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Corticosteroid Resistance in Smokers with Asthma

The study by Chaudhuri and colleagues (1) showed that cigarette smoking impairs the efficacy of corticosteroid therapy in subjects with asthma. Furthermore, the authors found a partial response to corticosteroids in the group of ex-smokers, suggesting that smoking-mediated corticosteroid insensitivity is partially reversible. Interestingly, an editorial by Dr. Bell (2) focused on the molecular mechanisms responsible for smoking-induced corticosteroid resistance, suggesting that oxidative stress should inhibit the corticosteroid effect in suppressing cytokine induction.

Corticosteroid-resistant asthma hits patients with severe disease, and a relative resistance is seen in patients who require inhaled and oral corticosteroids (corticosteroid-dependent asthma). Insensitivity to corticosteroids at molecular level can be induced by several mechanisms: reduced number of glucocorticoid receptor (GR), altered affinity of the ligand for GR, reduced ability of the GR to bind to DNA, or increased expression of the inflammatory transcription factor that competes for DNA binding. It has been demonstrated that nitric oxide (NO) treatment of GR modified ligand-binding affinity (3).

NO is a signaling molecule formed by NO synthase, of which two different functional isoforms (constitutive [cNOS] and inducible nitric oxide synthase [iNOS]) exist. NO is generally increased in Th2-driven inflammatory disease, such as asthma. Furthermore, NO may also interact with reactive oxygen species, such as ·O₂^–, to yield the powerful oxidant peroxynitrite (ONOO^–), which is responsible for most of the adverse effects (e.g., altered protein function) of NO through nitration (–NO₂· addition) pathway. 3-Nitrotyrosine (3-NT), a "nitrosative stress" biomarker, is detected in inflammatory disease characterized by the infiltration of leukocytes, and positive immunostaining with 3-NT antibodies has been observed in neutrophils. Neutrophil-derived myeloperoxidase (MPO) is considered a source of nitration also through the reaction between NO₂^– and hypochlorous acid.

We hypothesize the involvement of "nitrosative stress" induced by cigarette smoking in chronic airway inflammation affecting corticosteroid responsiveness. We found that healthy smokers showed increase of iNOS⁺ cells in the bronchial mucosa, in conjunction with an augmentation of CD3⁺ and CD8⁺ cells, compared with smokers with severe chronic obstructive pulmonary disease, showing neutrophilic (MPO⁺ cells) inflammation and increased 3-NT expression in the bronchial mucosa (4, 5). In addition, increase of neutrophils and interleukin-8 has been reported by Wenzel and colleagues (6) in bronchoalveolar lavage and bronchial biopsies from nonsmoking, severe steroid-dependent subjects with asthma. These findings suggest that cigarette smoking may increase oxidative stress and neutrophilia with the formation of MPO-dependent "nitrosative stress" in corticosteroid-dependent individuals with asthma, provoking a posttranslational modification of GR and subsequently a defective corticosteroid responsiveness.

Fabio L. M. Ricciardolo^a and Antonino Di Stefano^b

^a IRCCS Gaslini Institute Genoa, Italy
^b IRCCS S. Maugeri Foundation Veruno (NO), Italy

FOOTNOTES

Conflict of Interest Statement: F.L.M.R. and A.D.S. have no declared conflict of interest.

REFERENCES

1. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med 2003;168:1308–1311.[Abstract/Free Full Text]
2. Bell EH. Smoking: a neglected cause of glucocorticoid resistance in asthma. Am J Respir Crit Care Med 2003;168:1265–1266.[Free Full Text]
3. Galigniana MD, Piwien-Pilipuk G, Assreuy J. Inhibition of glucocorticoid receptor binding by nitric oxide. Mol Pharmacol 1999;55:317–323.[Abstract/Free Full Text]
4. Ricciardolo FLM, Capelli A, Caramori G, Rossi A, Donner CF, Di Stefano A. Inducible NOS overexpression is related to lymphocyte-driven inflammation in bronchial mucosa of smokers. Eur Respir J 2003;22:549s. (abstract).
5. Ricciardolo FLM, Capelli A, Rossi A, Donner CF, Di Stefano A. Increased nitrotyrosine expression in the bronchial mucosa of severe COPD. Am J Respir Crit Care Med 2003;167:A69. (abstract).
6. Wenzel SE, Szefler SJ, Leung DYM, Sloan SI, Rex MD, Martin RJ. Bronchoscopic evaluation of severe asthma: persistent inflammation associated with high dose glucocorticoids. Am J Respir Crit Care Med 1997;156:737–743.[Abstract/Free Full Text]

From the Authors:

We were interested to read the comments by Ricciardolo and Di Stefano on our finding (1) that the therapeutic response to oral corticosteroids is impaired in patients with asthma who are current cigarette smokers compared with never-smokers. On the basis of their preliminary finding in healthy smokers and smokers with chronic obstructive pulmonary disease (COPD), we agree that "nitrosative stress" could contribute to corticosteroid insensitivity in smokers with asthma. However, the extrapolation of results in healthy smokers and smokers with COPD might not necessarily apply to the mechanisms of corticosteroid resistance in smokers with asthma.

Several additional mechanisms could explain corticosteroid resistance in individuals with asthma who are active smokers (2). Potential mechanisms include the following alterations:

1. Pharmacokinetics of inhaled corticosteroids: for example, increased clearance secondary to heightened airway permeability or reduced access to target cells by increased bronchial sections.
   
2. Phenotype of airway inflammatory cells: for example, increased sputum neutrophil counts in individuals with asthma who have smoked for many years (3) are likely to respond poorly to corticosteroids.
   
3. Cytokine and mediator release: for example, exposure to cigarette smoke increases the production of proinflammatory cytokines such as interleukin (IL)-4 and tumor necrosis factor (TNF)-, which have been implicated in corticosteroid resistance (4).
   
4. Glucocorticoid receptor (GR) isoforms or binding affinity: for example, overexpression of GR ß on target cells due to the effects of cytokine and mediators such as IL-2 and IL-4 in combination, IL-8, IL-13, and TNF- might impair the response to corticosteroids by inhibiting the action of the ligand-activated GR (4).
   
5. Proinflammatory transcription factors: for example, nuclear factor-B can suppress both GR function by phosphorylation of the GR and the ability of the GR to bind to DNA (5).
   
6. Signaling pathways: for example, smokers have decreased histone deacetylase activity, which reduces sensitivity to corticosteroids (6).
   

We think it is likely that several of these mechanisms might contribute to corticosteroid resistance in smokers who have asthma. Further studies are required to examine the role of these pathways in individuals with asthma who are active smokers and following smoking cessation.

Neil C. Thomson, Rekha Chaudhuri and Eric Livingston

University of Glasgow Glasgow, United Kingdom

FOOTNOTES

Conflict of Interest Statement: N.C.T., R.C., and E.L. have no declared conflict of interest.

REFERENCES

1. Chaudhuri R, Livingston E, McMahon AD, Thomson L, Borland W, Thomson NC. Cigarette smoking impairs the therapeutic response to oral corticosteroids in chronic asthma. Am J Respir Crit Care Med 2003;168:1308–1311.
2. Thomson N, Chaudhuri R, Livingston E. Active cigarette smoking and asthma. Clin Exp Allergy 2003;33:1471–1475.[CrossRef][Medline]
3. Chalmers G, MacLeod K, Thomson L, Little S, McSharry C, Thomson N. Smoking and airway inflammation in patients with mild asthma. Chest 2001;120:1917–1922.[Abstract/Free Full Text]
4. Leung D, Bloom D. Update on glucocorticoid action and resistance. J Allergy Clin Immunol 2003;111:3–22.[CrossRef][Medline]
5. Schaaf M, Cidlowski J. Molecular mechanisms of glucocorticoid action and resistance. J Steroid Biochem Mol Biol 2002;83:37–48.[CrossRef][Medline]
6. Ito K, Lim S, Caramori G, Chung K, Barnes P, Adcock I. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression, and inhibits glucocorticoid actions in alveolar macrophages. FASEB J 2001;15:1110–1112.[Free Full Text]

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