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Apoptosis in the Airways

Another Balancing Act in the Epithelial Program

Pulmonary and Critical Care Medicine, Department of Medicine, and Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri

Address correspondence to: M. J. Holtzman, Washington University School of Medicine, Campus Box 8052, 660 South Euclid Avenue, St. Louis, MO 63110. E-mail: holtzmanm{at}msnotes.wustl.edu

Abbreviations: extracellular regulated kinase, ERK • c-Jun N-terminal kinase, JNK • mitogen-activated protein kinase, MAPK • MAPK kinase, MAPKK • MAPK kinase kinase, MAPKKK • transforming growth factor-ß, TGF-ß

	Introduction

Top Introduction Defining Apoptosis in the... Defining the Signaling Pathways... Apoptosis and Airway Function... Final Perspective References

 
The airway epithelium is a critical site of action for host defense and for the development of inflammatory disease, and the past 20 years of research have provided mounting evidence that the epithelial cells themselves may help to orchestrate immunity and inflammation. The current paradigms for host defense (especially against respiratory viral infection) and inflammatory disease (especially asthma) provide particular examples of how this innate control system can work, because endogenous epithelial networks can be critical for host integrity and homeostasis but can also be capable of driving inflammatory disease when abnormally adjusted (1). In this context, one of the critical issues for normal immune function becomes the maintenance of the epithelial shield in an appropriate state of readiness. In the past, this process was often couched in terms of epithelial damage and repair through pathways that regulated cell growth and differentiation (2). However, proper preservation of the epithelium may also depend on the pathways that control programmed cell death (i.e., apoptosis). Here again, the epithelial network for host defense provides a useful paradigm, because the targeted response to microbial attack (especially by viruses) is apoptosis of the infected host cell (3). It is natural to next ask whether epithelial cell apoptosis is also relevant to the pathogenesis of chronic inflammatory diseases such as asthma. The current issue of the AJRCMB contains an article by Pelaia and coworkers (4) that argues for this possibility and so provides a useful focus for this Perspective.

Of course, this subject has a long history. In fact, the view that epithelial damage and desquamation is part of inflammation and inflammatory disease dates back to the initial descriptions of mucositis in general and the corresponding pathology of asthma in particular. In that regard, collections of sloughed epithelial cells have been observed in sputum and bronchoalveolar lavage fluid from subjects with asthma, and denudation of the airway mucosa has been found in airway tissue from these same types of subjects. Indeed, this type of epithelial damage may be more prominent in asthma than other airway diseases such as chronic bronchitis (5). However, these observations are always tempered by the significant technical challenges to assessing the status of epithelial integrity in vivo, especially in human subjects (6). In addition, the state of the epithelium may change depending on the stage of the disease and the corresponding timing of the damage/repair cycle. For example, it is also possible to find epithelial hyperplasia (especially for mucous and ciliated cells) under some circumstances in experimental models of asthma and in corresponding conditions for subjects with asthma, including flares of the disease (7–9). It is therefore likely that damage reports of the epithelium contain the usual problem of studying an issue of flux by checking a single point in time. In this particular case, research must address whether assessments are being made during the destruction or the repair phase of the epithelial cycle, and, further, how and why the cycle is changing. Indeed, these observational timing differences are best resolved by addressing the underlying mechanism for these epithelial abnormalities. In that context, it is once again time to move beyond the notion that any process in the epithelium is passive, including its destruction.

	Defining Apoptosis in the Airway

Top Introduction Defining Apoptosis in the... Defining the Signaling Pathways... Apoptosis and Airway Function... Final Perspective References

 
Similar to the difficulties for assessing the damage/repair state of the epithelium, it is also challenging to simply determine the presence or absence of apoptosis in the airway. This difficulty stems at least in part from the nature of the apoptotic process. In particular, apoptosis (by design) provides for rapid clearance of dying cells, so these remnants are removed efficiently by the macrophage scavenger system and therefore difficult to detect at all. Accordingly, few apoptotic cells (detected by a positive TUNEL reaction) are present in the airways of subjects with asthma (10, 11). An additional problem for detection of apoptosis in the airways is that dying epithelial cells may be discarded into the lumen, perhaps before completing the later, TUNEL-positive stages of the apoptotic process. Indeed, using markers of earlier apoptotic events (e.g., cleavage/activation of the effector caspase-3 or cleavage/inactivation of the DNA repair enzyme poly[ADP-ribose] polymerase), some investigators find elevated levels of epithelial cell apoptosis in bronchial biopsies from individuals with asthma (12, 13). Nonetheless, there is a general consensus that apoptosis is difficult to detect (and even more difficult to quantify) in vivo, except in cases when there is massive cell death or where the normal clearance mechanisms have been compromised. In addition, current and future studies aim to determine whether apoptotic behavior is due to an inherent abnormality in the epithelial cell or is simply a reflection of the cell being embedded in an inflammatory milieu that promotes airway remodeling (13, 14).

Difficulties with detection and uncertainty over underlying mechanism has led some investigators to turn to studies of isolated airway epithelial cells to better define the role of apoptosis in asthma. Indeed, the article by Pelaia and colleagues in this issue of the AJRCMB is an example of this type of reductionist strategy (4). Under the premise that apoptosis may help shape the remodeling process, this group and others further reason that it is worthwhile to test specific (potentially asthmagenic) cytokines for their action on programs for epithelial cell death. The present work targets the cytokine transforming growth factor (TGF)-ß because it may be found at higher levels of expression in airway tissue from subjects with asthma and so may mediate the remodeling process (15–17). In this setting, Pelaia and colleagues present evidence that TGF-ß1 causes apoptosis of primary-culture airway epithelial cells based on a loss of cell membrane permeability and activation of caspase-3 (4). The study also demonstrates that the apoptotic effect depends on signaling through mitogen-activated protein kinase (MAPK) pathways and is inhibited by glucocorticoid treatment. Some might argue that at least some of these results are not surprising, because there is precedence for TGF-ß–induced apoptosis via MAPK pathways in other epithelial cell systems (18–20). However, as developed below, other outcomes for TGF-ß (and glucocorticoid) action were also possible. Moreover, these initial findings facilitate new questions for lung biology, beginning with how epithelial apoptosis occurs and moving toward what this teaches us about the role of epithelial apoptosis in health and disease.

	Defining the Signaling Pathways for Apoptosis

Top Introduction Defining Apoptosis in the... Defining the Signaling Pathways... Apoptosis and Airway Function... Final Perspective References

 
To determine how epithelial apoptosis occurs, and in particular how TGF-ß fuels this process, it is critical to define the way that TGF-ß signals to achieve its downstream goals. To begin, TGF-ß is generated as a latent form that requires protease/integrin-dependent activation, a process that itself is only poorly defined in the context of asthma. After processing is complete, active TGF-ß binds to a specific receptor (composed of two TGFßRI/RII heterodimers), and this ligand/receptor engagement initiates a signaling cascade mediated by members of the SMAD family of proteins. This family contains receptor-associated (R-SMAD), common-partner (Co-SMAD), and inhibitory (I-SMAD) members. The current view is that activated TGFßRI phosphorylates receptor-associated Smad2 and Smad3, which form a complex with co-SMAD Smad4 and enter the nucleus for transcriptional regulation, a process that is dampened by induction of inhibitory Smad6 and Smad7 (21). Phosphorylation/activation of epithelial Smad2 (and decreased Smad7) in airway tissue from individuals with asthma suggests that TGF-ß and the corresponding SMAD-signaling pathway are activated in the disease (22, 23).

The SMAD-signaling pathway has been a focus of work on TGF-ß signaling, but TGF-ß receptors can also activate a second signaling cascade mediated by members of the MAPK family of proteins. The complex MAPK network is capable of mediating an extraordinary array of signals that impact the cell membrane, so a simplified scheme for orientation to TGF-ß–related events and apoptosis is portrayed in Figure 1. In general, MAPK circuits are organized into a three-tiered kinase module with the first tier mediated by a MAPK kinase kinase (MAPKKK), the second by a MAPK kinase (MAPKK), and the third by a MAPK. To date, there are three well-characterized MAPK circuits, each named for their corresponding third-tier MAPK types: (i) stress-activated protein kinase (SAPK) or c-Jun N-terminal kinase (JNK) 1, 2, and 3; (ii) p38 MAPK , ß, , and ; and (iii) extracellular regulated kinases (ERK) 1 and 2. Each MAPK can act as a serine/threonine kinase to activate transcription factors in the nucleus and thereby modify gene expression. MAPK activity can also act on cytosolic signaling molecules and cytoskeletal proteins and thereby alter function at a post-translational level. This capability also allows for crosstalk between signaling cascades, e.g., ERK may phosphorylate Smad1 to enhance SMAD signaling (24). In the present study, Pelaia and coworkers found that TGF-ß activated predominantly p38 MAPK, but, in fact, all three MAPK circuits were activated and specific inhibitors of each were fully capable of blocking TGF-ß–induced apoptosis of airway epithelial cells. These findings imply that each MAPK circuit is necessary but not sufficient for TGF-ß–induced apoptosis and thereby raises the question of how these circuits are wired in airway epithelial cells. In that regard, previous studies of other types of epithelial cells indicate that TGF-ß receptor activation of Ras oncoprotein could serve to activate each of the MAPK circuits, but this possibility has not yet been tested in airway epithelial cells (25). Similarly, the site of action for glucocorticoid inhibition of TGF-ß–induced apoptosis remains uncertain. Because glucocorticoid treatment inhibits all three MAPK activities, the site of drug action is likely proximal in the TGF-ß/MAPK signaling pathway, so that early receptor-coupled steps, like Ras activation, would be suitable candidates for drug action. Here again, this possibility still needs to be determined.

View larger version (59K): [in this window] [in a new window]   Figure 1. Scheme for cytokine-driven MAPK-dependent pathways that regulate cellular apoptosis (red) and survival (blue). Each of the three MAPK signaling cascades (labeled 1–3) are organized into three-tiered modules that begin with receptor-linked MAPKKK activation followed by MAPKK activation and then MAPK activation. TGF-ß binding to its receptor leads to activation of each of the three MAPK cascades with predominant activation of p38-MAPK (labeled 2) and lesser activation of SAPK/JNK and ERK (labeled 1 and 3). This set of signals causes a pattern of transcription factor (TF) activation (labeled A, B, and C) and consequent gene expression of factors that act on downstream mitochondrial and caspase targets to cause apoptosis. MAPK pathways may also act at a post-translational level (e.g., SAPK/JNK action on BCL-2) to influence apoptosis. Because inhibitors of each MAPK pathway can block TGF-ß–induced apoptosis, each of these pathways appears necessary but not sufficient for causing apoptosis. Other types of cytokines (and TGF-ß itself in other systems) can activate other receptor/adaptor systems linked to MAPK signals that are anti-apoptotic and promote cell survival. This link in the ERK pathway (labeled with ?) and the site of glucocorticoid (GC) action to block MAPK-dependent apoptosis still need to be determined.

	Apoptosis and Airway Function in Health and Disease

Top Introduction Defining Apoptosis in the... Defining the Signaling Pathways... Apoptosis and Airway Function... Final Perspective References

 
As noted above, perhaps the most natural reason for planned decisions about cell death comes in the setting of microbial invasion, especially due to viral infection. But the present study by Pelaia and coworkers makes the further argument that epithelial apoptosis is a central feature of asthma as well. If epithelial apoptosis is either a cause or consequence of asthma, what role might this phenomenon play in asthma pathogenesis? The predominant (historically old) argument is that asthma is the battleground for a vicious cycle of epithelial damage and repair. In the present context, TGF-ß production may bequeath more TGF-ß, and so promote escalating levels of airway apoptosis, inflammation, and remodeling. Indeed, TGF-ß can auto-amplify its production via the combined actions of the SAPK/JNK and ERK pathways. The two pathways may combine to form active AP-1 and allow for the consequent transcription of the TGF-ß1 gene (25). In turn, overproduction of TGF-ß may trigger myofibroblast activation and subepithelial fibrosis (27–29). As a corollary, glucocorticoid treatment would block TGF-ß1–induced apoptosis (and subepithelial fibrosis) and thereby put a stop to this deleterious process. In support of this possibility, it appears that bronchial epithelial cells in biopsies from glucocorticoid-treated individuals with asthma displayed increased expression of the anti-apoptotic protein Bcl-2 (and less fibrosis) compared with untreated subjects (10). Evidence of increased expression of the ERK target c-fos in the epithelium of individuals with asthma further suggests that the ERK-MAPK pathway may be driving the process (30).

So, what's wrong with this picture? Perhaps nothing, but several questions remain. Do dying epithelial cells cause higher production of TGF-ß, and if so, how? Do glucocorticoids block this process, especially in vivo, and if so, how? If inhibition of TGF-ß is achieved, how will it influence the counter-regulatory and apparently beneficial role of this cytokine on epithelial and immune cell function, especially its capacity to protect against airway inflammation and hyperreactivity (23, 31, 32)? Moreover, what is the functional defect associated with TGF-ß overproduction, and, in the special setting of asthma, is airway fibrosis an important functional endpoint for treatment, or should we continue to concentrate on mucus hypersecretion and airway hyperreactivity? And, in a general sense, will interference with apoptosis also compromise host defense or normal damping of the immune response, which may already be abnormal in asthma (33)?

	Final Perspective

Top Introduction Defining Apoptosis in the... Defining the Signaling Pathways... Apoptosis and Airway Function... Final Perspective References

 
The epithelial barrier represents a critical line of defense against the environment, so airway epithelial cells are likely designed to be refractory to a number of potentially apoptotic stimuli, including potent death-receptor activators such as tumor necrosis factor- and Fas ligand (34). The relative resistance of airway epithelial cells to apoptosis is likely helpful in maintaining the integrity of the epithelial barrier during an inflammatory response, when immune cells, which express or secrete these death-receptor ligands, are trafficking through the lung. In contrast to their resistance to these types of death signals, primary airway epithelial cells readily undergo apoptosis in response to viral replication. In this case, apoptosis likely occurs, as part of the host response, in an attempt to limit virus replication and to prevent persistent infection. Thus, in the context of a virus infection, damage to the epithelial barrier may be the lesser evil. Given the proposal that asthma resembles a persistent antiviral response (1), perhaps this apoptotic/fibrotic phenotype should be expected in the disease and viral models of the disease as well (35). In any case, Pelaia and coworkers have now added TGF-ß to the (so far) short list of physiologic mediators known to cause apoptosis of airway epithelial cells. More work is now needed to determine if this effect also occurs in vivo, and to establish the upstream and downstream mediators of TGF-ß–induced apoptosis, as well as the more general rules for MAPK signaling in the epithelium. This information will allow for adjusting one more piece of the immunity/inflammation puzzle.

	Acknowledgments

 
The authors gratefully acknowledge their colleagues for invaluable assistance, advice, and information and the National Institutes of Health (Heart, Lung, and Blood Institute), Martin Schaeffer Fund, Ruth Kopolow Gift Fund, and Alan A. and Edith L. Wolff Charitable Trust for research support.

Received in original form April 24, 2003

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Top Introduction Defining Apoptosis in the... Defining the Signaling Pathways... Apoptosis and Airway Function... Final Perspective References

 

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