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The Proceedings of the American Thoracic Society 1:264-268 (2004)
© 2004 The American Thoracic Society

Corticosteroid Resistance in Airway Disease

Peter J. Barnes

National Heart and Lung Institute, Imperial College, London, United Kingdom

Correspondence and requests for reprints should be addressed to Professor P. J. Barnes, D.M., D.Sc., F.R.C.P., National Heart and Lung Institute, Imperial College, Dovehouse Street, London SW3 6LY, UK. E-mail: p.j.barnes{at}imperial.ac.uk


   ABSTRACT
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CORTICOSTEROID RESISTANCE IN...
 CORTICOSTEROID RESISTANCE IN...
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Resistance to the antiinflammatory effects of corticosteroids is very uncommon in asthma but common in chronic obstructive pulmonary disease. Recent understanding of the molecular mechanisms involved in the antiinflammatory actions of corticosteroids has revealed that there are several possible mechanisms for corticosteroid resistance. Certain cytokines activate p38 mitogen-activated protein kinase, which may interfere with the nuclear localization of glucocorticoid receptors (GRs). In other patients, nuclear localization of GR is normal but there is a reduction in acetylation of a lysine residue in histone-4, thus leading to impaired activation of certain antiinflammatory genes. In chronic obstructive pulmonary disease and severe asthma, oxidative stress may reduce the activity and expression of certain histone deacetylases and therefore interfere with the antiinflammatory action of corticosteroids. These mechanisms suggest that there may be several therapeutic approaches to treating corticosteroid resistance in the future, including antioxidants, p38 mitogen-activated protein kinase inhibitors, and theophylline, which activates histone deacetylases.

Key Words: steroid resistance • asthma • chronic obstructive pulmonary disease • histone deacetylase

Although corticosteroids are highly effective in the control of asthma and other chronic inflammatory and immune diseases, a small proportion of patients with asthma fail to respond even to high doses of oral corticosteroids (1, 2). Resistance to the therapeutic effects of corticosteroids is also recognized in other inflammatory and immune diseases, including rheumatoid arthritis and inflammatory bowel disease. Patients with corticosteroid-resistant asthma, although uncommon, present considerable management problems. Patients with chronic obstructive pulmonary disease (COPD) show a poor clinical response to corticosteroids and have a largely steroid-resistant pattern of inflammation (3). New insights into the mechanisms whereby corticosteroids suppress chronic inflammation have shed light on the molecular basis for corticosteroid resistance in asthma and COPD (4).


   CORTICOSTEROID RESISTANCE IN ASTHMA
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It is likely that there is a spectrum of steroid responsiveness in asthma, with the rare resistance at one end, but a relative resistance is seen in patients who require high doses of inhaled and oral steroids (corticosteroid-dependent asthma). Biopsy studies have demonstrated the typical eosinophilic inflammation of asthma in these patients (1).

Clinical Features
Corticosteroid-resistant (CR) asthma is defined as a failure to improve lung function by more than 15% after treatment with high doses of prednisolone (30–40 mg daily) for 2 weeks. It is important to verify that the oral steroid has been taken by measuring plasma prednisolone concentrations or showing a reduction in early morning cortisol level. These patients are not Addisonian and they do not suffer from the hormonal abnormalities described in the very rare familial glucocorticoid resistance. Plasma cortisol and adrenal suppression in response to exogenous cortisol is normal in these patients, so they unfortunately usually suffer from all of the side effects of corticosteroids.

Complete corticosteroid resistance in asthma is very rare, with a likely prevalence of less than 1:1,000 patients with asthma. Much more common is a reduced responsiveness to corticosteroids, described as corticosteroid-dependent (CD) asthma, where large inhaled or oral doses of corticosteroids are needed to control asthma adequately. It is likely that there is a range of responsiveness to corticosteroids and that corticosteroid resistance is at one extreme of this range.

It is important to establish that the patient who does not respond to corticosteroids has asthma, rather than COPD, "pseudoasthma" (a hysterical conversion syndrome involving vocal cord dysfunction), left ventricular failure or cystic fibrosis, none of which respond to corticosteroids (5, 6). It is also important to identify provoking factors (allergens, drugs, psychological problems) that may increase the severity of asthma and its resistance to therapy. Bronchial biopsy studies have demonstrated the typical eosinophilic inflammation of asthma in these patients (7). In a trial of oral prednisolone it is important to establish that the patient is taking the oral steroid by demonstrating suppression of plasma cortisol or by measurement of plasma prednisolone concentrations. Individuals with CD asthma are dependent on oral as opposed to inhaled steroids, and deteriorate when the dose of oral steroids is reduced; they usually have severe disease and are presumed to have a high degree of inflammation in their airways.

Molecular Mechanisms
Several mechanisms for corticosteroid resistance in asthma have been proposed (Table 1).


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  		TABLE 1. Proposed mechanisms of corticosteroid resistance in asthma

 
Abnormalities in glucocorticoid receptors.
In the extremely rare familial glucocorticoid resistance, which is associated with various endocrine abnormalities, there are several identified point mutations of the glucocorticoid receptor (GR) gene that may result in an abnormal GR structure, resulting in reduced corticosteroid binding affinity (8). In CR asthma there are no major abnormalities in GR structure, however (9). In CR asthma small differences in GR binding affinity and receptor density have been documented, but these are too small to have a significant effect on function (10). Sher and coworkers described two types of corticosteroid resistance: a reduced affinity of GR binding confined to T-lymphocytes which reverted to normal after 48 hours in culture, and a much less common reduction in GR density (in only 2/17 patients with CR asthma) which did not normalize with prolonged incubation (11).

Inflammatory cytokines.
There appear to be several mechanisms for resistance to the effects of corticosteroids in asthma, and these may differ between patients. Interleukin(IL)-2, IL-4, and IL-13, which show increased expression in bronchial biopsies of patients with CR asthma, induce a reduction in affinity of GR in inflammatory cells, such as T-lymphocytes and monocytes, resulting in local resistance to the antiinflammatory actions of corticosteroids (1, 12). The combination of IL-2 and IL-4 induces steroid resistance in vitro through activation of p38 mitogen-activated protein (MAP) kinase, which phosphorylates GR and reduces corticosteroid binding affinity and steroid-induced nuclear translocation of GR (13). The therapeutic implication is that p38 MAP kinase inhibitors now in clinical development might reduce this steroid resistance.

GR-ß.
Another proposed mechanism for steroid resistance in asthma is increased expression of an alternatively spliced form of the glucocorticoid receptor, GR-ß, which binds to DNA but not to corticosteroids. This may theoretically act as a dominant-negative inhibitor by competing with GR-{alpha} for binding to GRE sites or from interacting with coactivator molecules (14). However, there is no increased expression of GR-ß in the mononuclear cells of patients with steroid-dependent asthma which have a reduced responsiveness to corticosteroids in vitro, and GR-{alpha} is much more abundant than GR-ß, making it unlikely that it could have any functional inhibitory effect (15). Furthermore, overexpression of GR-ß has no effect on the inhibition by corticosteroids of inflammatory transcription factors by trans-repression, suggesting that this mechanism is unlikely to interfere with their anti-inflammatory actions (16).

Nuclear localization of GR.
In patients with CR and CD asthma there is a reduction in the inhibitory effect of corticosteroids on cytokine release in peripheral blood mononuclear cells, indicating that these cells are corticosteroid resistant in vitro (10, 17). In one group of patients, nuclear localization of GR in response to a high concentration of corticosteroids is impaired, and this may be due to the abnormalities such as the increased activation of p38 MAP kinase described above. Reduced nuclear localization of corticosteroids is likely to reduce the antiinflammatory action of corticosteroids (Figure 1).



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  		Figure 1. Possible mechanisms of corticosteroid resistance in asthma. In steroid-sensitive patients with asthma, corticosteroids induce nuclear localization of glucocorticoid receptors (GR), which interact with histone-4, resulting in acetylation of lysine residues (K)5 and K16 and activation of steroid-activated antiinflammatory genes. In Group 1 resistant patients there is defective nuclear localization of GR, which may be due to phosphorylation of GR by p38 mitogen-activated protein (MAP) kinase, which is activated by Th2 cytokines interleukin (IL)-2, IL-4, and IL-13. In Group 2 resistant patients there is normal nuclear localization but defective acetylation of K5, which presumably inhibits the activation of critical steroid-dependent genes.

 
Interaction with transcription factors.
Corticosteroids suppress the expression of inflammatory genes regulated by proinflammatory transcription factors such as activator protein-1 (AP-1) and nuclear factor-{kappa}B (NF-{kappa}B). There is some evidence that AP-1 activity is increased in peripheral blood mononuclear cells of patients with CR asthma and that this may counteract the antiinflammatory action of corticosteroids (17, 18). There is also increased activity of Jun N-terminal kinase, the MAP kinase that activates AP-1 (19).

Abnormal histone acetylation pattern.
In another group of patients with CR and CD asthma, nuclear localization of GR is normal and there is a defect in acetylation of histone-4, the mechanism by which corticosteroids activate steroid-responsive genes (20, 21). In this group of patients specific acetylation of lysine 5 of histone-4 is defective, and presumably this means that corticosteroids are not able to activate certain genes that are critical to the antiinflammatory action of high doses of corticosteroids (Figure 1). Whether this is a genetic defect is not yet known.

IL-10.
IL-10 is a potent antiinflammatory cytokine, and its secretion is defective from alveolar macrophages and circulating monocytes of patients with asthma, particularly in severe disease (22, 23). Corticosteroids increase macrophage secretion of IL-10, and this may contribute to their antiinflammatory actions. There is a reduction in T-lymphocyte secretion of IL-10 in patients with CR asthma, and this may contribute to the reduced responsiveness to the antiinflammatory actions of corticosteroids (24).

Cigarette smoking.
Patients with asthma who smoke cigarettes may be less responsive to the antiinflammatory actions of corticosteroids than nonsmokers. Treatment with corticosteroids is less effective in reducing inflammatory cells in bronchoalveolar lavage fluid and induced sputum in patients with asthma who are smokers (25, 26). The mechanisms for corticosteroid resistance in cigarette smokers may be a consequence of oxidative stress, as discussed below.

Viral infection.
It is possible that corticosteroid resistance may evolve as a result of viral infection, because many viruses are capable of activating transcription factors that could interfere with corticosteroid action. In children with severe CD asthma there is evidence for persistent adenovirus infection in the airways (27). Viruses may activate transcription factors, resulting in increased corticosteroid resistance. Guinea pigs with latent adenovirus show a marked reduction in the antiinflammatory effect of corticosteroids on allergen-induced lung inflammation (28).


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Although inhaled corticosteroids are highly effective in asthma, they provide little benefit in COPD, despite the fact that airway and lung inflammation is present. This may reflect the fact that the inflammation in COPD is not suppressed by corticosteroids, with no reduction in inflammatory cells, cytokines, or proteases in induced sputum even with oral corticosteroids (29–31).

Cellular and Molecular Mechanisms
Effect on neutrophils.
Corticosteroids do not suppress neutrophilic inflammation induced by inhalation of ozone in the airways of normal subjects (32). Indeed, corticosteroids prolong neutrophil survival in vitro by inhibiting apoptotic pathways (33).

Macrophage resistance.
There is some evidence that an active cellular corticosteroid resistance mechanism exists in COPD. For instance, in patients with COPD, corticosteroids fail to inhibit cytokines that they normally suppress. In vitro studies show that cytokine release from alveolar macrophages is markedly resistant to the inhibitory effects of corticosteroids compared with cells from normal smokers, and these in turn are more resistant than alveolar macrophages from nonsmokers (34).

Histone deacetylase dysfunction.
This lack of response to corticosteroids may be explained, at least in part, by an inhibitory effect of cigarette smoking and oxidative stress on histone deacetylases (HDACs), thus interfering with a critical antiinflammatory action of corticosteroids (35) (Figure 2). There is a striking reduction in the activity and expression of HDACs in peripheral lung of patients with COPD (36). Even in patients with COPD who have stopped smoking, the corticosteroid resistance persists (29, 30) and these patients are known to have continuing oxidative stress (37). The mechanisms whereby oxidative stress and cigarette smoking lead to selective dysfunction of HDACs is currently under investigation. This mechanism may also apply in severe asthma, where there is also evidence for increased oxidative stress (38).



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  		Figure 2. Stimulation of normal alveolar macrophages activates nuclear factor-{kappa}B (NF-{kappa}B) and other transcription factors to switch on histone acetyltransferase leading to histone acetylation and subsequently to transcription of genes encoding inflammatory proteins, such as tumor necrosis factor-{alpha} (TNF-{alpha}), interleukin-8 (IL-8), and matrix metalloproteinase-9 (MMP-9). Corticosteroids reverse this by binding to glucocorticoid receptors (GR) and recruiting histone deacetylase-2 (HDAC2). This reverses the histone acetylation induced by NF-{kappa}B and switches off the activated inflammatory genes. In patients with COPD, cigarette smoke activates macrophages, as in normal subjects, but oxidative stress (perhaps acting through the formation of peroxynitrite) impairs the activity of HDAC2. This amplifies the inflammatory response to NF-{kappa}B activation, but also reduces the antiinflammatory effect of corticosteroids as HDAC2 is now unable to reverse histone acetylation.

 

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CR asthma is often difficult to manage, as corticosteroids are ineffective but cause side effects when given orally. It is therefore advisable to slowly withdraw oral corticosteroids. Patients with CR asthma often have a good bronchodilator response to ß2-agonists, and treatment with a long-acting inhaled ß2-agonist is recommended. Indeed, it is possible that there is a molecular interaction between ß2-agonists and corticosteroids that may enhance the antiinflammatory effect of corticosteroids (39). This might be relevant in those patients with CR asthma with defective nuclear localization of GR, as ß2-agonists may enhance the nuclear localization of GR (40–42).

Steroid-sparing therapies, including methotrexate and ciclosporin A, are not beneficial. It is unlikely that more potent corticosteroid or dissociated steroid would overcome the mechanisms of resistance, but understanding the molecular mechanisms involved may lead to novel therapeutic approach. This approach may depend on the mechanisms of steroid resistance involved however, so that different approaches may be needed in different patients.

NF-{kappa}B Inhibitors
Many of the antiinflammatory effects of corticosteroids appear to be mediated via inhibition of the transcriptional effects of NF-{kappa}B, and now several potent small molecule inhibitors of I{kappa}B kinase-2 (IKK2, IKKß), which activates NF-{kappa}B in response to inflammatory stimuli, are in development (43, 44). However, corticosteroids have additional effects, so it is not certain whether IKK2 inhibitors will parallel the clinical effectiveness of corticosteroids; in addition, IKK2 inhibitors may have side effects, such as increased susceptibility to infections.

p38 MAP Kinase Inhibitors
p38 MAP kinase inhibitors might reduce steroid resistance and act as antiinflammatory treatments in patients with some forms of steroid-resistant asthma, but would not be expected to benefit the patients with the form of steroid resistance associated with a defect in acetylation of lysine 5 on histone-4. Several p38 MAP kinase inhibitors are now in clinical development, although their long-term safety is not yet known (45).

Antioxidants
In patients with COPD and severe asthma there is a marked increase in oxidative stress, which may induce steroid resistance as discussed above. This indicates that antioxidants that neutralize this oxidative stress in the airways might be of benefit and may restore corticosteroid sensitivity in these patients.

Theophylline
Our recent studies indicate that theophylline, at low therapeutic concentrations, is able to increase HDAC activity and can reverse the decrease in HDAC activity associated with oxidative stress and COPD. This action of theophylline is not mediated via phosphodiesterase inhibition or adenosine receptor antagonism, and therefore appears to be a novel action of theophylline (46). It may be possible to discover other drugs in this class which could form the basis of a new class of antiinflammatory drugs without the side effects due to phosphodiesterase inhibition and adenosine antagonism that limit the use of theophylline. These drugs may be useful in increasing responsiveness to corticosteroids and reversing corticosteroid resistance (47). Addition of low-dose theophylline is often beneficial in patients with severe CD asthma (48, 49), but further studies in COPD are indicated.


   ACKNOWLEDGMENTS
 
P.J.B. serves as a consultant to GlaxoSmithKline (GSK) and is a member of Scientific Advisory Boards for GSK, Boehringer Ingelheim, and Altana and has received lecture fees from GSK, AstraZeneca, Boehringer Ingelheim and unrestricted grants from GSK, AstraZeneca, and Boehringer Ingleheim.

(Received in original form February 18, 2004; accepted in final form August 3, 2004)


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  21. Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits IL-1ß-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol 2000;20:6891–6903.[Abstract/Free Full Text]
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  23. Tomita K, Lim S, Hanazawa T, Usmani O, Stirling R, Chung KF, Barnes PJ, Adcock IM. Attenuated production of intracellular IL-10 and IL-12 in monocytes from patients with severe asthma. Clin Immunol 2002;102:258–266.[CrossRef][Medline]
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  33. Meagher LC, Cousin JM, Seckl JR, Haslett C. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J Immunol 1996;156:4422–4428.[Abstract]
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  36. Ito K, Watanabe S, Kharitonov S, Hanazawa T, Adcock IM, Barnes PJ. Histone deacetylase activity and gene expression in COPD patients [abstract]. Eur Respir J 2001;18:316S.
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  39. Barnes PJ. Scientific rationale for combination inhalers with a long-acting ß2-agonists and corticosteroids. Eur Respir J 2002;19:182–191.[Abstract/Free Full Text]
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  43. Castro AC, Dang LC, Soucy F, Grenier L, Mazdiyasni H, Hottelet M, Parent L, Pien C, Palombella V, Adams J. Novel IKK inhibitors: beta-carbolines. Bioorg Med Chem Lett 2003;13:2419–2422.[CrossRef][Medline]
  44. Kishore N, Sommers C, Mathialagan S, Guzova J, Yao M, Hauser S, Huynh K, Bonar S, Mielke C, Albee L. A selective IKK-2 inhibitor blocks NF-{kappa}B-dependent gene expression in IL-1ß stimulated synovial fibroblasts. J Biol Chem 2003; .
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  46. Ito K, Lim S, Caramori G, Cosio B, Chung KF, Adcock IM, Barnes PJ. A molecular mechanism of action of theophylline: induction of histone deacetylase activity to decrease inflammatory gene expression. Proc Natl Acad Sci USA 2002;99:8921–8926.[Abstract/Free Full Text]
  47. Barnes PJ. Theophylline: new perspectives on an old drug. Am J Respir Crit Care Med 2003;167:813–818.[Free Full Text]
  48. Kidney J, Dominguez M, Taylor PM, Rose M, Chung KF, Barnes PJ. Immunomodulation by theophylline in asthma: demonstration by withdrawal of therapy. Am J Respir Crit Care Med 1995;151:1907–1914.[Abstract]
  49. Evans DJ, Taylor DA, Zetterstrom O, Chung KF, O'Connor BJ, Barnes PJ. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 1997;337:1412–1418.[Abstract/Free Full Text]



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Eur. Respir. J., November 1, 2006; 28(5): 897 - 899.
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