Mechanisms underlying corticosteroid resistance in patients with asthma: a review of current knowledge

References

• Benedek TG. History of the development of corticosteroid therapy. Clin Exp Rheumatol. 2011;29(5 Suppl 68):S-5–12.
   Web of Science ®Google Scholar
• Schacke H, Docke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002;96(1):23–43. doi:10.1016/S0163-7258(02)00297-8
   PubMed Web of Science ®Google Scholar
• Barnes PJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2013;131(3):636–645. doi:10.1016/j.jaci.2012.12.1564
   PubMed Web of Science ®Google Scholar
• Lambrecht BN, Hammad H. The airway epithelium in asthma. Nat Med. 2012;18(5):684–692. doi:10.1038/nm.2737
   PubMed Web of Science ®Google Scholar
• Lambrecht BN, Hammad H. The immunology of asthma. Nat Immunol. 2015;16(1):45–56. doi:10.1038/ni.3049
   PubMed Web of Science ®Google Scholar
• Levy ML, Bacharier LB, Bateman E, et al. Key recommendations for primary care from the 2022 Global Initiative for Asthma (GINA) update. NPJ Prim Care Respir Med. 2023;33(1):7. doi:10.1038/s41533-023-00330-1
   PubMed Web of Science ®Google Scholar
• ten Brinke A, Zwinderman AH, Sterk PJ, et al. “Refractory” eosinophilic airway inflammation in severe asthma: effect of parenteral corticosteroids. Am J Respir Crit Care Med. 2004;170(6):601–605. doi:10.1164/rccm.200404-440OC
   PubMed Web of Science ®Google Scholar
• Bhavsar P, Hew M, Khorasani N, et al. Relative corticosteroid insensitivity of alveolar macrophages in severe asthma compared with non-severe asthma. Thorax. 2008;63(9):784–790. doi:10.1136/thx.2007.090027
   PubMed Web of Science ®Google Scholar
• Hew M, Bhavsar P, Torrego A, et al. Relative corticosteroid insensitivity of peripheral blood mononuclear cells in severe asthma. Am J Respir Crit Care Med. 2006;174(2):134–141. doi:10.1164/rccm.200512-1930OC
   PubMed Web of Science ®Google Scholar
• Milara J, Ballester B, de Diego A, et al. The pan-JAK inhibitor LAS194046 reduces neutrophil activation from severe asthma and COPD patients in vitro. Sci Rep. 2022;12(1):5132. doi:10.1038/s41598-022-09241-6
   PubMed Web of Science ®Google Scholar
• Milara J, Lluch J, Almudever P, et al. Roflumilast N-oxide reverses corticosteroid resistance in neutrophils from patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol. 2014;134(2):314–322. doi:10.1016/j.jaci.2014.02.001
   PubMed Web of Science ®Google Scholar
• Hong L, Herjan T, Bulek K, et al. Mechanisms of corticosteroid resistance in type 17 asthma. J Immunol. 2022;209(10):1860–1869. doi:10.4049/jimmunol.2200288
   PubMed Web of Science ®Google Scholar
• Milara J, Morell A, de Diego A, et al. Mucin 1 deficiency mediates corticosteroid insensitivity in asthma. Allergy. 2019;74(1):111–121. doi:10.1111/all.13546
   PubMed Web of Science ®Google Scholar
• Milara J, Peiro T, Armengot M, et al. Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2015;135(2):470–476. doi:10.1016/j.jaci.2014.07.011
   PubMed Web of Science ®Google Scholar
• Ramos-Ramirez P, Tliba O. Glucocorticoid insensitivity in asthma: the unique role for airway smooth muscle cells. Int J Mol Sci. 2022;23(16):8966. doi:10.3390/ijms23168966
   PubMed Web of Science ®Google Scholar
• Lamberts SW. Hereditary glucocorticoid resistance. Ann Endocrinol (Paris). 2001;62(2):164–167.
   PubMedGoogle Scholar
• Carmichael J, Paterson IC, Diaz P, et al. Corticosteroid resistance in chronic asthma. Br Med J (Clin Res Ed). 1981;282(6274):1419–1422. doi:10.1136/bmj.282.6274.1419
   PubMedGoogle Scholar
• Murray CS. Can inhaled corticosteroids influence the natural history of asthma? Curr Opin Allergy Clin Immunol. 2008;8(1):77–81. doi:10.1097/ACI.0b013e3282f41769
   PubMed Web of Science ®Google Scholar
• Hew M, Chung KF. Corticosteroid insensitivity in severe asthma: significance, mechanisms and aetiology. Intern Med J. 2010;40(5):323–334. doi:10.1111/j.1445-5994.2010.02192.x
   PubMed Web of Science ®Google Scholar
• Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med. 2008;178(3):218–224. doi:10.1164/rccm.200711-1754OC
   PubMed Web of Science ®Google Scholar
• Moore WC, Meyers DA, Wenzel SE, et al. Identification of asthma phenotypes using cluster analysis in the severe asthma research program. Am J Respir Crit Care Med. 2010;181(4):315–323. doi:10.1164/rccm.200906-0896OC
   PubMed Web of Science ®Google Scholar
• Siroux V, Basagana X, Boudier A, et al. Identifying adult asthma phenotypes using a clustering approach. Eur Respir J. 2011;38(2):310–317. doi:10.1183/09031936.00120810
   PubMed Web of Science ®Google Scholar
• Wysocki K, Park SY, Bleecker E, et al. Characterisation of factors associated with systemic corticosteroid use in severe asthma: data from the severe asthma research program. J Allergy Clin Immunol. 2014;133(3):915–918. doi:10.1016/j.jaci.2013.10.031
   PubMed Web of Science ®Google Scholar
• Moorman JE, Akinbami LJ, Bailey CM, et al. National surveillance of asthma: United States, 2001-2010. Vital Health Stat. 2012;3(35):1–58.
   Google Scholar
• Kroes JA, Zielhuis SW, van Roon EN, et al. Prediction of response to biological treatment with monoclonal antibodies in severe asthma. Biochem Pharmacol. 2020;179:113978. doi:10.1016/j.bcp.2020.113978
   PubMed Web of Science ®Google Scholar
• Masaki K, Miyata J, Kamatani T, et al. Risk factors for poor adherence to inhaled corticosteroid therapy in patients with moderate to severe asthma. Asian Pac J Allergy Immunol. 2023;41(2): 113–120. doi:10.12932/AP-311219-0731
   PubMed Web of Science ®Google Scholar
• Abdo M, Pedersen F, Kirsten AM, et al. Longitudinal impact of sputum inflammatory phenotypes on small airway dysfunction and disease outcomes in asthma. J Allergy Clin Immunol Pract. 2022;10(6):1545–1553 e1542. doi:10.1016/j.jaip.2022.02.020
   PubMed Web of Science ®Google Scholar
• Hodgson D, Anderson J, Reynolds C, et al. A randomised controlled trial of small particle inhaled steroids in refractory eosinophilic asthma (SPIRA). Thorax. 2015;70(6):559–565. doi:10.1136/thoraxjnl-2014-206481
   PubMed Web of Science ®Google Scholar
• Eger K, Kroes JA, Ten Brinke A, et al. Long-term therapy response to anti-il-5 biologics in severe asthma-a real-life evaluation. J Allergy Clin Immunol Pract. 2021;9(3):1194–1200. doi:10.1016/j.jaip.2020.10.010
   PubMed Web of Science ®Google Scholar
• Louis R, Harrison TW, Chanez P, et al. Severe asthma standard-of-care background medication reduction with benralizumab: ANDHI in practice substudy. J Allergy Clin Immunol Pract. 2023;11(6):1759–1770.e7. doi:10.1016/j.jaip.2023.03.009
   PubMedGoogle Scholar
• Heaney LG, Busby J, Bradding P, et al. Remotely monitored therapy and nitric oxide suppression identifies nonadherence in severe asthma. Am J Respir Crit Care Med. 2019;199(4):454–464. doi:10.1164/rccm.201806-1182OC
   PubMed Web of Science ®Google Scholar
• Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716–725. doi:10.1038/nm.2678
   PubMed Web of Science ®Google Scholar
• Dixon AE, Holguin F, Sood A, et al. An official American thoracic society workshop report: obesity and asthma. Proc Am Thorac Soc. 2010;7(5):325–335. doi:10.1513/pats.200903-013ST
   PubMedGoogle Scholar
• Kerstjens HA, Casale TB, Bleecker ER, et al. Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials. Lancet Respir Med. 2015;3(5):367–376. doi:10.1016/S2213-2600(15)00031-4
   PubMed Web of Science ®Google Scholar
• Kerstjens HA, Engel M, Dahl R, et al. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med. 2012;367(13):1198–1207. doi:10.1056/NEJMoa1208606
   PubMed Web of Science ®Google Scholar
• Khurana S, Paggiaro P, Buhl R, et al. Tiotropium reduces airflow obstruction in asthma patients, independent of body mass index. J Allergy Clin Immunol Pract. 2019;7(7):2425–2428 e2427. doi:10.1016/j.jaip.2019.03.007
   PubMed Web of Science ®Google Scholar
• Hammad H, Lambrecht BN. The basic immunology of asthma. Cell. 2021;184(6):1469–1485. doi:10.1016/j.cell.2021.02.016
   PubMed Web of Science ®Google Scholar
• Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med. 2021;384(19):1800–1809. doi:10.1056/NEJMoa2034975
   PubMed Web of Science ®Google Scholar
• Peters MC, McGrath KW, Hawkins GA, et al. Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: a cross-sectional analysis of two cohorts. Lancet Respir Med. 2016;4(7):574–584. doi:10.1016/S2213-2600(16)30048-0
   PubMed Web of Science ®Google Scholar
• Wen H, Gris D, Lei Y, et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol. 2011;12(5):408–415. doi:10.1038/ni.2022
   PubMed Web of Science ®Google Scholar
• Wood LG, Garg ML, Gibson PG. A high-fat challenge increases airway inflammation and impairs bronchodilator recovery in asthma. J Allergy Clin Immunol. 2011;127(5):1133–1140. doi:10.1016/j.jaci.2011.01.036
   PubMed Web of Science ®Google Scholar
• Kim RY, Pinkerton JW, Essilfie AT, et al. Role for NLRP3 inflammasome-mediated, IL-1beta-dependent responses in severe, steroid-resistant asthma. Am J Respir Crit Care Med. 2017;196(3):283–297. doi:10.1164/rccm.201609-1830OC
   PubMed Web of Science ®Google Scholar
• Winnica D, Que LG, Baffi C, et al. L-citrulline prevents asymmetric dimethylarginine-mediated reductions in nitric oxide and nitrosative stress in primary human airway epithelial cells. Clin Exp Allergy. 2017;47(2):190–199. doi:10.1111/cea.12802
   PubMed Web of Science ®Google Scholar
• Xie Y, Abel PW, Casale TB, et al. T(H)17 cells and corticosteroid insensitivity in severe asthma. J Allergy Clin Immunol. 2022;149(2):467–479. doi:10.1016/j.jaci.2021.12.769
   PubMed Web of Science ®Google Scholar
• Allam V, Pavlidis S, Liu G, et al. Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma. Thorax. 2023;78(7):661–673. doi:10.1136/thorax-2021-218555
   PubMed Web of Science ®Google Scholar
• Kuo CS, Pavlidis S, Loza M, et al. T-helper cell type 2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur Respir J. 2017;49(2):1602135. doi:10.1183/13993003.02135-2016
   PubMed Web of Science ®Google Scholar
• Rossios C, Pavlidis S, Hoda U, et al. Sputum transcriptomics reveal upregulation of IL-1 receptor family members in patients with severe asthma. J Allergy Clin Immunol. 2018;141(2):560–570. doi:10.1016/j.jaci.2017.02.045
   PubMed Web of Science ®Google Scholar
• Simpson JL, Phipps S, Baines KJ, et al. Elevated expression of the NLRP3 inflammasome in neutrophilic asthma. Eur Respir J. 2014;43(4):1067–1076. doi:10.1183/09031936.00105013
   PubMed Web of Science ®Google Scholar
• Svenningsen S, Nair P. Asthma endotypes and an overview of targeted therapy for asthma. Front Med. 2017;4:158. doi:10.3389/fmed.2017.00158
   PubMed Web of Science ®Google Scholar
• Tliba O, Panettieri RA Jr. Paucigranulocytic asthma: uncoupling of airway obstruction from inflammation. J Allergy Clin Immunol. 2019;143(4):1287–1294. doi:10.1016/j.jaci.2018.06.008
   PubMed Web of Science ®Google Scholar
• Demarche S, Schleich F, Henket M, et al. Detailed analysis of sputum and systemic inflammation in asthma phenotypes: are paucigranulocytic asthmatics really non-inflammatory? BMC Pulm Med. 2016;16(1):46. doi:10.1186/s12890-016-0208-2
   PubMedGoogle Scholar
• Schleich FN, Manise M, Sele J, et al. Distribution of sputum cellular phenotype in a large asthma cohort: predicting factors for eosinophilic vs neutrophilic inflammation. BMC Pulm Med. 2013;13(1):11. doi:10.1186/1471-2466-13-11
   PubMed Web of Science ®Google Scholar
• Feng Y, Liu X, Wang Y, et al. Delineating asthma according to inflammation phenotypes with a focus on paucigranulocytic asthma. Chin Med J (Engl). 2023;136(13):1513–1522. doi:10.1097/CM9.0000000000002456
   PubMed Web of Science ®Google Scholar
• Papaioannou AI, Fouka E, Ntontsi P, et al. Paucigranulocytic asthma: potential pathogenetic mechanisms, clinical features and therapeutic management. J Pers Med. 2022;12(5):850. doi:10.3390/jpm12050850
   PubMed Web of Science ®Google Scholar
• Fitzpatrick AM, Moore WC. Severe asthma phenotypes - how should they guide evaluation and treatment? J Allergy Clin Immunol Pract. 2017;5(4):901–908. doi:10.1016/j.jaip.2017.05.015
   PubMed Web of Science ®Google Scholar
• Israel E, Reddel HK, Drazen JM. Severe and difficult-to-treat asthma in adults. N Engl J Med. 2017;377(10):965–976. doi:10.1056/NEJMra1608969
   PubMed Web of Science ®Google Scholar
• Lee JX, Phipatanakul W, Gaffin JM. Environment and the development of severe asthma in inner city population. Curr Opin Allergy Clin Immunol. 2023;23(2):179–184. doi:10.1097/ACI.0000000000000890
   PubMed Web of Science ®Google Scholar
• Mikhail I, Grayson MH. Asthma and viral infections: an intricate relationship. Ann Allergy Asthma Immunol. 2019;123(4):352–358. doi:10.1016/j.anai.2019.06.020
   PubMed Web of Science ®Google Scholar
• Simpson JL, Carroll M, Yang IA, et al. Reduced antiviral interferon production in poorly controlled asthma is associated with neutrophilic inflammation and high-dose inhaled corticosteroids. Chest. 2016;149(3):704–713. doi:10.1016/j.chest.2015.12.018
   PubMed Web of Science ®Google Scholar
• Ackland J, Barber C, Heinson A, et al. Nontypeable Haemophilus influenzae infection of pulmonary macrophages drives neutrophilic inflammation in severe asthma. Allergy. 2022;77(10):2961–2973. doi:10.1111/all.15375
   PubMed Web of Science ®Google Scholar
• Mukherjee M, Svenningsen S, Nair P. Glucocortiosteroid subsensitivity and asthma severity. Curr Opin Pulm Med. 2017;23(1):78–88. doi:10.1097/MCP.0000000000000337
   PubMed Web of Science ®Google Scholar
• Essilfie AT, Horvat JC, Kim RY, et al. Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma. Thorax. 2015;70(5):458–467. doi: 10.1136/thoraxjnl-2014-206067
   PubMed Web of Science ®Google Scholar
• Essilfie AT, Simpson JL, Dunkley ML, et al. Combined Haemophilus influenzae respiratory infection and allergic airways disease drives chronic infection and features of neutrophilic asthma. Thorax. 2012;67(7):588–599. doi:10.1136/thoraxjnl-2011-200160
   PubMed Web of Science ®Google Scholar
• Essilfie AT, Simpson JL, Horvat JC, et al. Haemophilus influenzae infection drives IL-17-mediated neutrophilic allergic airways disease. PLOS Pathog. 2011;7(10):e1002244. doi:10.1371/journal.ppat.1002244
   PubMed Web of Science ®Google Scholar
• Horvat JC, Starkey MR, Kim RY, et al. Chlamydial respiratory infection during allergen sensitisation drives neutrophilic allergic airways disease. J Immunol. 2010;184(8):4159–4169. doi:10.4049/jimmunol.0902287
   PubMed Web of Science ®Google Scholar
• Horvat JC, Starkey MR, Kim RY, et al. Early-life chlamydial lung infection enhances allergic airways disease through age-dependent differences in immunopathology. J Allergy Clin Immunol. 2010;125(3):617-625, 625 e611–625 e616. doi:10.1016/j.jaci.2009.10.018
   Web of Science ®Google Scholar
• Kim RY, Horvat JC, Pinkerton JW, et al. MicroRNA-21 drives severe, steroid-insensitive experimental asthma by amplifying phosphoinositide 3-kinase-mediated suppression of histone deacetylase 2. J Allergy Clin Immunol. 2017;139(2):519–532. doi:10.1016/j.jaci.2016.04.038
   PubMed Web of Science ®Google Scholar
• Ahmad T, Barnes PJ, Adcock IM. Overcoming steroid insensitivity in smoking asthmatics. Curr Opin Invest Drugs. 2008;9(5):470–477.
   PubMedGoogle Scholar
• Kim RY, Pinkerton JW, Gibson PG, et al. Inflammasomes in COPD and neutrophilic asthma. Thorax. 2015;70(12):1199–1201. doi:10.1136/thoraxjnl-2014-206736
   PubMed Web of Science ®Google Scholar
• Beato M, Klug J. Steroid hormone receptors: an update. Hum Reprod Update. 2000;6(3):225–236. doi:10.1093/humupd/6.3.225
   PubMed Web of Science ®Google Scholar
• Whitfield GK, Jurutka PW, Haussler CA, et al. Steroid hormone receptors: evolution, ligands, and molecular basis of biologic function. J Cell Biochem. 1999;Suppl 32-33:110–122.
   PubMedGoogle Scholar
• Zhou J, Cidlowski JA. The human glucocorticoid receptor: one gene, multiple proteins and diverse responses. Steroids. 2005;70(5–7):407–417. doi:10.1016/j.steroids.2005.02.006
   PubMed Web of Science ®Google Scholar
• Pujols L, Mullol J, Picado C. Importance of glucocorticoid receptors in upper and lower airways. Front Biosci (Landmark Ed). 2010;15(2):789–800. doi:10.2741/3646
   PubMedGoogle Scholar
• Pujols L, Mullol J, Roca-Ferrer J, et al. Expression of glucocorticoid receptor alpha- and beta-isoforms in human cells and tissues. Am J Physiol Cell Physiol. 2002;283(4):C1324–1331. doi:10.1152/ajpcell.00363.2001
   PubMed Web of Science ®Google Scholar
• Duma D, Jewell CM, Cidlowski JA. Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification. J Steroid Biochem Mol Biol. 2006;102(1–5):11–21. doi:10.1016/j.jsbmb.2006.09.009
   PubMed Web of Science ®Google Scholar
• Hollenberg SM, Weinberger C, Ong ES, et al. Primary structure and expression of a functional human glucocorticoid receptor cDNA. Nature. 1985;318(6047):635–641. doi:10.1038/318635a0
   PubMed Web of Science ®Google Scholar
• Presul E, Schmidt S, Kofler R, et al. Identification, tissue expression, and glucocorticoid responsiveness of alternative first exons of the human glucocorticoid receptor. J Mol Endocrinol. 2007;38(1–2):79–90. doi:10.1677/jme.1.02183
   PubMed Web of Science ®Google Scholar
• Turner JD, Muller CP. Structure of the glucocorticoid receptor (NR3C1) gene 5’ untranslated region: identification, and tissue distribution of multiple new human exon 1. J Mol Endocrinol. 2005;35(2):283–292. doi:10.1677/jme.1.01822
   PubMed Web of Science ®Google Scholar
• Burnstein KL, Jewell CM, Cidlowski JA. Human glucocorticoid receptor cDNA contains sequences sufficient for receptor down-regulation. J Biol Chem. 1990;265(13):7284–7291. doi:10.1016/S0021-9258(19)39112-4
   PubMed Web of Science ®Google Scholar
• Schoneveld OJ, Gaemers IC, Lamers WH. Mechanisms of glucocorticoid signalling. Biochim Biophys Acta. 2004;1680(2):114–128. doi:10.1016/j.bbaexp.2004.09.004
   PubMed Web of Science ®Google Scholar
• Stahn C, Buttgereit F. Genomic and nongenomic effects of glucocorticoids. Nat Clin Pract Rheumatol. 2008;4(10):525–533. doi:10.1038/ncprheum0898
   PubMedGoogle Scholar
• Schaaf MJ, Cidlowski JA. AUUUA motifs in the 3‘UTR of human glucocorticoid receptor alpha and beta mRNA destabilize mRNA and decrease receptor protein expression. Steroids. 2002;67(7):627–636. doi:10.1016/S0039-128X(02)00015-6
   PubMed Web of Science ®Google Scholar
• Vandevyver S, Dejager L, Libert C. Comprehensive overview of the structure and regulation of the glucocorticoid receptor. Endocr Rev. 2014;35(4):671–693. doi:10.1210/er.2014-1010
   PubMed Web of Science ®Google Scholar
• Riester A, Issler O, Spyroglou A, et al. ACTH-dependent regulation of microRNA as endogenous modulators of glucocorticoid receptor expression in the adrenal gland. Endocrinology. 2012;153(1):212–222. doi:10.1210/en.2011-1285
   PubMed Web of Science ®Google Scholar
• Oakley RH, Cidlowski JA. Cellular processing of the glucocorticoid receptor gene and protein: new mechanisms for generating tissue-specific actions of glucocorticoids. J Biol Chem. 2011;286(5):3177–3184. doi:10.1074/jbc.R110.179325
   PubMed Web of Science ®Google Scholar
• Lewis-Tuffin LJ, Cidlowski JA. The physiology of human glucocorticoid receptor beta (hGrbeta) and glucocorticoid resistance. Ann N Y Acad Sci. 2006;1069:1–9. doi:10.1196/annals.1351.001
   PubMed Web of Science ®Google Scholar
• Lu NZ, Cidlowski JA. Glucocorticoid receptor isoforms generate transcription specificity. Trends Cell Biol. 2006;16(6):301–307. doi:10.1016/j.tcb.2006.04.005
   PubMed Web of Science ®Google Scholar
• Kumar R, Thompson EB. The structure of the nuclear hormone receptors. Steroids. 1999;64(5):310–319. doi:10.1016/S0039-128X(99)00014-8
   PubMed Web of Science ®Google Scholar
• Luisi BF, Xu WX, Otwinowski Z, et al. Crystallographic analysis of the interaction of the glucocorticoid receptor with DNA. Nature. 1991;352(6335):497–505. doi:10.1038/352497a0
   PubMed Web of Science ®Google Scholar
• Cheung J, Smith DF. Molecular chaperone interactions with steroid receptors: an update. Mol Endocrinol. 2000;14(7):939–946. doi:10.1210/mend.14.7.0489
   PubMedGoogle Scholar
• Pratt WB, Toft DO. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev. 1997;18(3):306–360. doi:10.1210/edrv.18.3.0303
   PubMed Web of Science ®Google Scholar
• Rexin M, Busch W, Gehring U. Protein components of the nonactivated glucocorticoid receptor. J Biol Chem. 1991;266(36):24601–24605. doi:10.1016/S0021-9258(18)54271-X
   PubMed Web of Science ®Google Scholar
• Vandevyver S, Dejager L, Libert C. On the trail of the glucocorticoid receptor: into the nucleus and back. Traffic. 2012;13(3):364–374. doi:10.1111/j.1600-0854.2011.01288.x
   PubMed Web of Science ®Google Scholar
• Morishima Y, Murphy PJ, Li DP, et al. Stepwise assembly of a glucocorticoid receptor.Hsp90 heterocomplex resolves two sequential ATP-dependent events involving first hsp70 and then hsp90 in opening of the steroid binding pocket. J Biol Chem. 2000;275(24):18054–18060. doi:10.1074/jbc.M000434200
   PubMed Web of Science ®Google Scholar
• Gronemeyer H, Gustafsson JA, Laudet V. Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov. 2004;3(11):950–964. doi:10.1038/nrd1551
   PubMed Web of Science ®Google Scholar
• Hakim A, Barnes PJ, Adcock IM, et al. Importin-7 mediates glucocorticoid receptor nuclear import and is impaired by oxidative stress, leading to glucocorticoid insensitivity. Faseb J. 2013;27(11):4510–4519. doi:10.1096/fj.12-222604
   PubMed Web of Science ®Google Scholar
• Pratt WB, Silverstein AM, Galigniana MD. A model for the cytoplasmic trafficking of signalling proteins involving the hsp90-binding immunophilins and p50cdc37. Cell Signal. 1999;11(12):839–851. doi:10.1016/S0898-6568(99)00064-9
   PubMed Web of Science ®Google Scholar
• Tao T, Lan J, Lukacs GL, et al. Importin 13 regulates nuclear import of the glucocorticoid receptor in airway epithelial cells. Am J Respir Cell Mol Biol. 2006;35(6):668–680. doi:10.1165/rcmb.2006-0073OC
   PubMed Web of Science ®Google Scholar
• Hayashi R, Wada H, Ito K, et al. Effects of glucocorticoids on gene transcription. Eur J Pharmacol. 2004;500(1–3):51–62. doi:10.1016/j.ejphar.2004.07.011
   PubMed Web of Science ®Google Scholar
• Adcock IM, Caramori G. Cross-talk between pro-inflammatory transcription factors and glucocorticoids. Immunol Cell Biol. 2001;79(4):376–384. doi:10.1046/j.1440-1711.2001.01025.x
   PubMed Web of Science ®Google Scholar
• Almawi WY, Melemedjian OK. Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids. J Mol Endocrinol. 2002;28(2):69–78. doi:10.1677/jme.0.0280069
   PubMed Web of Science ®Google Scholar
• Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol. 2011;163(1):29–43. doi:10.1111/j.1476-5381.2010.01199.x
   PubMed Web of Science ®Google Scholar
• Necela BM, Cidlowski JA. Mechanisms of glucocorticoid receptor action in noninflammatory and inflammatory cells. Proc Am Thorac Soc. 2004;1(3):239–246. doi:10.1513/pats.200402-005MS
   PubMedGoogle Scholar
• Ito K, Barnes PJ, Adcock IM. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol. 2000;20(18):6891–6903. doi:10.1128/MCB.20.18.6891-6903.2000
   PubMed Web of Science ®Google Scholar
• Zhao F, Zhou G, Ouyang H, et al. Association of the glucocorticoid receptor D641V variant with steroid-resistant asthma: a case-control study. Pharmacogenet Genomics. 2015;25(6):289–295. doi:10.1097/FPC.0000000000000130
   PubMed Web of Science ®Google Scholar
• DeRijk RH, Schaaf M, de Kloet ER. Glucocorticoid receptor variants: clinical implications. J Steroid Biochem Mol Biol. 2002;81(2):103–122. doi:10.1016/S0960-0760(02)00062-6
   PubMed Web of Science ®Google Scholar
• Hawkins GA, Amelung PJ, Smith RS, et al. Identification of polymorphisms in the human glucocorticoid receptor gene (NR3C1) in a multi-racial asthma case and control screening panel. DNA Seq. 2004;15(3):167–173. doi:10.1080/10425170410001704517
   PubMed Web of Science ®Google Scholar
• Panek M, Pietras T, Antczak A, et al. The N363S and I559N single nucleotide polymorphisms of the h-GR/NR3C1 gene in patients with bronchial asthma. Int J Mol Med. 2012;30(1):142–150. doi:10.3892/ijmm.2012.956
   PubMed Web of Science ®Google Scholar
• Irusen E, Matthews JG, Takahashi A, et al. p38 mitogen-activated protein kinase-induced glucocorticoid receptor phosphorylation reduces its activity: role in steroid-insensitive asthma. J Allergy Clin Immunol. 2002;109(4):649–657. doi:10.1067/mai.2002.122465
   PubMed Web of Science ®Google Scholar
• Bhavsar P, Khorasani N, Hew M, et al. Effect of p38 MAPK inhibition on corticosteroid suppression of cytokine release in severe asthma. Eur Respir J. 2010;35(4):750–756. doi:10.1183/09031936.00071309
   PubMed Web of Science ®Google Scholar
• Mercado N, Hakim A, Kobayashi Y, et al. Restoration of corticosteroid sensitivity by p38 mitogen activated protein kinase inhibition in peripheral blood mononuclear cells from severe asthma. PLoS One. 2012;7(7):e41582. doi:10.1371/journal.pone.0041582
   PubMed Web of Science ®Google Scholar
• Mercado N, To Y, Kobayashi Y, et al. p38 mitogen-activated protein kinase-gamma inhibition by long-acting beta2 adrenergic agonists reversed steroid insensitivity in severe asthma. Mol Pharmacol. 2011;80(6):1128–1135. doi:10.1124/mol.111.071993
   PubMed Web of Science ®Google Scholar
• Kobayashi Y, Mercado N, Barnes PJ, et al. Defects of protein phosphatase 2A causes corticosteroid insensitivity in severe asthma. PLoS One. 2011;6(12):e27627. doi:10.1371/journal.pone.0027627
   PubMed Web of Science ®Google Scholar
• Li LB, Goleva E, Hall CF, et al. Superantigen-induced corticosteroid resistance of human T cells occurs through activation of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MEK-ERK) pathway. J Allergy Clin Immunol. 2004;114(5):1059–1069. doi:10.1016/j.jaci.2004.08.005
   PubMed Web of Science ®Google Scholar
• Abraham SM, Lawrence T, Kleiman A, et al. Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J Exp Med. 2006;203(8):1883–1889. doi:10.1084/jem.20060336
   PubMed Web of Science ®Google Scholar
• Galigniana MD, Piwien-Pilipuk G, Assreuy J. Inhibition of glucocorticoid receptor binding by nitric oxide. Mol Pharmacol. 1999;55(2):317–323. doi:10.1124/mol.55.2.317
   PubMed Web of Science ®Google Scholar
• Ito K, Hanazawa T, Tomita K, et al. Oxidative stress reduces histone deacetylase 2 activity and enhances IL-8 gene expression: role of tyrosine nitration. Biochem Biophys Res Commun. 2004;315(1):240–245. doi:10.1016/j.bbrc.2004.01.046
   PubMed Web of Science ®Google Scholar
• Osoata GO, Yamamura S, Ito M, et al. Nitration of distinct tyrosine residues causes inactivation of histone deacetylase 2. Biochem Biophys Res Commun. 2009;384(3):366–371. doi:10.1016/j.bbrc.2009.04.128
   PubMed Web of Science ®Google Scholar
• Lewis BW, Ford ML, Rogers LK, et al. Oxidative stress promotes corticosteroid insensitivity in asthma and COPD. Antioxidants. 2021;10(9):1335. doi:10.3390/antiox10091335
   Web of Science ®Google Scholar
• Adcock IM, Lane SJ, Brown CR, et al. Abnormal glucocorticoid receptor-activator protein 1 interaction in steroid-resistant asthma. J Exp Med. 1995;182(6):1951–1958. doi:10.1084/jem.182.6.1951
   PubMed Web of Science ®Google Scholar
• Gupta SC, Sundaram C, Reuter S, et al. Inhibiting NF-kappaB activation by small molecules as a therapeutic strategy. Biochim Biophys Acta. 2010;1799(10–12):775–787. doi:10.1016/j.bbagrm.2010.05.004
   PubMed Web of Science ®Google Scholar
• Lane SJ, Adcock IM, Richards D, et al. Corticosteroid-resistant bronchial asthma is associated with increased c-fos expression in monocytes and T lymphocytes. J Clin Invest. 1998;102(12):2156–2164. doi:10.1172/JCI2680
   PubMed Web of Science ®Google Scholar
• Loke TK, Mallett KH, Ratoff J, et al. Systemic glucocorticoid reduces bronchial mucosal activation of activator protein 1 components in glucocorticoid-sensitive but not glucocorticoid-resistant asthmatic patients. J Allergy Clin Immunol. 2006;118(2):368–375. doi: 10.1016/j.jaci.2006.04.055
   PubMed Web of Science ®Google Scholar
• Milara J, Diaz-Platas L, Contreras S, et al. MUC1 deficiency mediates corticosteroid resistance in chronic obstructive pulmonary disease. Respir Res. 2018;19(1):226. doi:10.1186/s12931-018-0927-4
   PubMedGoogle Scholar
• Zhang H, Liu Q, Kong L, et al. Mucin 1 downregulation impairs the anti-necroptotic effects of glucocorticoids in human bronchial epithelial cells. Life Sci. 2019;221:168–177. doi:10.1016/j.lfs.2019.02.013
   PubMed Web of Science ®Google Scholar
• Ramamoorthy S, Cidlowski JA. Ligand-induced repression of the glucocorticoid receptor gene is mediated by an NCoR1 repression complex formed by long-range chromatin interactions with intragenic glucocorticoid response elements. Mol Cell Biol. 2013;33(9):1711–1722. doi:10.1128/MCB.01151-12
   PubMed Web of Science ®Google Scholar
• Bray PJ, Cotton RG. Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms. Hum Mutat. 2003;21(6):557–568. doi:10.1002/humu.10213
   PubMed Web of Science ®Google Scholar
• Derijk RH, de Kloet ER. Corticosteroid receptor polymorphisms: determinants of vulnerability and resilience. Eur J Pharmacol. 2008;583(2–3):303–311. doi:10.1016/j.ejphar.2007.11.072
   PubMed Web of Science ®Google Scholar
• van Rossum EF, Koper JW, van den Beld AW, et al. Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index. Clin Endocrinol (Oxf). 2003;59(5):585–592. doi:10.1046/j.1365-2265.2003.01888.x
   PubMed Web of Science ®Google Scholar
• Nicolaides NC, Galata Z, Kino T, et al. The human glucocorticoid receptor: molecular basis of biologic function. Steroids. 2010;75(1):1–12. doi:10.1016/j.steroids.2009.09.002
   PubMed Web of Science ®Google Scholar
• Mohamed NA, Abdel-Rehim AS, Farres MN, et al. Influence of glucocorticoid receptor gene NR3C1 646 C>G polymorphism on glucocorticoid resistance in asthmatics: a preliminary study. Cent Eur J Immunol. 2015;40(3):325–330. doi:10.5114/ceji.2015.54594
   PubMed Web of Science ®Google Scholar
• Pietras T, Panek M, Tworek D, et al. The Bcl I single nucleotide polymorphism of the human glucocorticoid receptor gene h-GR/NR3C1 promoter in patients with bronchial asthma: pilot study. Mol Biol Rep. 2011;38(6):3953–3958. doi:10.1007/s11033-010-0512-5
   PubMed Web of Science ®Google Scholar
• Fu G, Fu L, Cai Y, et al. Association between polymorphisms of glucocorticoid receptor genes and asthma: a meta-analysis. Cell Mol Biol (Noisy-le-Grand). 2018;64(5):13–23. doi:10.14715/cmb/2018.64.5.3
   PubMed Web of Science ®Google Scholar
• Lane SJ, Arm JP, Staynov DZ, et al. Chemical mutational analysis of the human glucocorticoid receptor cDNA in glucocorticoid-resistant bronchial asthma. Am J Respir Cell Mol Biol. 1994;11(1):42–48. doi:10.1165/ajrcmb.11.1.8018337
   PubMed Web of Science ®Google Scholar
• Corrigan CJ, Brown PH, Barnes NC, et al. Glucocorticoid resistance in chronic asthma. Glucocorticoid pharmacokinetics, glucocorticoid receptor characteristics, and inhibition of peripheral blood T cell proliferation by glucocorticoids in vitro. Am Rev Respir Dis. 1991;144(5):1016–1025. doi:10.1164/ajrccm/144.5.1016
   PubMedGoogle Scholar
• Lane SJ, Lee TH. Glucocorticoid receptor characteristics in monocytes of patients with corticosteroid-resistant bronchial asthma. Am Rev Respir Dis. 1991;143(5 Pt 1):1020–1024. doi:10.1164/ajrccm/143.5_Pt_1.1020
   PubMedGoogle Scholar
• Sher ER, Leung DY, Surs W, et al. Steroid-resistant asthma. Cellular mechanisms contributing to inadequate response to glucocorticoid therapy. J Clin Invest. 1994;93(1):33–39. doi:10.1172/JCI116963
   PubMed Web of Science ®Google Scholar
• Ito K, Getting SJ, Charron CE. Mode of glucocorticoid actions in airway disease. ScientificWorldjournal. 2006;6:1750–1769. doi:10.1100/tsw.2006.274
   PubMed Web of Science ®Google Scholar
• Vazquez-Tello A, Semlali A, Chakir J, et al. Induction of glucocorticoid receptor-beta expression in epithelial cells of asthmatic airways by T-helper type 17 cytokines. Clin Exp Allergy. 2010;40(9):1312–1322. doi:10.1111/j.1365-2222.2010.03544.x
   PubMed Web of Science ®Google Scholar
• Webster JC, Oakley RH, Jewell CM, et al. Proinflammatory cytokines regulate human glucocorticoid receptor gene expression and lead to the accumulation of the dominant negative beta isoform: a mechanism for the generation of glucocorticoid resistance. Proc Natl Acad Sci, USA. 2001;98(12):6865–6870. doi:10.1073/pnas.121455098
   PubMed Web of Science ®Google Scholar
• Fakhri S, Tulic M, Christodoulopoulos P, et al. Microbial superantigens induce glucocorticoid receptor beta and steroid resistance in a nasal explant model. Laryngoscope. 2004;114(5):887–892. doi:10.1097/00005537-200405000-00019
   PubMed Web of Science ®Google Scholar
• Pujols L, Mullol J, Picado C. Alpha and beta glucocorticoid receptors: relevance in airway diseases. Curr Allergy Asthma Rep. 2007;7(2):93–99. doi:10.1007/s11882-007-0005-3
   PubMed Web of Science ®Google Scholar
• Hamilos DL, Leung DY, Muro S, et al. Grbeta expression in nasal polyp inflammatory cells and its relationship to the anti-inflammatory effects of intranasal fluticasone. J Allergy Clin Immunol. 2001;108(1):59–68. doi:10.1067/mai.2001.116428
   PubMed Web of Science ®Google Scholar
• Vazquez-Tello A, Halwani R, Hamid Q, et al. Glucocorticoid receptor-beta up-regulation and steroid resistance induction by IL-17 and IL-23 cytokine stimulation in peripheral mononuclear cells. J Clin Immunol. 2013;33(2):466–478. doi:10.1007/s10875-012-9828-3
   PubMed Web of Science ®Google Scholar
• Weigel NL, Moore NL. Steroid receptor phosphorylation: a key modulator of multiple receptor functions. Mol Endocrinol. 2007;21(10):2311–2319. doi:10.1210/me.2007-0101
   PubMedGoogle Scholar
• Barnes PJ. Corticosteroid resistance in airway disease. Proc Am Thorac Soc. 2004;1(3):264–268. doi:10.1513/pats.200402-014MS
   PubMedGoogle Scholar
• Milara J, Morell A, Ballester B, et al. MUC4 impairs the anti-inflammatory effects of corticosteroids in patients with chronic rhinosinusitis with nasal polyps. J Allergy Clin Immunol. 2017;139(3):855–862 e813. doi:10.1016/j.jaci.2016.06.064
   PubMed Web of Science ®Google Scholar
• Takeno S, Hirakawa K, Ueda T, et al. Nuclear factor-kappa B activation in the nasal polyp epithelium: relationship to local cytokine gene expression. Laryngoscope. 2002;112(1):53–58. doi:10.1097/00005537-200201000-00010
   PubMed Web of Science ®Google Scholar
• Valera FC, Queiroz R, Scrideli C, et al. Evaluating budesonide efficacy in nasal polyposis and predicting the resistance to treatment. Clin Exp Allergy. 2009;39(1):81–88. doi:10.1111/j.1365-2222.2008.03144.x
   PubMed Web of Science ®Google Scholar
• Valera FC, Scrideli C, Queinoz R, et al. NF-kappaB expression predicts clinical outcome for nasal polyposis. Rhinology. 2010;48(4):408–441. doi:10.4193/Rhino09.161
   PubMed Web of Science ®Google Scholar
• Manetsch M, Ramsay EE, King EM, et al. Corticosteroids and beta(2)-agonists upregulate mitogen-activated protein kinase phosphatase 1: in vitro mechanisms. Br J Pharmacol. 2012;166(7):2049–2059. doi:10.1111/j.1476-5381.2012.01923.x
   PubMed Web of Science ®Google Scholar
• Papi A, Contoli M, Adcock IM, et al. Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor kappaB and c-Jun N-terminal kinase activation. J Allergy Clin Immunol. 2013;132(5):1075–1085 e1076. doi:10.1016/j.jaci.2013.05.028
   PubMed Web of Science ®Google Scholar
• Barnes PJ, Adcock IM, Ito K. Histone acetylation and deacetylation: importance in inflammatory lung diseases. Eur Respir J. 2005;25(3):552–563. doi:10.1183/09031936.05.00117504
   PubMed Web of Science ®Google Scholar
• Rahman I, Marwick J, Kirkham P. Redox modulation of chromatin remodeling: impact on histone acetylation and deacetylation, NF-kappaB and pro-inflammatory gene expression. Biochem Pharmacol. 2004;68(6):1255–1267. doi:10.1016/j.bcp.2004.05.042
   PubMed Web of Science ®Google Scholar
• Kim KC, Lillehoj EP. MUC1 mucin: a peacemaker in the lung. Am J Respir Cell Mol Biol. 2008;39(6):644–647. doi:10.1165/rcmb.2008-0169TR
   PubMed Web of Science ®Google Scholar
• Ueno K, Koga T, Kato K, et al. MUC1 mucin is a negative regulator of toll-like receptor signaling. Am J Respir Cell Mol Biol. 2008;38(3):263–268. doi:10.1165/rcmb.2007-0336RC
   PubMed Web of Science ®Google Scholar
• Kato K, Lillehoj EP, Park YS, et al. Membrane-tethered MUC1 mucin is phosphorylated by epidermal growth factor receptor in airway epithelial cells and associates with TLR5 to inhibit recruitment of MyD88. J Immunol. 2012;188(4):2014–2022. doi:10.4049/jimmunol.1102405
   PubMed Web of Science ®Google Scholar
• Kyo Y, Kato K, Park YS, et al. Antiinflammatory role of MUC1 mucin during infection with nontypeable Haemophilus influenzae. Am J Respir Cell Mol Biol. 2012;46(2):149–156. doi:10.1165/rcmb.2011-0142OC
   PubMedGoogle Scholar
• Li Y, Dinwiddie DL, Harrod KS, et al. Anti-inflammatory effect of MUC1 during respiratory syncytial virus infection of lung epithelial cells in vitro. Am J Physiol Lung Cell Mol Physiol. 2010;298(4):L558–563. doi:10.1152/ajplung.00225.2009
   PubMed Web of Science ®Google Scholar
• Ballester B, Milara J, Cortijo J. The role of mucin 1 in respiratory diseases. Eur Respir Rev. 2021;30(159):200149. doi: 10.1183/16000617.0149-2020
   PubMed Web of Science ®Google Scholar
• Schlossmacher G, Stevens A, White A. Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells. J Endocrinol. 2011;211(1):17–25. doi:10.1530/JOE-11-0135
   PubMed Web of Science ®Google Scholar
• Park YM, Bochner BS. Eosinophil survival and apoptosis in health and disease. Allergy Asthma Immunol Res. 2010;2(2):87–101. doi:10.4168/aair.2010.2.2.87
   PubMed Web of Science ®Google Scholar
• Grunwell JR, Stephenson ST, Tirouvanziam R, et al. Children with neutrophil-predominant severe asthma have proinflammatory neutrophils with enhanced survival and impaired clearance. J Allergy Clin Immunol Pract. 2019;7(2):516–525 e516. doi:10.1016/j.jaip.2018.08.024
   PubMed Web of Science ®Google Scholar
• Banuelos J, Shin S, Cao Y, et al. BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis. Allergy. 2016;71(5):640–650. doi:10.1111/all.12840
   PubMed Web of Science ®Google Scholar
• Tian BP, Xia LX, Bao ZQ, et al. Bcl-2 inhibitors reduce steroid-insensitive airway inflammation. J Allergy Clin Immunol. 2017;140(2):418–430. doi:10.1016/j.jaci.2016.11.027
   PubMed Web of Science ®Google Scholar
• Damera G, Jiang M, Zhao H, et al. Aclidinium bromide abrogates allergen-induced hyperresponsiveness and reduces eosinophilia in murine model of airway inflammation. Eur J Pharmacol. 2010;649(1–3):349–353. doi:10.1016/j.ejphar.2010.09.043
   PubMed Web of Science ®Google Scholar
• Kim Y, Hou V, Huff RD, et al. Potentiation of long-acting beta(2)-agonist and glucocorticoid responses in human airway epithelial cells by modulation of intracellular cAMP. Respir Res. 2021;22(1):266. doi:10.1186/s12931-021-01862-1
   PubMed Web of Science ®Google Scholar
• Milara J, Cervera A, de Diego A, et al. Non-neuronal cholinergic system contributes to corticosteroid resistance in chronic obstructive pulmonary disease patients. Respir Res. 2016;17(1):145. doi:10.1186/s12931-016-0467-8
   PubMedGoogle Scholar
• Milara J, Contreras S, de Diego A, et al. In vitro anti-inflammatory effects of AZD8999, a novel bifunctional muscarinic acetylcholine receptor antagonist /β2-adrenoceptor agonist (MABA) compound in neutrophils from COPD patients. PLoS One. 2019;14(1):e0210188. doi:10.1371/journal.pone.0210188
   PubMed Web of Science ®Google Scholar
• Barnes PJ. Theophylline. Am J Respir Crit Care Med. 2013;188(8):901–906. doi:10.1164/rccm.201302-0388PP
   PubMed Web of Science ®Google Scholar
• Cosio BG, Shafiek H, Iglesias A, et al. Oral low-dose theophylline on top of inhaled fluticasone-salmeterol does not reduce exacerbations in patients with severe COPD: a pilot clinical trial. Chest. 2016;150(1):123–130. doi:10.1016/j.chest.2016.04.011
   PubMed Web of Science ®Google Scholar
• Ranjani R, Vinotha ATS. A prospective randomized controlled study: theophylline on oxidative stress and steroid sensitivity in chronic obstructive pulmonary disease patients. Int J Pharm Investig. 2017;7(3):119–124. doi:10.4103/jphi.JPHI_58_17
   PubMedGoogle Scholar
• Milara J, Navarro A, Almudever P, et al. Oxidative stress-induced glucocorticoid resistance is prevented by dual PDE3/PDE4 inhibition in human alveolar macrophages. Clin Exp Allergy. 2011;41(4):535–546. doi:10.1111/j.1365-2222.2011.03715.x
   PubMed Web of Science ®Google Scholar
• Ortiz JL, Milara J, Lluch J, et al. Phosphodiesterase-4 inhibition improves corticosteroid insensitivity in pulmonary endothelial cells under oxidative stress. Allergy. 2013;68(1):64–73. doi:10.1111/all.12055
   PubMed Web of Science ®Google Scholar
• An TJ, Rhee CK, Kim JH, et al. Effects of macrolide and corticosteroid in neutrophilic asthma mouse model. Tuberc Respir Dis (Seoul). 2018;81(1):80–87. doi:10.4046/trd.2017.0108
   PubMed Web of Science ®Google Scholar
• Abrams EM, Szefler SJ, Becker AB. Does inhaled steroid therapy help emerging asthma in early childhood? Lancet Respir Med. 2017;5(10):827–834. doi:10.1016/S2213-2600(17)30295-3
   PubMed Web of Science ®Google Scholar