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Respiratory Pharmacology Group, Faculty of Medicine, Imperial College London, London, United Kingdom
Correspondence and requests for reprints should be addressed to Maria G. Belvisi, Ph.D., Respiratory Pharmacology Group, Faculty of Medicine, Imperial College London, National Heart & Lung Institute, Guy Scadding Building, Dovehouse Street, London SW3 6LY, UK. E-mail: m.belvisi{at}Imperial.ac.uk
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ABSTRACT |
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 TOP ABSTRACT INFLAMMATORY CELLS IN ASTHMA...REGULATION OF INFLAMMATORY CELL...REGULATION OF INFLAMMATORY CELL...EFFECTIVENESS OF GLUCOCORTICOID...REFERENCES |
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and interleukin (IL)-1ß, together with cytokines derived from type 2 T-helper lymphocytes, such as IL-4, IL-5, and IL-13. In fact, inhibitors of IL-4 and IL-5 show promise as therapeutic agents. In COPD, the predominant inflammatory cell types are CD8+ T lymphocytes, macrophages, and neutrophils. Glucocorticoids inhibit eosinophils in asthma, neutrophils in COPD and severe asthma, mast cells and basophils in asthma and COPD, and macrophages in COPD. However, it is generally assumed that neutrophils are less sensitive to glucocorticoids than are eosinophils and T cells, and that macrophages from patients with COPD are less sensitive to steroid treatment under certain circumstances. These differences in the responsiveness of activated inflammatory cells may help to explain why inhaled corticosteroid treatment has been more beneficial for patients with asthma than for patients with COPD.
Key Words: asthma • chronic obstructive pulmonary disease • inhaled corticosteroids • mechanisms
This article concentrates on the differences in the inflammatory cell profiles observed in animal models and in the lungs of patients with asthma or chronic obstructive pulmonary disease (COPD). It discusses the effects of glucocorticoids in experimental models of both diseases and on disease progression. In particular, this article focuses on the effect of steroids on eosinophil, neutrophil, mast cell/basophil, and macrophage function.
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INFLAMMATORY CELLS IN ASTHMA AND COPD |
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TOPABSTRACTINFLAMMATORY CELLS IN ASTHMA...REGULATION OF INFLAMMATORY CELL...REGULATION OF INFLAMMATORY CELL...EFFECTIVENESS OF GLUCOCORTICOID...REFERENCES |
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Inflammatory mediators.
It is now generally recognized that cytokines play an important role in the inflammatory response that is evident in the asthmatic airway (Figure 1). Several key mediators have been implicated, including tumor necrosis factor (TNF)- and interleukin (IL)-1ß, together with cytokines that are derived from Th2 cells (e.g., IL-4, IL-5, IL-13, and IL-9) that seem to be more specifically linked to the pathology seen in allergic airway diseases such as asthma (6).
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Eosinophil chemotactic cytokines (CC chemokines), such as eotaxin and RANTES (the chemokine regulated upon activation, normal T-cell expressed and secreted), are also important in asthmatic inflammation and are involved in the recruitment of primed eosinophils from the circulation into the airway (11, 12). Enzymes released from inflammatory cells may also be involved in asthma pathology. For example, mast cell products such as tryptase and chymase may play a role in AHR (13).
COPD
Inflammatory cells.
Chronic obstructive pulmonary disease is characterized by reduced maximum expiratory flow. The airways of patients with COPD are markedly inflamed, but the predominant inflammatory cell types differ from those evident in asthma pathology. The fixed airway obstruction is associated with an airway inflammatory profile consisting mainly of an increased number of T lymphocytes (predominantly CD8+), macrophages, and neutrophils (14, 15).
Fabbri and coworkers (16) recently evaluated airway inflammation in patients with fixed airflow obstruction due to asthma or COPD. Compared with patients with COPD with similarly severe disease and of similar age, subjects with a history of asthma had significantly more eosinophils in peripheral blood, sputum, BAL fluid, and airway mucosa; fewer neutrophils in sputum and BAL fluid; a higher CD4+/CD8+ ratio of T cells infiltrating the airway mucosa; and a thicker reticular layer of the epithelial basement membrane (16). Furthermore, in contrast with asthma, infiltration of the airways with neutrophils, macrophages, and CD8+ lymphocytes in COPD was associated with remodeling of the airways, characterized by goblet cell metaplasia and mucus plugging, smooth muscle hypertrophy, airway wall fibrosis, and destruction of lung parenchyma (16). These data contrast with those from Wenzel and associates, who described a prominent neutrophilia in bronchial biopsy specimens of patients with asthma who had a similar degree of airflow obstruction (5, 17). However, Fabbri and coworkers studied patients who were steroid-dependent and had been receiving high doses of inhaled and/or oral glucocorticosteroids for many years, indicating more severe disease.
Studies of induced sputum show that the increase in neutrophils is greater in patients with COPD than in smokers without airway obstruction (18, 19). Neutrophil activation markers (e.g., myeloperoxidase) are elevated in the sputum supernatant of subjects with COPD, suggesting that neutrophils might be involved in the pathophysiology of this disease (18, 19). Studies have also investigated the inflammatory cell profile in the lung parenchyma, where the macrophage was the major cell type found, together with CD8+ T cells, in areas of parenchymal destruction.
Inflammatory mediators.
It has been hypothesized that the cells that initiate the response to toxic agents such as cigarette smoke are in all probability macrophages and the epithelial cells that line the airway (14). Data have suggested that activated epithelial cells and macrophages have a part in the pathology of COPD by releasing neutrophil-specific chemotactic factors (CXC chemokines), such as IL-8 and growth-related oncogene- (14). Furthermore, the level of IL-8 in induced sputum is correlated with disease severity (as assessed by FEV1% predicted) and the neutrophilic burden (18). TNF- is also present in high concentrations in induced sputum from patients with COPD, which may lead to an increase in IL-8 gene expression via the activation of nuclear factor-
B (NF-B) (18). Leukotriene B4 is also likely to be a key mediator involved in the pathophysiology of COPD compared with asthma, given its role as a potent neutrophil chemoattractant. Elevated levels of leukotriene B4 have been found in induced sputum of patients with COPD (20, 21).
The pathogenesis of airway obstruction/emphysema is multifactorial, involving macrophages, neutrophilic airway inflammation, protease–antiprotease imbalance, oxidative stress, and recurrent infection. Protease–antiprotease imbalance is thought to play a key role in cigarette smoke–induced chronic lung disease, and it has received considerable attention in recent years. It proposes that an antiprotease "shield" protects the normal lung from locally elaborated proteases and that emphysema is the result of an abnormal increase in proteases and/or reduction in pulmonary antiproteases, which leads to parenchymal destruction (22). Investigators have previously suggested that the various proteases, particularly elastase, break down the connective tissue within the lung structures to produce emphysema. Most work has focused on the role of the serine proteases neutrophil elastase and proteinase-3 and the cathepsin family, which have been demonstrated to produce emphysema in animal models (23, 24). 1-Antitrypsin inhibits the action of neutrophil elastase in the parenchyma and its absence may account for the emphysema seen in the syndrome known as 1-antitrypsin deficiency. However, there is now increasing evidence that matrix metalloproteinases (MMPs) might play a role in cigarette smoking–related emphysema (25, 26).
With regard to the expression of MMPs in the lung, several researchers have shown increased concentrations of MMP-1, MMP-8, and MMP-9 in BAL fluid from patients with emphysema (27, 28). Furthermore, there appears to be an increase in the expression and activity of MMP-1, MMP-2, and MMP-9, but not MMP-12, in the lung parenchyma of patients with emphysema (29–31). The main cellular sources of enzymatic activity in the lower respiratory tract are neutrophils and alveolar macrophages, both of which are increased in the smoker's lung. Many studies have focused on the proteolytic potential of neutrophils, which includes neutrophil elastase and MMPs with collagenase and gelatinase activity (MMP-9, MMP-8) (32). However, some studies have implicated alveolar macrophages as the major inflammatory effector cells in the lungs of patients with emphysema. In fact, researchers have found that there is a direct relationship between the number of alveolar macrophages and lung destruction, and that MMPs are produced during macrophage-dependent lung injury. Thus, recently there has been considerable interest in the potential role of macrophage-derived MMPs (MMP-1, MMP-2, MMP-3, MMP-9, and MMP-12) in matrix degradation in emphysema. Additional studies using transgenic and gene-targeted mice have supported expression data generated in human normal and diseased tissues and have confirmed a role for MMPs in the pathogenesis of emphysema. In particular, studies in MMP-12 knockout mice have showed that MMP-12 is involved in the development of smoke-induced emphysema (33). However, the role of macrophage-derived MMP-12 in the genesis of human emphysema is still far from clear. Furthermore, in recent studies no difference has been demonstrated between patients with emphysema and normal volunteers with respect to the level of MMP-12 within BAL fluid (34).
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REGULATION OF INFLAMMATORY CELL FUNCTION BY GLUCOCORTICOIDS |
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TOPABSTRACTINFLAMMATORY CELLS IN ASTHMA...REGULATION OF INFLAMMATORY CELL...REGULATION OF INFLAMMATORY CELL...EFFECTIVENESS OF GLUCOCORTICOID...REFERENCES |
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It has been known for some time that glucocorticoids inhibit the formation of eosinophil-rich colonies in in vitro bone marrow assays, but these assays are often difficult to interpret given the presence of cells other than eosinophil progenitor cells in the culture systems used. The current theory is that glucocorticoids probably suppress eosinophil maturation by inhibiting the production and/or release of IL-5 and other eosinopoietic factors from cells within the bone marrow rather than by directly affecting CD34+ progenitors. Similarly, glucocorticoids do not appear to have a direct effect on adhesion per se but rather are reported to inhibit the accumulation of eosinophils at the site of inflammation by inhibiting the generation of chemoattractants and the upregulation of certain adhesion molecules (38).
Scientific dogma would suggest that the induction of apoptosis of airway tissue eosinophils is a major component of the pharmacologic profile of steroids used for the treatment of asthma (39, 40). In fact, spontaneous or steroid-induced eosinophil apoptosis can be easily shown in vitro (41, 42). Eosinophil apoptosis in diseased airway tissues in vivo, with or without steroid treatment, has not been compellingly demonstrated (43), but it is certainly clear that apoptotic eosinophils are often found in the airway lumen (44).
Neutrophils
Neutrophils have been implicated in the pathophysiology of COPD and more severe asthma (17, 45). It is generally assumed that neutrophils are less sensitive to glucocorticoids than, for example, eosinophils and T cells (46). Interestingly, in contrast to T cells, glucocorticoid treatment inhibits neutrophil cell death in vitro (47, 48). The antiinflammatory effects of steroids are mediated through activation of the glucocorticoid receptor (GR). There are actually two homologous mRNAs and protein isoforms, termed GR- and GR-ß. The differences in structure between the two receptors make GR-ß unable to bind glucocorticoids, reduce its binding affinity for DNA recognition sites, abolish its ability to transactivate glucocorticoid-sensitive genes, and allow it to function as a dominant inhibitor of GR-, possibly through the formation of antagonistic GR-/GR-ß heterodimers (49, 50). GR-ß attenuates pathways mediated by the glucocorticoid response element (GRE) and so may provide a natural mechanism for reducing glucocorticoid-mediated apoptosis. In fact, one study has suggested that dexamethasone reduces the rate of spontaneous cell death by neutrophils, and that preincubation of neutrophils with IL-8 enhances the protective effect (51).
Mast Cells and Basophils
The initial response after antigen challenge is characterized by mast cell degranulation and the release of mast cell–derived mediators (e.g., histamine and prostaglandin D2). Human mast cells and basophils have been implicated as a major source of inflammatory cytokines such as IL-4 and IL-5, and these observations have led investigators to examine whether steroids can modulate the synthesis/release of these mediators (52, 53).
Glucocorticoids have been shown to reduce the numbers of mast cells in airway mucosal biopsy specimens from human subjects with mild atopic asthma (54). Investigators have found that prolonged in vitro incubation with steroids (12–24 hours) inhibited IgE-mediated histamine release from basophils (55), whereas incubation of mast cells from lung parenchyma with steroids for similar time periods did not alter the release of histamine, prostaglandin D2, or leukotriene C4 (56). Interestingly, in more recent studies, short preincubation of human basophils with several glucocorticoids inhibited the immunologic release of IL-4 but not histamine, suggesting that different mechanisms control the release of cytokines and histamine (57). These in vitro data are supported by in vivo studies that suggest a minimal effect of glucocorticoids on mast cell degranulation and the appearance of mast cell mediators after segmental antigen challenge in subjects with asthma (58). The failure of steroids to inhibit mast cell mediator release in vivo is similar to results in nasal and cutaneous challenge model systems and is consistent with the in vitro data described above.
In a double-blind, placebo-controlled, randomized study in which patients with COPD received inhaled fluticasone for 3 months, fluticasone affected the numbers of subepithelial mast cells found in biopsy tissue. This reduction in mast cell numbers may account for the effect of fluticasone on the improvement of symptoms during this time and the decrease in exacerbations seen in long-term studies (59, 60).
Macrophages
Macrophages are derived from circulating monocytes, and during the differentiation process the profile of MMP expression in these cells changes from a predominantly MMP-7 phenotype toward expression of MMP-2 and MMP-9. Human macrophages are known to produce several MMPs, including MMP-1, MMP-2, MMP-3, MMP-9, and MMP-12 (34). Furthermore, alveolar macrophages from patients with COPD release greater amounts of MMP-1 and MMP-9, with greater enzymatic activity (at least for MMP-1 and MMP-9), than do macrophages from healthy smokers and nonsmokers. Interestingly, alveolar macrophages from nonsmokers release more tissue inhibitor of metalloproteinase-1 (TIMP-1) than do cells from healthy smokers and subjects with COPD (34).
Recent experiments have shown that basal release of IL-8 was approximately fivefold greater from alveolar macrophages in patients with COPD than from those in smokers, whereas levels of granulocyte macrophage colony–stimulating factor (GM-CSF) were similar for each group. IL-1ß and cigarette smoke increased IL-8 and GM-CSF release by macrophages from both smokers and patients with COPD. Dexamethasone did not inhibit basal or stimulated IL-8 release from patients with COPD, but inhibited its release in smokers. In contrast, dexamethasone inhibited basal and IL-1ß–stimulated GM-CSF release but not cigarette smoke–stimulated release (61). In addition, corticosteroids fail to decrease MMP-9 activity induced by cigarette smoke, in spite of decreasing MMP-9 protein release. This lack of effect of corticosteroids may be one of the reasons for the lack of efficacy of corticosteroids seen clinically in COPD treatment (62).
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REGULATION OF INFLAMMATORY CELL FUNCTION BY GLUCOCORTICOIDS IN ANIMAL MODELS |
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TOPABSTRACTINFLAMMATORY CELLS IN ASTHMA...REGULATION OF INFLAMMATORY CELL...REGULATION OF INFLAMMATORY CELL...EFFECTIVENESS OF GLUCOCORTICOID...REFERENCES |
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Steroid-induced eosinophil apoptosis can be readily demonstrated in vitro, and this may be a major mechanism by which eosinophilia is inhibited by steroids in vivo. However, recent data suggest that steroid treatment may not increase eosinophil apoptosis in vivo in a rat model and that steroids permit elimination of eosinophils into the airway lumen, a process that slowly resolves established lung eosinophilia. The authors of this study suggest that the reduced tissue eosinophilia seen after several days of steroid treatment in this model may be explained by inhibition of eosinophil recruitment together with unimpeded clearance of lung tissue eosinophils into the airway lumen (63) (Figure 2).
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Given the lack of support for the importance of eosinophils and eosinophil-related cytokines (e.g., IL-5) in AHR, a recent study has examined the possibility that the effects of dexamethasone may be due to a reduction in IL-13. However, the murine model of allergic inflammation showed that anti–IL-5/antieotaxin treatment was as effective as dexamethasone in reducing levels of IL-13 and eosinophil recruitment, but had no effect on AHR (64).
COPD
Aerosol or intranasal administration of lipopolysaccharide (LPS) induces intense lung inflammation, with macrophage activation and recruitment of neutrophils to the interstitium, alveoli, and airways of guinea pigs, rats, and mice (65, 66). This response requires the upregulation of adhesion molecules on circulating leukocytes and the pulmonary vascular endothelium and the expression of endogenous chemotactic factors.
The mechanism of pulmonary neutrophil migration in rats given topical LPS has been partially characterized and involves production by airway cells of inflammatory cytokines such as TNF- and IL-1, as well as CXC chemokines, which in rats include the family of cytokine-induced neutrophil chemoattractants (CINCs) and macrophage inflammatory protein-2 (MIP-2), also known as CINC-3. CD18 integrins have also been shown to play a role in full polymorphonuclear cell migration. Expression of CD18 adhesion molecules on the polymorphonuclear cell surface can be induced by exposure to LPS or TNF- and to chemokines such as CINC-1 and MIP-2. Several studies have demonstrated that steroids can inhibit the inflammatory cascade after LPS administration, as measured by the early expression of several of these proinflammatory cytokines and the subsequent accumulation of neutrophils in the airways (65–67).
Exposure of A/J mice to tobacco smoke on multiple occasions (11 consecutive daily exposures) induced a pulmonary inflammation that included increases in neutrophils and macrophages. Treatment with dexamethasone had no effect on the increase in neutrophils seen in BAL fluid after tobacco smoke exposure (68). This lack of activity of a steroid in a tobacco smoke model is also seen in elastase models of airway inflammation (M. A. Birrell and M. G. Belvisi, unpublished observations). It is in contrast to the steroid sensitivity of the LPS models, but it is similar to the lack of antiinflammatory activity of steroids seen in COPD.
In fact, in contrast to the lack of activity of steroids in some models, previous investigations have shown that corticosteroids affect the development and maturation of the developing lung in utero and in neonatal animals in a negative fashion. Systemic corticosteroids are routinely used for the treatment of acute exacerbations of COPD, and inhaled corticosteroids are more frequently being prescribed for the long-term treatment of patients with COPD. Because corticosteroids can affect matrix metalloproteinases and because the concept of protease/antiprotease imbalance is an important concept regarding the pathogenesis of emphysema, a recent study examined the effects of chronic steroid treatment on lung structure in adult rats. Interestingly, methylprednisolone causes matrix metalloproteinase–dependent emphysema in adult rats, and the animals showed increased matrix metalloproteinase-9 activity in their lungs on zymography. Rats treated concomitantly with methylprednisolone and a broad-spectrum matrix metalloproteinase inhibitor (GM6001) did not develop emphysema. These data suggest that systemic treatment of adult rats with the antiinflammatory steroid methylprednisolone increases the activity of matrix metalloproteinases in the lung and causes emphysema (69).
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EFFECTIVENESS OF GLUCOCORTICOID TREATMENT IN AIRWAY INFLAMMATORY DISEASES |
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TOPABSTRACTINFLAMMATORY CELLS IN ASTHMA...REGULATION OF INFLAMMATORY CELL...REGULATION OF INFLAMMATORY CELL...EFFECTIVENESS OF GLUCOCORTICOID...REFERENCES |
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The antiinflammatory properties of steroids are thought to be mediated via the GR. The finding that the rank order of potency of various steroids in eliciting antiinflammatory events correlates with their affinity for the GR supports this contention. The GR is ubiquitously expressed in most cell types, and activation mediates both the antiinflammatory effects and the various side effects elicited by these ligands. The GR is a ligand-activated transcription factor. In the absence of ligand binding the receptor is localized in the cytoplasm as a protein complex together with heat shock proteins hsp90, hsp70, and hsp40, along with p60/Hop and other chaperone molecules. Upon ligand binding the complex dissociates and the receptor translocates to the nucleus, where it can bind to a GRE in a target gene promoter and regulate transcription, a process known as transactivation. The positive regulation of target genes is mediated by a specific binding of the GR-DNA to GREs in the promoter or enhancer regions of responsive genes, followed by an induction or increase in gene transcription (e.g., tyrosine aminotransferase, phosphoenolpyruvate carboxykinase). However, negative regulation by GREs has also been reported, so that the activated GR can bind to negative GREs, leading to the repression of gene transcription. This mechanism has been described for the regulation of the osteocalcin and the proopiomelanocortin gene promoters. The GR may interact with other transcription factors (e.g., activator protein [AP]-1, NF-B, Smad3), preventing an activation of transcription by these factors. In these cases the gene expression is controlled without DNA binding, a process known as transrepression.
It is now recognized that therapeutic, antiinflammatory effects of the GR–ligand complex are mediated by transrepression and by transactivation, as well as by other mechanisms. For example, genes that code for antiinflammatory proteins are induced by the GR via a GR-DNA interaction (e.g., lipocortin, IL-1 receptor antagonist, secretory leukocyte protease inhibitor, IL-10). Alternatively, the majority of the proinflammatory genes coding for cytokines, chemokines, and adhesion molecules are regulated by NF-B and AP-1. In this situation the GR acts as a monomer with the subunits of the particular transcription factor, inhibiting its activity and suppressing the expression of various proinflammatory mediators. Based on the large number of proinflammatory genes regulated in this way, a hypothesis was formulated that the transrepression mechanism is largely responsible for GR-mediated antiinflammatory reactions and that the side effects are mediated predominantly via the transactivation mechanism. Evidence to support this hypothesis has been provided by a study investigating the glucocorticoid responsiveness in GR-mutated mice. The mutation prevented dimerization of the receptor and, therefore, the capacity for DNA binding. Interestingly, all DNA-dependent regulatory mechanisms of the GR were disrupted, but the classical glucocorticoid-mediated antiinflammatory effects were observed. Thus, mechanisms solely mediated by GR–protein interactions seem to be sufficient to mediate the antiinflammatory effects. In contrast, it has been demonstrated that some side effects are mediated predominantly via transrepression (e.g., skin atrophy, suppression of the hypothalamic-pituitary-adrenal axis), whereas others are mediated predominantly by transactivation (diabetes mellitus, glaucoma). Even more confusing, some side effects (e.g., osteoporosis) are thought to be mediated by both transactivation and transrepression (85).
COPD
The role of ICSs in the treatment of COPD is still controversial (86). Recent data indicates that ICSs do affect selected aspects of airway inflammation in COPD. Studies have reported a reduction in the CD8:CD4 ratio in the epithelium and in the numbers of subepithelial mast cells in the group treated with fluticasone (500 µg twice daily via dry powder inhaler over a 3-month period) compared with the placebo group. The selective antiinflammatory effect correlated with an improvement of symptoms and a small reduction in the numbers of exacerbations (59, 60). In addition, it has recently been reported that prednisolone has a beneficial effect in patients with COPD who have increased numbers of sputum eosinophils (87).
However, long-term trials have demonstrated that there is no effect of ICS on the annual decline in lung function seen in patients with COPD (88–91). However, in patients with more severe disease, there is a small beneficial effect of high-dose ICS on the frequency of exacerbations and the quality of life (92), and in severe exacerbations of COPD, oral corticosteroids do appear to have a small effect on recovery rate (93). Furthermore, 10 to 20% of patients with COPD respond to oral steroids, although this may be due to coexisting asthma (86). These data generated in long-term clinical trials are consistent with data from a study that described no clinical benefit in lung function or symptom scores, and no reduction in induced sputum inflammatory cells, percentage neutrophils, or IL-8 levels, after 4 weeks of treatment with inhaled fluticasone. Sputum supernatant elastase activity, MMP-1, MMP-9, secretory leukocyte protease inhibitor, and TIMP-1 were similarly unaffected by treatment (94).
CONCLUSIONS
Current clinical data describe distinct histopathologic and functional phenotypes in patients with asthma and COPD, even though both diseases are characterized by airflow limitation. These differences, in particular those observed between the responsiveness of activated inflammatory cells such as eosinophils and neutrophils, may help to explain the beneficial effects of ICS treatment in patients with asthma compared with patients with COPD.
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ACKNOWLEDGMENTS |
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(Received in original form February 17, 2004; accepted in final form April 13, 2004)
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REFERENCES |
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TOPABSTRACTINFLAMMATORY CELLS IN ASTHMA...REGULATION OF INFLAMMATORY CELL...REGULATION OF INFLAMMATORY CELL...EFFECTIVENESS OF GLUCOCORTICOID...REFERENCES |
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in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 1996;153:530–534.[Abstract]
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