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Antiinflammatory Therapies Other Than Corticosteroids

University of Nebraska Medical Center, Omaha, Nebraska

Correspondence and requests for reprints should be addressed to Stephen I. Rennard, M.D., University of Nebraska Medical Center, 985125 Nebraska Medical Center, Omaha, NE 68198. E-mail: srennard{at}unmc.edu

	ABSTRACT

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Antiinflammatory therapy for chronic obstructive pulmonary disease (COPD) can be directed at several stages of the inflammatory process. Much attention has been focused on blocking the damaging effects of toxic mediators released by inflammatory cells, including antioxidants and antiproteases. An alternate strategy is to block the recruitment of inflammatory cells into the lung, such as by inhibiting the production of chemotactic factors driving inflammatory cell recruitment, the ability of inflammatory cells to respond to chemotactic factors, and the ability of inflammatory cells to migrate. Moreover, mediators released by inflammatory cells, particularly tumor necrosis factor-, probably have systemic effects in COPD. Blocking the release of these cytokines or blocking their ability to act on distal tissues represents another potential therapeutic option. It is also important to recognize that the various components of the inflammatory response are not independent. The action of proteases released by inflammatory cells, for example, can generate chemotactic factors, lead to activation of inflammatory cells, and modulate repair responses. The complex network of regulatory molecules that controls the inflammatory response, therefore, presents a number of potential therapeutic targets with the promise of altering the disease process in COPD.

Key Words: antiproteases • lung repair • oxidants • proteases • tumor necrosis factor-

Inflammation is a term credited to Celsus. It was used as a metaphor because the dermal response to injury was reminiscent of a fire, characterized by redness (rubor), heat (calor), swelling (tumor), and pain (dolor), some of the Latin terms that are still used in medical schools. In addition to these four cardinal features, loss of function (functio laesa) was added by Virchow. A sixth feature, repair, could also be added, because new growth occurs after injury in tissues, just as it occurs in the aftermath of fires in forests, prairies, and even cities.

While the metaphor remains apt, the semantics have tended to oversimplify the biological issues. The "inflammatory process" is an incredibly complex and diverse set of interactions mediated by nearly all cells and involving thousands of molecular moieties interacting in complex combinations. Nevertheless, it has remained useful to consider agents as "antiinflammatory" if they downregulate some of these cellular and molecular processes. Similarly, it has become standard to regard many pathologic conditions as "inflammatory" if some of these diverse processes are involved pathogenetically. Although the overencompassing term "inflammation" will undoubtedly retain its utility, defining precisely what is or is not an inflammatory or antiinflammatory treatment will become increasingly difficult in the current era of advancing biological understanding.

Despite these limitations, inflammatory processes are considered central to the pathogenesis of chronic obstructive pulmonary disease (COPD) and asthma. As such, therapeutic agents that target inflammatory processes hold the promise of improving these conditions by alleviating acute symptoms and, possibly, by favorably altering the long-term natural history of the conditions. Glucocorticoids have proved strikingly effective both in treating and preventing acute exacerbations in asthma (1), although whether they alter the natural history of the disease is much less clear (2). In COPD, glucocorticoids also have beneficial, if less marked, effects on acute exacerbations (3, 4). However, clinical trials suggest that inhaled glucocorticoids have no benefit on the rate at which lung function declines in COPD, although an extremely modest effect below the power of current studies to detect is not excluded (5).

The modest benefits associated with glucocorticoid therapy, together with current concepts of the pathogenesis of asthma and COPD, suggest that alternate antiinflammatory strategies could be beneficial. The limits of glucocorticoid therapy for both conditions make the discovery of such therapeutic approaches extremely desirable. With the current understanding of the complexity of the inflammatory process, there are hundreds of potential therapeutic targets with potential relevance for asthma and COPD. Several score of these are currently being pursued, and reviews providing partial descriptions of these approaches are available elsewhere (6–9). This paper reviews the strategies for targeting inflammation in obstructive lung diseases, and it highlights some of the problems facing clinical development and the need for new paradigms for assessing clinical outcomes.

	BLOCKING ACCUMULATION OF INFLAMMATORY CELLS

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Although all cells can participate in inflammatory reactions, leukocytes are specialized cells whose major role is participation in inflammation. The leukocytes that accumulate in asthma and COPD have, therefore, attracted much attention as potential therapeutic targets. Asthma, for example, is characterized by accumulation of eosinophils within the airways. Glucocorticoids, which have a therapeutic benefit in asthma, strikingly reduce eosinophil accumulation and activation (6–8), and other strategies may have the same effect. Antibodies to interleukin (IL)-5, one of the several cytokines responsible for eosinophil recruitment and survival, resulted in substantial reductions in blood eosinophil levels and more modest reductions in tissue eosinophil levels in individuals with atopic asthma (9). Unfortunately, there were no changes in either symptoms or the altered physiology characterizing asthma (10). The partial response of airway eosinophilia makes definitive conclusions difficult. These investigations have called into question the role of eosinophils in the pathophysiology of asthma and raise a crucially important point: Studies finding inflammatory cells in association with a disease, even when related to disease severity, do not establish a cause-and-effect role for those cells. (The presence of many firemen at a fire does not mean they caused it!) Furthermore, even if such cells had a pathoetiologic role, inhibiting them after the fact may be without benefit. (It is too late to ban matches after a fire is started). Finally, interpretation may be difficult. (Some firemen use water to fight fires, but some use fire!) These problems not withstanding, a number of specific cell types have been associated with asthma and COPD and have, justifiably, attracted considerable attention (11).

Mast cells and mast cell–derived mediators are believed to play a role in both asthma and COPD. Neutrophils are also increased in both conditions, and they are more prominent as disease worsens and, in particular, during acute exacerbations. Lymphocyte accumulations characterize both diseases. Interestingly, these accumulations are characterized by larger numbers of CD4⁺ cells in asthma and of CD8⁺ cells in COPD, although both conditions are characterized by heterogeneous populations. Mononuclear phagocytes are also increased in both conditions, particularly in COPD, although these cells also accumulate in large numbers in the lungs of smokers who do not develop severe airflow limitation and symptoms (12). While these inflammatory cells are believed to play an important pathogenic role, the varying susceptibility of individuals with apparently similar inflammation is not understood. In addition, although smoking cessation in normal individuals is associated with a reduction in inflammation (13, 14), cross-sectional studies suggest that former smokers with COPD have inflammatory responses similar to those of current smokers with COPD (15–17). Because smoking cessation is widely recognized as a means to dramatically improve the natural history of COPD (18), this could call into question the role of inflammatory cells.

Several strategies have been suggested as means to block inflammatory cell accumulation (Figure 1). As these cells generally originate outside the lung, migrate through the circulation, and then accumulate and are activated within the lung, several factors could be targeted. These include the cytokines that drive cellular production, the factors that are responsible for the chemotactic migration of cells into target tissues, the adhesion molecules that permit the circulating cells to attach to blood vessels in preparation for migration into tissues, and the factors responsible for cell survival and clearance/apoptosis. In many cases, the same cytokines may drive several of these steps. A variety of agents in each of these general categories are currently under investigation. It is likely that blockade of inflammatory cell recruitment will be successful in both asthma and COPD. As noted above, eosinophils have been successfully targeted in asthma, although the clinical benefits of this strategy remain in doubt. In COPD, phosphodiesterase (PDE)-4 inhibitors, which can block several steps involved in inflammatory cell recruitment, have been reported to reduce inflammatory cell accumulations (19, 20).

View larger version (14K): [in this window] [in a new window]   Figure 1. Schematic representation of approaches to blocking inflammatory cells. Inflammatory cells present in tissues generally originate in the bone marrow, migrate through the circulation, and are attracted into tissues, where they may be activated and from which they are eventually cleared. Some inflammatory cells can reside in specialized tissues (e.g., lymph nodes), where cell proliferation and differentiation may take place. Steps that might be targeted to block inflammatory cells include their: (1) production, (2) release into the circulation, (3) emigration from the circulation, (4) recruitment into tissues, (5) activation, (6) elimination, and (7) residence in tissues. Each of these steps represents a complex series of biological processes regulated by several mediators. Often a single mediator affects multiple steps in the process.

	BLOCKING THE EFFECTS OF TOXIC INFLAMMATORY MEDIATORS

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Inhibitors of proteases released by inflammatory cells have also been explored in COPD. The congenital deficiency of ₁-protease inhibitor (PI) is associated with accelerated and premature emphysema (23), and observational registry studies suggest that replacement of ₁-PI can reduce the rate at which lung function is lost in deficient individuals (24). Interestingly, it may also reduce exacerbations (25). Synthetic inhibitors of neutrophil-derived serine proteases have been developed, specifically with the intent to replace the function of ₁-PI (26). Interestingly, there appear to be important interactions between the oxidants and proteases released by inflammatory cells. For example, ₁-PI has a methionyl residue near the active site that interacts with neutrophil elastase. Oxidation of this residue to the sulfoxide eliminates antielastase activity (27). It has been suggested that the release of oxidants by neutrophils can locally inactivate ₁-PI, thus providing an inhibitor-free zone in which neutrophil elastase can act (28). Interestingly, smokers and patients with COPD have increased levels of ₁-PI in their bronchoalveolar lavage fluid, but the majority is inactivated (29, 30). Oxidized ₁-PI is present in the lungs of smokers and, while several mechanisms exist for inactivation of ₁-PI, these findings suggest that inflammatory processes, through release of oxidants, may lead to an acquired PI deficiency.

Proteases in addition to neutrophil elastase are likely to play important roles in the pathogenesis of COPD and asthma as well. The matrix metalloproteinases (MMPs), a large family of enzymes that require zinc at the active site, have been the subject of much recent study (31, 32). Mice deficient in MMP-12 (sometimes termed macrophage metalloelastase) do not develop emphysema when exposed to cigarette smoke, as do control mice expressing MMP-12 (33). Interestingly, a major role of MMP-12 may be indirect, as the MMP-12–deficient mice show a marked reduction in the recruitment of macrophages into the lung in response to cigarette smoke. A reduction in MMP-12–derived elastin fragments, which have been shown to be chemotactic for macrophages (34, 35), has been suggested as a mechanism. The interesting possibility, therefore, is that a PI may prove to have an important antiinflammatory action, in the case of an MMP-12 inhibitor, by decreasing macrophage recruitment. Consistent with this concept, ₁-PI replacement therapy has been associated with a reduction in lower respiratory tract inflammation in deficient individuals (36). Other classes of proteases, including the cysteine proteases, may play similar roles (37).

There appears to be a complex network of interactions among proteases, antiproteases, oxidants, and inflammatory cells. The MMPs, for example, are capable of degrading inhibitors of serine proteases (31). Serine proteases, in turn, can degrade the tissue inhibitors of metalloproteinases. In addition, serine proteases are capable of proteolytically converting some latent MMPs to their proteolytically active forms. The redundancy and complexity of the interacting network of the components of the inflammatory process creates two interesting possibilities. First, a specific inhibitor of one part of the network may be without clinical effect as redundant components can replace the function inhibited. Alternatively, inhibition of one component that is strategically located within the network could have widespread antiinflammatory effects. The search for key strategically located targets, therefore, has become a major goal in the development of clinically effective antiinflammatories.

	BLOCKING THE SYSTEMIC EFFECTS OF INFLAMMATION

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Although the systemic effects of asthma are less clear, it is now widely recognized that COPD is a systemic disorder. Some patients with COPD, for example, lose a significant amount of weight, which is associated with poor survival (38). Moreover, COPD is characterized by a reduction in lean body mass, a major determinant of reduced exercise performance (39).

Circulating inflammatory mediators may be responsible for these systemic effects. Tumor necrosis factor (TNF)-, for example, has been associated with the development of cachexia in a number of conditions (40–42). TNF- is produced in the lungs of patients with COPD (46–48) and individuals with asthma, and increased levels in the circulation have been associated with weight loss in some studies (49–51). Another study has associated weight loss in patients with COPD with increased production of TNF- by monocytes in response to endotoxin (43). Interestingly, TNF- production may have sources other than the lung in COPD. TNF- levels increase after exercise in patients with COPD, (44) and a relationship between tissue hypoxia and TNF- production has been suggested (54, 55). Circulating TNF- may also contribute to the development of COPD (45).

Polymorphisms in the TNF- receptor have been suggested to be a risk factor for the development of COPD (46, 47) or for its progression (48), although these observations have not been confirmed in other studies (49, 50). It is possible, nevertheless, that genetic variation in TNF- signaling may account for some of the variability in COPD susceptibility or natural history. Whatever the mechanisms involved, TNF- produced in the lung may contribute to both weight loss and reduction in lean body mass in patients with COPD. Consistent with this, patients with COPD have been reported to have evidence of skeletal muscle apoptosis (51), although whether this is driven by TNF- or by other factors remains to be established.

Although it is likely that other mediators contribute to the systemic manifestations of COPD, TNF- has become an attractive therapeutic target. This is particularly so as antibodies to TNF- have proven effective in the treatment of other diseases characterized by active inflammatory processes, including rheumatoid arthritis and Crohn's disease (52, 53). Studies with anti–TNF- antibodies in patients with COPD are currently underway. Other therapeutic strategies could target TNF-, however, and these serve as excellent examples of approaches to the development of novel antiinflammatory therapies (Figure 2).

View larger version (15K): [in this window] [in a new window]   Figure 2. Schematic representation of potential therapeutic targets in the TNF- pathway. Drug development programs are designing inhibitors of TNF- gene transcription, inhibitors of enzymes to block release of TNF- from cell surfaces, antibodies or receptor analogs to bind TNF- in the circulation and prevent its action, and inhibitors of the several pathways activated by TNF- receptors. In addition, some programs are exploring strategies to block either the cells that produce TNF- or the cells that respond to it.

There are a variety of other approaches to blocking TNF- release. After synthesis, TNF- is incorporated into the cell membrane, and its secretion requires proteolytic release (57). This suggests that TNF- signaling may interact with the local protease milieu. These interactions could be furthered by interactions with the TNF- receptor, which is also subject to release from cells by proteolytic cleavage. The circulating form of the receptor is believed to function as a competitive inhibitor of TNF-. Complex interactions, therefore, are likely between TNF- and the local proteolytic milieu. PDE-4 inhibitors have also been reported to inhibit TNF- release (58, 59), although the step at which they act remains to be defined.

It is also possible to block the action of TNF- by interfering with the signaling pathways activated by TNF- inside cells. TNF- interacts with two receptors that in turn activate a complex cascade of signal transduction systems (60, 61). Interestingly, this includes activation of MAP kinases, including p38, as well as signaling through nuclear factor-B, activator protein-1, and lipid mediators, including ceramide. In addition, TNF- can activate intracellular proteases and can stimulate the release of reactive oxidant species. It remains to be determined whether any of these targets represents redundant pathways, the inhibition of one of which would have little effect, or is crucially located, such that inhibition would have widespread effects.

	MODULATING REPAIR

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The lung has considerable capacity to repair itself after injury. The airway epithelium, for example, very rapidly can initiate a process following injury that can lead to recruitment of new epithelial cells, their subsequent proliferation and redifferentiation, and restoration of normal epithelial structure (62, 63). Concurrent with this is the recruitment of subjacent mesenchymal cells that accumulate during the repair process and, under some circumstances, can completely resorb, resulting in restoration of normal structure. It is likely that alveolar structures can undergo similar repair processes after injury. Collagen turnover in the normal lung has been estimated to range from 3 to 10% per day, consistent with an active remodeling/repair process (64). In response to injury, new synthesis of collagen and elastin can be rapidly induced. Whether an injury leads to long-term tissue dysfunction depends not only on the nature of the injury but also on the adequacy of the repair response.

As noted above, repair responses are integral parts of the inflammatory process. Many mediators classically regarded as inflammatory are potent participants in repair processes. Transforming growth factor-ß, for example, has long been recognized as a potent activator of mesenchymal cells and as a stimulator of extracellular connective tissue matrix production (65). It also has potent effects on inflammatory cells, causing switching of antibody production in ß cells and inhibiting a number of inflammatory processes (66). Proinflammatory mediators such as IL-1 and TNF- also can affect repair responses. TNF- and IL-1 are potent inducers of MMPs, which can degrade the extracellular matrix (67). Similarly, cytokines released by type 2 T-helper lymphocytes, including IL-4 and IL-13, have potent effects on fibroblast recruitment and proliferation and on matrix protein and cytokine production (68–72). It is clear, therefore, that repair processes will be importantly affected by the mediators present in the local inflammatory milieu. Although least well understood, these repair processes present yet additional potential opportunities for therapeutic intervention with antiinflammatory agents. Specifically, agents that can manipulate repair responses so that tissue structure and function can be restored could have major effects in altering the natural history of diseases such as asthma or COPD.

	PROBLEMS WITH DRUG DEVELOPMENT

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The first problem facing developers of antiinflammatory drugs for asthma and COPD is the traditional clinical approach to these conditions. Both asthma and COPD have been defined, at least in part, in terms of spirometry (1), and spirometric measures have been crucial in the assessment of therapeutics for both conditions. However, spirometry is a very indirect reflection of inflammation and, thus, of the benefits of antiinflammatory agents. Other problems include agents that affect the natural history of the disorders may improve spirometry over time frames of years, and clinical benefits in tissues other than the lung may not be measurable by spirometry.

Several strategies have been used to assess inflammation in the lungs more directly than spirometry does. These include invasive studies, such as bronchoscopy with either biopsy, bronchoalveolar lavage, or endobronchial brushings (73), and less invasive methods, such as induced sputum (74), exhaled breath condensate (75), or gas analysis (76). Systemic manifestations of inflammation also provide opportunities to gauge both the magnitude of inflammation and the response to antiinflammatory therapies. To date, however, none of these methods is well enough established that it can serve as an end point for either drug development or clinical management. The development of such measures is urgently needed and is the subject of considerable active investigation.

It seems highly likely that these novel approaches will be applied to the investigation of a variety of antiinflammatory strategies. It also seems likely that evaluation of asthma and COPD patients with these novel methods will result in a refinement in the classification of these disorders, and that certain antiinflammatory therapies may be highly useful in some subsets of patients with asthma or COPD, but not in all. Defining and identifying these subsets would be a major advance, both for the development of novel therapies and for clinical management. Unfortunately, the complexity of the cells and mediators participating in the inflammatory network poses a major problem (Figure 3). As discussed earlier, it is difficult to predict from a model system whether blockade of a single part of the network will be ineffective because of redundancy, or whether that target represents such a key strategic point that inhibition will be highly effective. The complexity of the network also makes it extremely likely that potential interventions could have synergistic interactions that may be important therapeutically. However, the current clinical development paradigms are designed to evaluate single agents and so are ill-suited to detect synergism.

View larger version (22K): [in this window] [in a new window]   Figure 3. Schematic representation of potential therapeutic inhibition of inflammatory mediators.

	ACKNOWLEDGMENTS

 
S.I.R. has participated as a speaker in scientific meetings and courses under the sponsorship of GlaxoSmithKline (GSK) and has consulted with GSK with relevance to the topics noted in the present manuscript and serves on Advisory Boards for Roche and Altana and has been sponsored by GSK for several clinical trials and has received laboratory support over three years the total for this approximates $1,800,000 and has also conducted clinical trials for Roche $60,000 and Altana $80,000 and has conducted both clinical trials and basic studies under the sponsorship of Centocor $140,000 and has conducted clinical trials for Pfizer $80,000 and a patent is pending on the use of PDE4 inhibitors in repair and is a co-inventor of the patent owned by the University of Nebraska Medical Center.

(Received in original form February 18, 2004; accepted in final form August 20, 2004)

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