshiba and coworkers showed that intrabronchial delivery of active caspase 3 or nodularin (a serine/threonine kinase inhibitor) caused alveolar apoptosis and emphysema that started as early as 2 h after instillation. Whereas alveolar apoptosis was no longer evident 6 h after instillation, morphometrically detectable and physiologically significant airspace enlargement persisted for at least 15 d, followed by gradual recovery. Remarkably, this approach did not cause inflammation or other forms of lung pathology. Although one may prematurely suggest that intrabronchial instillation of an apoptotic agent is "unphysiologic," the 5,000 plus chemical compounds and in excess of 10 (15) free radical molecules present in the cigarette smoke can directly trigger several of the molecular pathways involved in the apoptosis process (Figure 2). Piecing together pathobiologically relevant processes and using reductionist approaches such as that of Aoshiba and associates will allow us to revisit chronic cigarette smoke models to better understand the uniqueness of the destructive process in emphysema. It is becoming progressively apparent that excessive proteolysis, lung cell apoptosis, and oxidative stress interact as means by which the lung is destroyed in emphysema.



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  		Figure 1. TUNEL assay showing increased numbers of alveolar septal apoptotic cells in emphysematous lungs (A) (arrows) as compared with scarce TUNEL-positive cells in normal lungs (B).

 


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  		Figure 2. Schema of mitochondrial and receptor-mediated pathways of apoptosis. Cigarette smoke may engage apoptosis by means of oxidative stress, survival factor signaling, mitochondrial and nuclear DNA damage, or lymphocyte-dependent or TNF-receptor signaling.

 
The observations noted above raise several important questions about the lung responses to injury and the relation between lung apoptosis and emphysema. Most striking is the rapidity and extent with which the structural alterations appeared after the transfer of active caspase 3 or nodularin to {bsim} 3% of cells, as assessed by ß-galactosidase staining (4). Although the concept of continuous lung cell and matrix turnover is not new, the finding of structural changes, which, surprisingly, occur a few hours after cellular damage, imply a high rate of such turnover by lung parenchymal cells. Indeed, the lung is unique in that alveolar cells are constantly exposed to physical and chemical stresses (i.e., the highest oxygen levels of any organ in the body), to a degree perhaps only matched by that of the gastrointestinal tract. Cell damage, apoptosis, apoptotic cell removal, and cellular replacement are ongoing and presumably highly regulated to maintain homeostasis of the entire alveolar unit. Overinduction of apoptosis and/or blockade of cellular replenishment would both be expected to disrupt alveolar septal homeostasis.

When compared with the rapid development of emphysema caused by intrabronchial instillation of an apoptotic inducer, the emphysema triggered by VEGF receptor blockade takes longer to develop, possibly reflecting the kinetics of neutralization of VEGF receptors, the rate of apoptosis of septal endothelial cells, or degree of inhibition of cell replenishment. The adult lung generates an abundant amount of the VEGF protein, which, when released from matrix or cellular (epithelial, smooth muscle, and endothelial cells) stores, interacts with target cells via binding to VEGF-R1 (Flt) and/or VEGFR-2 (Kdr) receptors. In the lung, alveolar macrophages and smooth muscle cells express VEGF-R1, and endothelial and type II cells express VEGF-R2. It is intriguing to speculate that the observations by Aoshiba and coworkers and by Kasahara and colleagues (8) support the interdependence of the alveolar structure on both endothelial and epithelial integrity, and that loss of either leads to a similar structural alteration—emphysema. On the other hand, it is not yet clear whether damage to one cell type "mandates" effects on the other—either directly via cell–cell interaction (9) or indirectly through soluble mediators. Because, during embryogenesis, the development of airways and pulmonary circulation are coupled and interdependent, it is conceivable that the two cell types are exquisitely dependent on each other, and that common growth and maintenance factors are involved in synchronous alveolar septal cell survival in the adult life.

Although the initial cell damage induced in the studies by Aoshiba and colleagues or Kasahara and coworkers appeared to be primarily apoptotic, the role of other forms of cell death or postapoptotic cytolysis (leading to release of cellular contents) in emphysema development cannot be ruled out. Notwithstanding the specific form(s) of lung cell death, it is remarkable that instillation of a proapoptotic agent or interruption of VEGF signaling caused emphysema rather than other lung pathologies, which have also been associated with apoptosis. It is not yet clear whether chronic cigarette smoke–induced emphysema follows a similar paradigm as described in these models, but the elucidation of the mechanisms involved in the specific nature of the lung injury response, i.e., emphysema, may help us to understand how cigarette smoke acts on the lung.

The difficulty of detecting apoptotic cells in normal organs underscores the prompt and efficient clearance of apoptotic cells, a central process in tissue homeostasis, because apoptotic cells can be a source of autoimmune reaction against self antigens and excessive proteases (10). This removal occurs by unique phagocytic processes common to most cell types in the body, including those present in the alveolar wall (epithelial, endothelial, fibroblasts, etc.), as well as of macrophages and dendritic cells. Near-neighbor removal is the norm and is quickly followed by cell replenishment. In fact, we have suggested that detection of significant numbers of apoptotic cells in a tissue should immediately imply either a massive injurious stimulus or, more likely, a defect in the clearance mechanisms (10). This concept might reasonably explain the increased numbers of apoptotic cells in patients with emphysema (6) as well as to the models under discussion. Intrabronchial instillation of active caspase 3 might not only induce the aforementioned massive apoptosis, but also disable the very cells normally involved in the clearance. In the VEGF receptor antagonist system, a similar impairment of clearance might implicate these receptors in apoptotic cell uptake.

The elucidation of the role of apoptosis as a critical mechanism of alveolar septal destruction does not preclude a potential participation of proteolysis in the pathogenesis of emphysema—in alterations of the composition and turnover of matrix itself, in induction of apoptotic changes in epithelial or endothelial cells that detached from their matrix attachments, and/or in alteration of the lung response to increased number of apoptotic cells. Aoshiba and associates provided provocative data of detection of an elastolytic activity in apoptotic lung epithelial cells, which conceptually could act downstream of apoptosis, and thus amplify the destruction of alveolar elastin and alveolar cell apoptosis. Thus, apoptosis in this setting is not an isolated, bland event. This feedback mechanism demonstrates a dynamic role for apoptosis as a pivotal process in the regulation of local tissue proteolysis.

The emphysema model of Aoshiba and colleagues and the one based on VEGF receptor blockade are remarkable for lack of inflammation. Although this finding might be explained by the well-documented ability of apoptotic cells to suppress inflammatory responses, it is well recognized that patients with COPD have significant lung inflammation, which participates in the development of the disease (11). The contribution of inflammation to emphysema is underscored by the finding that, in integrin {alpha}vß6 knockouts, removal of one source of this inflammatory suppression, namely active transforming growth factor-ß, itself can lead to spontaneous matrix metalloprotease (MMP)-12–dependent airspace enlargement, and targeted inducible overexpression of interferon-{gamma} or interleukin-13 causes murine emphysema (12–14). Interestingly, interferon-{gamma} did not cause mucus metaplasia and was associated with a macrophage and neutrophil-rich inflammatory response, whereas interleukin-13 caused a macrophage-, lymphocyte-, and eosinophil-rich inflammatory response, mucus metaplasia, and airway remodeling. Importantly, in both circumstances, impressive increases in proteases and decreases in selected antiproteases were noted. The fact that the emphysematous alterations in these mice could be ameliorated by interventions that block MMPs or cathepsins links mechanistically tissue inflammation and the protease/antiprotease imbalance. Furthermore, proteases derived from the inflammatory reaction themselves can hinder apoptotic cell recognition and proper uptake, possibly leading to tissue damage due to prolonged persistence of apoptotic cell products (15). Overinduction of proteases in lung parenchymal cells can also account for the protease/antiprotease imbalance, even in absence of inflammation; lung MMP-9 overexpression has been reported in methylprednisolone-treated lungs (16) and in mice harboring skin tumors, which stimulate at a distance lung endothelial cell expression via VEGF-R1 (17).

Like protease/antiprotease imbalance and apoptosis, oxidative stress is equally central in the process of tissue destruction in COPD (Figure 3). There is overwhelming evidence of markers of oxidative stress in smokers lungs, caused by chronic inflammation and cigarette smoking itself (18). Importantly, oxidative stress modifies cellular signaling and interacts with all prevailing pathogenetic processes proposed to cause COPD, in particular protease/antiprotease imbalance and apoptosis. Although most of the experimental evidence points to oxidative stress leading to apoptosis, it is evident that the converse is also true; i.e., that in the process of apoptosis, there is progressive inhibition of mitochondrial respiratory electron transport, in particular of Complexes I and II, thus leading to inappropriate free radical generation during the process of cell death (19). This mutual positive feedback loop between oxidative stress and apoptosis participates in the VEGF receptor blockade–induced emphysema, because both a caspase inhibitor (Z-Asp-CH2) and a superoxide dismutase mimetic (M40419) blocked the development of emphysema and significantly reduced lung markers of oxidative stress and apoptosis (20). It is possible that the mouse lungs treated with active caspase 3 or roleterin might also had increased oxidative stress, which would have been instrumental in creating the observed emphysematous phenotype.



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  		Figure 3. Diagram outlining the interrelationship between protease/antiprotease imbalance, oxidative stress, and apoptosis as destructive processes in emphysema.

 
Because of the studies outlined in this review, including that by Aoshiba and colleagues, it is becoming increasingly clear that the pathogenesis schema based on lung inflammation, protease/antiprotease imbalance, oxidative stress, and apoptosis may not be as separate from one another as previously thought (Figure 3). The identification of alveolar septal cell apoptosis as a critical element in the pathogenesis of emphysema obliges us to refocus on the very nature of alveolar septum morphogenesis and the cellular and molecular requirements for its maintenance throughout an individual's lifetime. Such a conceptual framework provides a means to study the link between inflammation, protease/antiprotease imbalance, and alveolar septal cell destruction in emphysema, and to (re)define how cigarette smoke ultimately damages the lung. Although there are numerous animal models of emphysema which highlight primary alveolar insults (such as inflammation or disruption of endothelial cell function), apoptosis, oxidative stress, and proteolytic damage of the alveolar septum are emerging as central and unifying processes in COPD, with clear implications in the development of therapeutic targets and biomarkers of the disease. But it is imperative that these novel pathobiological elements in emphysema be investigated and validated with studies using human diseased lungs.


   Acknowledgments
 
This work was supported by the NIH grant to R.M.T. (1RO1 HL60195).

Received in original form March 28, 2003


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