Mecanismos de acción y resistencia a glucocorticoides en asma y enfermedad pulmonar obstructiva crónica

Autores/as

  • Alcibey Alvarado González Caja Costarricense del Seguro Social, Hospital San Juan de Dios
  • Isabel Arce Jiménez Universidad de Costa Rica

DOI:

https://doi.org/10.51481/amc.v55i4.811

Palabras clave:

asma, enfermedad pulmonar obstructiva crónica, resistencia a medicamentos, glucocorticoides, inflamación

Resumen

El asma bronquial y la enfermedad pulmonar obstructiva crónica son dos problemas mayores de salud: su incidencia se encuentra en aumento y representan, indiscutiblemente, una causa importante de morbilidad y mortalidad a nivel mundial. Los glucocorticoides se han posicionado como la droga de elección en el tratamiento de padecimientos inmunológicos e inflamatorios crónicos, como el asma bronquial y la enfermedad obstructiva crónica. Estas drogas suprimen la inflamación en múltiples vías moleculares, característica que les confiere destacada eficacia. Su principal acción en dosis terapéuticas se produce por la transrepresión de genes inflamatorios activos, mediante el reclutamiento y actividad de la enzima histona-desacetilasa-2 y la remodelación de la cromatina. En dosis altas, funcionan más bien como transactivadores, acetilando las histonas y estimulando la transcripción de genes antinflamatorios, y potencialmente, también de varios genes relacionados con efectos secundarios. Además, se les reconoce acciones postranscripcionales, que modifican la estabilidad de secuencias de ARN mensajero. A pesar de esto, una respuesta disminuida a los glucocorticoides se presenta en pacientes con asma severa, en asmáticos que fuman y en quienes tienen enfermedad pulmonar obstructiva crónica. Varios mecanismos moleculares de resistencia a glucocorticoides han sido identificados. Se están investigando otros tratamientos antinflamatorios que permitan controlar los síntomas de estos pacientes, así como drogas que puedan revertir los mecanismos moleculares de la resistencia. Problemáticamente, estas terapias podrían ser demasiado específicas para resultar eficaces, como es el caso de los esteroides disociados, en el que es difícil separar efectos antinflamatorios y secundarios.

Citas

Barnes P J, Adcock I M. How do corticosteroids work in asthma? Ann Intern Med 2003;139:359-70.

Barnes P J. Immunology of asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 2008;8:183-92.

Barnes P J, Adcock I M. Glucocorticoid resistance in inflammatory diseases. Lancet 2009;373:1905-17.

Barnes P J. Biochemical basis of asthma therapy. J Biol Chem 2011;286:32899-905.

Barnes PJ, Adcock IM. Transcription factors and asthma. Eur Respir J 1998;12:221-34

Busse WW, Lemanske RF, Jr. Asthma. N Engl J Med 2001;344:35062.

Barnes P J, Chung K F, Page C. Inflammatory mediators of asthma: an update. Pharmacol Rev 1998;50:515-96.

Adcock IM. Glucocorticoid-regulated transcription factors. Pulm Pharmacol Ther 2001;14:211-9.

Hart L, Krishnan V, Adcock I M, Barnes P J, Chung K F. Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am J Respir Crit Care Med 1998;158:1585-92.

Barnes PJ, Karin M. Nuclear factor-kappaB: a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 1997;336:1066-71.

Adcock IM, Barnes PJ. Molecular mechanisms of corticosteroid resistance. Chest 2008;134:394-401.

Bannister A, Schneider R, Kouzarides T. Histone methylation: dynamic or static? Cell 2002;109:801-6.

Ogryzko V, Schiltz R, Russanova V, Howard B, Nakatani Y. The transcriptional coactivators p300 and CBP are histone acetyltransferases. Cell 1996;87:953-9.

Ito K, Ito M, Elliott W M, Cosio B, Caramori G, Kon O M, et al. Decreased histone deacetylase activity in chronic obstructive pulmonary disease. N Engl J Med 2005;352:1967-76.

Berger S. An embarrassment of niches: the many covalent modifications of histones in transcriptional regulation. Oncogene 2001;20:3007-13.

Roth S, Denu J, Allis C. Histone acetyltransferases. Annu Rev Biochem 2001; 70:81-120.

To M, Yamamura S, Akashi K, Charron C, Barnes P, Ito K. Defect of adaptation to hypoxia in patients with COPD due to reduction of histone deacetylase 7. Chest 2012;141:1233-42.

Kagoshima M, Wilcke T, Ito K, Tsapruni L, Barnes P J, Punchard N, Adckock I M. Glucocorticoid-mediated transrepression is regulated by histone acetylation and DNA methylation. Eur J Pharmacol 2001;429:327-34.

Jenuwein T. Translating the Histone Code. Science 2001;293:1074-80

Ito K, Chung K F, Adcock I M. Update on glucocorticoid action and resistance. J Allergy Clin Immunol 2006;117:522-43.

Anand R, Marmorstein R. Structure and mechanism of lysinespecific demethylase enzymes. J Biol Chem 2007;282:35425-9.

ten Brinke A, Zwinderman A, Sterk P, Rabe K, Bel E. “Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am J Respir Crit Care Med 2004;170:601-5.

Barnes P J. Glucocorticosteroids: current and future directions. Br J Pharmacol 2011;163:29-43.

Barnes P J. Mechanisms and resistance in glucocorticoid control of inflammation. J Steroid Biochem Mol Biol 2010;120:76-85.

Thomson N, Chaudhuri R, Livingston E. Asthma and cigarette smoking. Eur Respir J 2004;24:822-33.

Yang IA, Fong KM, Sim EH, Black PN, Lasserson TJ. Inhaled corticosteroids for stable chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2007:CD002991.

Suissa S, Ernst P, Vandemheen K, Aaron S. Methodological issues in therapeutic trials of COPD. Eur Respir J 2008;31:927-33.

Bourbeau J, Christodoulopoulos P, Maltais F, Yamauchi Y, Olivenstein R, Hamid Q. Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial. Thorax 2007;62:938-43.

Culpitt S V, Rogers D F, Shah P, Matos D C, Russell E K R, E Louise, et al. Impaired inhibition by dexamethasone of cytokine release by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2003;167:24-31.

Chikanza I, Kozaci D. Corticosteroid resistance in rheumatoid arthritis: molecular and cellular perspectives. Rheumatology 2004;43:1337-45.

Marwick J, Adcock I M, Chung K F. Overcoming reduced glucocorticoid sensitivity in airway disease: molecular mechanisms and therapeutic approaches. Drugs 2010; 70:929-48.

Yan Z-q, Hansson G. Innate immunity, macrophage activation, and atherosclerosis. Immunol Rev 2007;219:187-203.

Irusen E, Matthews JG, Takahashi A, Barnes PJ, Chung KF, Adcock IM. p38 Mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroidinsensitive asthma. J Allergy Clin Immunol 2002;109:649-57.

Miller A, Webb M, Copik A, Wang Y, Johnson B H, Kumar R, Thompson EB.p38 Mitogen-activated protein kinase (MAPK) is a key mediator in glucocorticoid-induced apoptosis of lymphoid cells: correlation between p38 MAPK activation and site-specific phosphorylation of the human glucocorticoid receptor at serine 211. Mol Endocrinol 2005;19:1569-83.

Szatmáry Z, Garabedian M, Vilcek J. Inhibition of glucocorticoid receptor-mediated transcriptional activation by p38 mitogenactivated protein (MAP) kinase. J Biol Chem 2004;279:4370815.

Bhavsar P, Hew M, Khorasani N, Torrego A, Barnes P J, Adcock I M, Chung K F. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma. Thorax 2008;63:784-90.

Lane S, Adcock I M, Richards D, Hawrylowicz C, Barnes P J, Lee T. Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes. J Clin Invest 1998;102:2156-64.

Hawrylowicz C. Regulatory T cells and IL-10 in allergic inflammation. J Exp Med 2005;202:1459-63.

Matthews J, Ito K, Barnes P J, Adcock I M. Defective glucocorticoid receptor nuclear translocation and altered histone acetylation patterns in glucocorticoid-resistant patients. J Allergy Clin Immunol 2004;113:1100-8.

Bledsoe R K, Montana V G, Stanley T B, Delves C J, McKee D D, Consler T G, et al. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell 2002;110:93-105.

Dastidar SG, Rajagopal D, Ray A. Therapeutic benefit of PDE4 inhibitors in inflammatory diseases. Curr Opin Investig Drugs 2007;8:364-72.

Medicherla S, Fitzgerald M F, Spicer D, Woodman P, Ma J Y, Kapoun A M, et al. p38alpha-selective mitogen-activated protein kinase inhibitor SD-282 reduces inflammation in a subchronic model of tobacco smoke-induced airway inflammation. J Pharmacol Exp Ther 2008;324:921-9.

Chaudhuri R, Livingston E, McMahon A D, Lafferty J, Fraser I, Spears M, et al. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med 2006;174:127-33.

Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richard D F, et al. Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients. J Clin Invest 2006;116:146-55.

Hoi AY, Iskander MN, Morand EF. Macrophage migration inhibitory factor: a therapeutic target across inflammatory diseases. Inflamm Allergy Drug Targets 2007;6:183-90.

Wada H, Kagoshima M, Ito K, Barnes PJ, Adcock IM. 5-Azacytidine suppresses RNA polymerase II recruitment to the SLPI gene. Biochem Biophys Res Commun 2005;331:93-9.

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Publicado

2013-10-21 — Actualizado el 2013-10-21

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Cómo citar

González, A. A., & Jiménez, I. A. (2013). Mecanismos de acción y resistencia a glucocorticoides en asma y enfermedad pulmonar obstructiva crónica. Acta Médica Costarricense, 55(4), 162–168. https://doi.org/10.51481/amc.v55i4.811