Glucocorticoid (GC) is currently the most effective drug for controlling persistent asthma; however, there is a significant difference in the response to GC among patients with asthma. Steroid-resistant asthma is one of the subtypes of asthma and has poor response to high-dose GC treatment. It may affect the quality of life of patients and even threaten their lives. Therefore, it is of great significance to explore the pathogenesis of steroid-resistant asthma and related targeted treatment strategy. In recent years, a variety of pathogeneses have been found to participate in the development and progression of steroid-resistant asthma, including the reduction in the binding between GC receptor and GC, the increase in the expression of GC receptor β, over-activation of nuclear transcription factor activating protein 1 and nuclear factor-κB, abnormality in histone acetylation, and immune-mediated cytokine dysregulation. In addition, many studies have shown that vitamin D can improve the sensitivity to GC among patients with steroid-resistant asthma. This article reviews the pathogenesis of steroid-resistant asthma and the influence of vitamin D.
YAN Yu-Xiao, LI Yu-Ning.
Pathogenesis of steroid-resistant asthma and the influence of vitamin D[J]. Chinese Journal of Contemporary Pediatrics. 2019, 21(7): 724-729 https://doi.org/10.7499/j.issn.1008-8830.2019.07.020
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参考文献
[1] Cosmi L, Liotta F, Annunziato F. Th17 regulating lower airway disease[J]. Curr Opin Allergy Clin Immunol, 2016, 16(1):1-6. [2] Trevor JL, Deshane JS. Refractory asthma:mechanisms, targets, and therapy[J]. Allergy, 2014, 69(7):817-827. [3] Yang X, Jiang Y, Wang C. Does IL-17 respond to the disordered lung microbiome and contribute to the neutrophilic phenotype in asthma?[J]. Mediators Inflamm, 2016, 2016:6470364. [4] Chambers ES, Nanzer AM, Pfeffer PE, et al. Distinct endotypes of steroid-resistant asthma characterized by IL-17A(high) and IFN-gamma(high) immunophenotypes:potential benefits of calcitriol[J]. J Allergy Clin Immunol, 2015, 136(3):628-637. [5] Nanzer AM, Chambers ES, Ryanna K, et al. Enhanced production of IL-17A in patients with severe asthma is inhibited by 1α, 25-dihydroxyvitamin D3 in a glucocorticoid-independent fashion[J]. J Allergy Clin Immunol, 2013, 132(2):297-304. [6] Kerley CP, Elnazir B, Faul J, et al. Vitamin D as an adjunctive therapy in asthma. Part 1:a review of potential mechanisms[J]. Pulm Pharmacol Ther, 2015, 32:60-74. [7] Hamzaoui A, Berraies A, Hamdi B, et al. Vitamin D reduces the differentiation and expansion of Th17 cells in young asthmatic children[J]. Immunobiology, 2014, 219(11):873-879. [8] Maltby S, Tay HL, Yang M, et al. Mouse models of severe asthma:understanding the mechanisms of steroid resistance, tissue remodelling and disease exacerbation[J]. Respirology, 2017, 22(5):874-885. [9] Vargas JE, Porto BN, Puga R, et al. Identifying a biomarker network for corticosteroid resistance in asthma from bronchoalveolar lavage samples[J]. Mol Biol Rep, 2016, 43(7):697-710. [10] 魏海霞, 范贤明. Th17细胞与激素抵抗型哮喘[J]. 临床肺科杂志, 2012, 17(11):2068-2070. [11] Rodriguez JM, Monsalves-Alvarez M, Henriquez S, et al. Glucocorticoid resistance in chronic diseases[J]. Steroids, 2016, 115:182-192. [12] 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]. J Clin Immunol, 2013, 33(2):466-478. [13] Hansbro PM, Kim RY, Starkey MR, et al. Mechanisms and treatments for severe, steroid-resistant allergic airway disease and asthma[J]. Immunol Rev, 2017, 278(1):41-62. [14] Zhang Y, Leung DY, Goleva E. Vitamin D enhances glucocorticoid action in human monocytes:involvement of granulocyte-macrophage colony-stimulating factor and mediator complex subunit 14[J]. J Biol Chem, 2013, 288(20):14544-14553. [15] 杨海华, 龙丰, 李圣青, 等. 1,25-(OH)2D3对激素抵抗型哮喘患者T淋巴细胞JNK/AP-1和糖皮质激素受体的影响[J]. 中国呼吸与危重监护杂志, 2017, 16(2):155-159. [16] Lan N, Luo G, Yang X, et al. 25-Hydroxyvitamin D3-deficiency enhances oxidative stress and corticosteroid resistance in severe asthma exacerbation[J]. PLoS One, 2014, 9(11):e111599. [17] Mann EH, Chambers ES, Pfeffer PE, et al. Immunoregulatory mechanisms of vitamin D relevant to respiratory health and asthma[J]. Ann N Y Acad Sci, 2014, 1317:57-69. [18] Zhang Y, Leung DY, Goleva E. Anti-inflammatory and corticosteroid-enhancing actions of vitamin D in monocytes of patients with steroid-resistant and those with steroid-sensitive asthma[J]. J Allergy Clin Immunol, 2014, 133(6):1744-1752. [19] Barnes PJ. Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease[J]. J Allergy Clin Immunol, 2013, 131(3):636-645. [20] 赖天文. 组蛋白去乙酰化酶2及白慢阻肺及哮喘中的分子机制研究[D]. 杭州:浙江大学, 2017. [21] Irvin C, Zafar I, Good J, et al. Increased frequency of d介素17A在ual-positive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma[J]. J Allergy Clin Immunol, 2014, 134(5):1175-1186. [22] Kim RY, Pinkerton JW, Essilfie AT, et al. Role for NLRP3 inflammasome-mediated, IL-1β-dependent responses in severe, steroid-resistant asthma[J]. Am J Respir Crit Care Med, 2017, 196(3):283-297. [23] Mikami Y, Matsuzaki H, Horie M, et al. Lymphotoxin beta receptor signaling induces IL-8 production in human bronchial epithelial cells[J]. PLoS One, 2014, 9(12):e114791. [24] Suzuki Y, Maazi H, Sankaranarayanan I, et al. Lack of autophagy induces steroid-resistant airway inflammation[J]. J Allergy Clin Immunol, 2016, 137(5):1382-1389. [25] Dejager L, Dendoncker K, Eggermont M, et al. Neutralizing TNFα restores glucocorticoid sensitivity in a mouse model of neutrophilic airway inflammation[J]. Mucosal Immunol, 2015, 8(6):1212-1225. [26] O'Connell D, Bouazza B, Kokalari B, et al. IFN-γ-induced JAK/STAT, but not NF-κB, signaling pathway is insensitive to glucocorticoid in airway epithelial cells[J]. Am J Physiol Lung Cell Mol Physiol, 2015, 309(4):L348-L359. [27] Gauthier M, Chakraborty K, Oriss TB, et al. Severe asthma in humans and mouse model suggests a CXCL10 signature underlies corticosteroid-resistant Th1 bias[J]. JCI Insight, 2017, 2(13). pii:94580. [28] Afsal K, Selvaraj P, Harishankar M. 1, 25-dihydroxyvitamin D3 downregulates cytotoxic effector response in pulmonary tuberculosis[J]. Int Immunopharmacol, 2018, 62:251-260. [29] Shirazi HA, Rasouli J, Ciric B, et al. 1,25-Dihydroxyvitamin D3 suppressed experimental autoimmune encephalomyelitis through both immunomodulation and oligodendrocyte maturation[J]. Exp Mol Pathol, 2017, 102(3):515-521. [30] 姬晓霖. 维生素D对糖皮质激素抵抗型慢性鼻-鼻窦炎治疗作用的影响[D]. 太原:山西医科大学, 2018. [31] Kundu R, Theodoraki A, Haas CT, et al. Cell-type-specific modulation of innate immune signalling by vitamin D in human mononuclear phagocytes[J]. Immunology, 2017, 150(1):55-63. [32] Kabata H, Moro K, Fukunaga K, et al. Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation[J]. Nat Commun, 2013, 4:2675. [33] Saglani S. Childhood severe asthma:new insights on remodelling and biomarkers[J]. Paediatr Respir Rev, 2017, 24:11-13. [34] Kabata H, Moro K, Koyasu S, et al. Mechanisms to suppress ILC2-induced airway Inflammation[J]. Ann Am Thorac Soc, 2016, 13 Suppl 1:S95. [35] Khorasanizadeh M, Eskian M, Gelfand EW, et al. Mitogen-activated protein kinases as therapeutic targets for asthma[J]. Pharmacol Ther, 2017, 174:112-126. [36] Li LB, Leung DY, Goleva E. Activated p38 MAPK in peripheral blood monocytes of steroid resistant asthmatics[J]. PLoS One, 2015, 10(10):e0141909. [37] Lea S, Harbron C, Khan N, et al. Corticosteroid insensitive alveolar macrophages from asthma patients; synergistic interaction with a p38 mitogen-activated protein kinase (MAPK) inhibitor[J]. Br J Clin Pharmacol, 2015, 79(5):756-766. [38] Xu QA, Li ZF, Zhang P, et al. Effects of 1,25-dihydroxyvitamin D3 on macrophage cytokine secretion stimulated by porphyromonas gingivalis[J]. Jpn J Infect Dis, 2016, 69(6):482-487. [39] Bahar-Shany K, Ravid A, Koren R. Upregulation of MMP-9 production by TNF alpha in keratinocytes and its attenuation by vitamin D[J]. J Cell Physiol, 2010, 222(3):729-737. [40] 黄懿洁, 鲁正荣. 婴幼儿喘息性疾病与维生素D的相关性[J]. 儿科药学杂志, 2017, 23(2):61-63. [41] 王美佳. 支气管哮喘患者中性粒细胞激素反应性和血浆CC10水平与临床表型关系的研究[D]. 武汉:华中科技大学, 2017. [42] 熊安吉. 不同剂量1, 25(OH)2D3协同甲强龙对哮喘小鼠气道炎症的影响及机制[D]. 泸州:泸州医学院, 2014. [43] 郭海琴, 马文娴, 吴昌归. 重症哮喘发病机制的研究进展[J]. 临床肺科杂志, 2017, 22(10):1903-1909. [44] Hosoda H, Tamura H, Nagaoka I. Evaluation of the lipopolysaccharide-induced transcription of the human TREM-1 gene in vitamin D3-matured THP-1 macrophage-like cells[J]. Int J Mol Med, 2015, 36(5):1300-1310. [45] Tian BP, Xia LX, Bao ZQ, et al. Bcl-2 inhibitors reduce steroid-insensitive airway inflammation[J]. J Allergy Clin Immunol, 2017, 140(2):418-430. [46] 田宝平. 哮喘的免疫调节以及靶向治疗研究[D]. 杭州:浙江大学, 2016. [47] 卫承华. 1, 25(OH)2VitD3对视网膜母细胞瘤细胞增殖、凋亡和bax/bcl-2基因表达的影响[D]. 上海:复旦大学, 2009. [48] 桂明才, 李兵, 戚思国, 等. 1, 25-二羟维生素D3通过PI3K/AKT/Bcl-2信号通路诱导喉癌细胞Hep-2细胞凋亡[J]. 重庆医科大学学报, 2017, 42(11):1422-1425. [49] 李方平, 赖星, 徐雪松, 等. PP2A在调节性T细胞与Kupffer细胞中免疫调节的研究进展[J]. 免疫学杂志, 2018, 34(8):726-730. [50] Kobayashi Y, Mercado N, Barnes PJ, et al. Defects of protein phosphatase 2A causes corticosteroid insensitivity in severe asthma[J]. PLoS One, 2011, 6(12):e27627. [51] 曾山, 熊彬. 激素抵抗型哮喘与炎性因子相关性的研究进展[J]. 广东医学, 2017, 38(3):478-480. [52] Kobayashi Y, Ito K, Kanda A, et al. Protein tyrosine phosphatase PTP-RR regulates corticosteroid sensitivity[J]. Respir Res, 2016, 17:30. [53] 戴芳芳, 朱黎明, 戴爱国. 1-磷酸鞘氨醇与肺部疾病的研究进展[J]. 临床与病理杂志, 2015, 35(1):111-117. [54] Fuerst E, Foster HR, Ward JP, et al. Sphingosine-1-phosphate induces pro-remodelling response in airway smooth muscle cells[J]. Allergy, 2014, 69(11):1531-1539. [55] Sousa AR, Marshall RP, Warnock LC, et al. Responsiveness to oral prednisolone in severe asthma is related to the degree of eosinophilic airway inflammation[J]. Clin Exp Allergy, 2017, 47(7):890-899. [56] 蓝楠, 李国平. 氧化应激与重症哮喘研究进展[J]. 实用医学杂志, 2012, 28(3):508-510. [57] Marcinkowska E, Gocek E. Heat shock protein 90 interacts with vitamin D receptor in human leukemia cells[J]. J Steroid Biochem Mol Biol, 2010, 121(1-2):114-116. [58] 姚彬, 佟万成, 朱元珏, 等. 热休克蛋白70、90基因在糖皮质激素抵抗型哮喘患者血单个核细胞中的表达[J]. 中华结核和呼吸杂志, 1998, 21(5):289-292. [59] 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]. J Allergy Clin Immunol, 2013, 132(5):1075-1085.