激素抵抗型哮喘发病机制和维生素D对其部分机制的影响
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摘要
糖皮质激素(GC)是目前最有效控制持续性哮喘的药物。然而,哮喘人群对GC治疗效果存在明显差异。激素抵抗型(SR)哮喘应用高剂量GC治疗效果不佳,且严重影响该类患者的生活质量,甚至危及生命。因此探究SR哮喘发病的具体机制及针对性治疗策略具有重要意义。近年来发现多种发病机制参与SR哮喘的发生发展,包括糖皮质激素受体(GR)与GC结合力的降低、GRβ表达的增加、核转录因子活化蛋白1(AP-1)和核因子-κB(NF-κB)的过度激活、组蛋白乙酰化的异常及免疫介导的细胞因子失调等。此外,国内外多项研究表明维生素D可提高SR哮喘人群对GC的敏感性。该文就SR哮喘发病机制及维生素D参与其相关机制综述如下。[中国当代儿科杂志,2019,21(7):724-729]
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.[Chin J Contemp Pediatr,2019,21(7):724-729]
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.[Chin J Contemp Pediatr,2019,21(7):724-729]
引文
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[24]Suzuki Y,Maazi H,Sankaranarayanan I,et al.Lack of autophagy induces steroid-resistant airway inflammation[J].JAllergy Clin Immunol,2016,137(5):1382-1389.
[25]Dejager L,Dendoncker K,Eggermont M,et al.Neutralizing TNFαrestores glucocorticoid sensitivity in a mouse model of neutrophilic airway inflammation[J].Mucosal Immunol,2015,8(6):1212-1225.
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[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.
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[33]Saglani S.Childhood severe asthma:new insights on remodelling and biomarkers[J].Paediatr Respir Rev,2017,24:11-13.
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[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-9production 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 steroidinsensitive 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.
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[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.
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[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及白介素17A在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 dualpositive TH2/TH17 cells in bronchoalveolar lavage fluid characterizes a population of patients with severe asthma[J].JAllergy Clin Immunol,2014,134(5):1175-1186.
[22]Kim RY,Pinkerton JW,Essilfie AT,et al.Role for NLRP3inflammasome-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].JAllergy Clin Immunol,2016,137(5):1382-1389.
[25]Dejager L,Dendoncker K,Eggermont M,et al.Neutralizing TNFαrestores 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 D3suppressed 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.Mitogenactivated 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-9production 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 steroidinsensitive 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.
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