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Ian M. Adcock, PhD; Peter J. Barnes, FRS
Author and Funding Information

National Heart and Lung Institute Imperial College London London, UK

Correspondence to: Ian M. Adcock, PhD, Imperial College London, NHLI, Guy Scadding Building, Dovehouse St, London SW3 6LY, United Kingdom; e-mail: ian.adcock@imperial.ac.uk


The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).


Chest. 2009;135(2):586. doi:10.1378/chest.08-2716
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To the Editor:

We thank Drs. Tonello and Poli for their interest in our recent review in CHEST (August 2008)1 and for highlighting the potential role that 11β-hydroxysteroid dehydrogenase (11β-HSD) may play in glucocorticoid (GC) sensitivity in airways disease. 11β-HSD2 reversibly converts hydrocortisone, which is the major endogenous human GC, into its inactive metabolite, cortisone, and is predominantly expressed in the epithelium and vascular endothelium in both asthmatic and nonasthmatic subjects.2 This hypothesis has been previously proposed by Pretorius and colleagues,3 who emphasized that in cells where both GC receptors (GR) and mineralocorticoid receptors are expressed a loss of 11β-HSD expression will allow the activation of mineralocorticoid receptors by GCs rather than the correct interaction with GRs.

Feinstein and Schleimer4 have reported that the 11β-HSD inhibitor glycyrrhetinic acid could enhance the potency of hydrocortisone to suppress cytokine expression in primary human epithelial cells by 33-fold. However, most synthetic GCs including budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate, and triamcinolone acetonide are not metabolized by 11β-HSD.4 Interestingly, in this small study (22 subjects) there was an inverse relationship between the inhaled GC dose required for effective treatment and the extent of epithelial 11β-HSD staining. The authors contended that 11β-HSD acts here as an oxidoreductase that regenerates rather than inactivates inhaled GCs.2

To our knowledge, the expression and activity of 11β-HSD has not been determined in patients with severe asthma or COPD, where Tonello and Poli correctly state that oxidative stress is high. The ability of GCs to increase 11β-HSD expression under the control of CCAAT/enhancer-binding protein (C/EBP) β has been previously shown.5 Primary human epithelial cells elicit an acute-phase response following stimulation, and GCs can spare the expression of host defense molecules, including complements, collectins, and other antimicrobial proteins. In that study by Zhang et al,5 the knockdown of C/EBPβ blocked the induction of host defense molecules by GC but had no effect on inflammatory gene expression. The expression of C/EBPα, but not C/EBPβ, is markedly reduced in airway smooth muscle of asthmatic patients,6 and in culture budesonide enhanced C/EBPβ expression.7 In contrast, the expression of C/EBPα and C/EBPβ was unaltered in COPD patients but was attenuated by budesonide.7 However, the expression of C/EBP isoforms is not known in patients with severe asthma. Since there is disease-specific expression and regulation of C/EBP isoforms, there remains a possibility that pharmacologic manipulation of 11β-HSD activity might act to enhance the activity of endogenous GCs and thereby overcome GC resistance, particularly in relation to the induction of innate immune mediators.

Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid resistance. Chest. 2008;134:394-401. [PubMed] [CrossRef]
 
Orsida BE, Krozowski ZS, Walters EH. Clinical relevance of airway 11β-hydroxysteroid dehydrogenase type II enzyme in asthma. Am J Respir Crit Care Med. 2002;165:1010-1014. [PubMed]
 
Pretorius E, Wallner B, Marx J. Cortisol resistance in conditions such as asthma and the involvement of 11β-HSD-2: a hypothesis. Horm Metab Res. 2006;38:368-376. [PubMed]
 
Feinstein MB, Schleimer RP. Regulation of the action of hydrocortisone in airway epithelial cells by 11β-hydroxysteroid dehydrogenase. Am J Respir Cell Mol Biol. 1999;21:403-408. [PubMed]
 
Zhang N, Truong-Tran QA, Tancowny B, et al. Glucocorticoids enhance or spare innate immunity: effects in airway epithelium are mediated by CCAAT/enhancer binding proteins. J Immunol. 2007;179:578-589. [PubMed]
 
Roth M, Johnson PR, Borger P, et al. Dysfunctional interaction of C/EBPα and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N Engl J Med. 2004;351:560-574. [PubMed]
 
Borger P, Matsumoto H, Boustany S, et al. Disease-specific expression and regulation of CCAAT/enhancer-binding proteins in asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2007;119:98-105. [PubMed]
 

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References

Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid resistance. Chest. 2008;134:394-401. [PubMed] [CrossRef]
 
Orsida BE, Krozowski ZS, Walters EH. Clinical relevance of airway 11β-hydroxysteroid dehydrogenase type II enzyme in asthma. Am J Respir Crit Care Med. 2002;165:1010-1014. [PubMed]
 
Pretorius E, Wallner B, Marx J. Cortisol resistance in conditions such as asthma and the involvement of 11β-HSD-2: a hypothesis. Horm Metab Res. 2006;38:368-376. [PubMed]
 
Feinstein MB, Schleimer RP. Regulation of the action of hydrocortisone in airway epithelial cells by 11β-hydroxysteroid dehydrogenase. Am J Respir Cell Mol Biol. 1999;21:403-408. [PubMed]
 
Zhang N, Truong-Tran QA, Tancowny B, et al. Glucocorticoids enhance or spare innate immunity: effects in airway epithelium are mediated by CCAAT/enhancer binding proteins. J Immunol. 2007;179:578-589. [PubMed]
 
Roth M, Johnson PR, Borger P, et al. Dysfunctional interaction of C/EBPα and the glucocorticoid receptor in asthmatic bronchial smooth-muscle cells. N Engl J Med. 2004;351:560-574. [PubMed]
 
Borger P, Matsumoto H, Boustany S, et al. Disease-specific expression and regulation of CCAAT/enhancer-binding proteins in asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2007;119:98-105. [PubMed]
 
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