
喘息婴幼儿外周血气道炎症相关介质水平的研究
Levels of airway inflammatory mediators in peripheral blood in infants and young children with wheezing
目的 通过检测喘息婴幼儿外周血相关炎症介质水平,从辅助性T细胞(Th)1/Th2失衡及气道炎症两个方面探讨婴幼儿喘息发生的可能机制。方法 选取急性喘息发作婴幼儿50例为喘息组,25例健康婴幼儿为健康对照组。喘息组患儿依据喘息发生次数分为首次喘息组(首发组)25例和反复喘息组(反复组,发作次数≥ 2次)25例;根据是否存在哮喘发生的高危因素分为有高危因素组22例和无高危因素组28例;根据病原学检测结果分为病原学阳性组23例和病原学阴性组27例。检测各组外周血Th1细胞因子白介素(IL)-2,Th2细胞因子IL-4、IL-5、IL-13、转化生长因子-β1(TGF-β1),以及总IgE (TIgE)水平。喘息组患儿同时送检外周血嗜酸性粒细胞(EOS)计数,并采集标本进行呼吸道病原学检测。结果 喘息组外周血IL-4、IL-5、IL-13、TGF-β1及TIgE水平较健康对照组均明显升高(P < 0.05);外周血IL-2、IL-4、IL-5、IL-13、TGF-β1及TIgE水平在首发组与反复组,有哮喘高危因素组与无哮喘高危因素组,以及病原学阳性组与病原学阴性组之间比较,差异均无统计学意义(P > 0.05)。相关性分析表明喘息组外周血EOS计数与IL-4水平呈正相关(P < 0.01);IL-4水平与IL-5、IL-13水平呈正相关(P < 0.01);IL-5水平与IL-13水平呈正相关(P < 0.01);IL-2水平与TGF-β1水平呈正相关(P < 0.05)。结论 喘息婴幼儿存在Th1/Th2失衡,表现为Th2优势表达;IL-4、IL-5、IL-13、TGF-β1及IgE共同参与了婴幼儿喘息性疾病的发病过程。喘息婴幼儿存在气道炎症,与喘息发作次数、是否存在哮喘高危因素及病原学检测是否阳性无关。
Objective To examine the levels of airway inflammatory mediators in peripheral blood in infants and young children with wheezing and to study the possible pathogenesis of wheezing from the aspects of T helper cell 1 (Th1)/T helper cell 2 (Th2) imbalance and airway inflammation. Methods A total of 50 children aged 1 month to 3 years with an acute wheezing episode were enrolled as the wheezing group, and 25 age-matched healthy infants were enrolled as the healthy control group. According to the number of wheezing episodes, the wheezing group was divided into a first-episode group (n=25) and a recurrent wheezing (number of episodes ≥ 2) group (n=25). According to the presence or absence of high-risk factors for asthma, the wheezing group was divided into a high-risk factor group (n=22) and a non-high-risk factor group (n=28). According to the results of pathogen detection, the wheezing group was divided into a positive pathogen group (n=23) and a negative pathogen group (n=27). Levels of interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13), transforming growth factor-β1 (TGF-β1), and total IgE (TIgE) in peripheral blood were measured for each group. For children with wheezing, eosinophil (EOS) count in peripheral blood was measured, and related samples were collected for respiratory pathogen detection. Results The wheezing group had significantly higher levels of IL-4, IL-5, IL-13, TGF-β1, and TIgE in peripheral blood than the healthy control group (P < 0.05). There were no significant differences in the levels of IL-2, IL-4, IL-5, IL-13, TGF-β1, and TIgE in peripheral blood between the first-episode and recurrent wheezing groups, between the high-risk factor and non-high-risk factor groups, and between the positive pathogen and negative pathogen groups (P > 0.05). The correlation analysis showed that in children with wheezing, EOS count was positively correlated with IL-4 level (P < 0.01), IL-4 level was positively correlated with IL-5 and IL-13 levels (P < 0.01), IL-5 level was positively correlated with IL-13 level (P < 0.01), and IL-2 level was positively correlated with TGF-β1 level (P < 0.05). Conclusions Th1/Th2 imbalance with a predominance of Th2 is observed in infants and young children with wheezing. IL-4, IL-5, IL-13, TGF-β1, and IgE are involved in the pathogenesis of wheezing in these children. Airway inflammation is also observed in these children with wheezing, but it is not associated with the number of wheezing episodes, presence or absence of high-risk factors for asthma, or results of pathogen detection.
Wheezing / Inflammatory mediator / Total IgE / Infant and young child
[1] Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life[J]. N Engl J Med, 1995, 332(3):133-138.
[2] Fehrenbach H, Wagner C, Wegmann M. Airway remodeling in asthma:what really matters[J]. Cell Tissue Res, 2017, 367(3):551-569.
[3] Lezmi G, Gosset P, Deschildre A, et al. Airway remodeling in preschool children with severe recurrent wheeze[J]. Am J Respir Crit Care Med, 2015, 192(2):164-171.
[4] Turato G, Barbato A, Baraldo S, et al. Nonatopic children with multitrigger wheezing have airway pathology comparable to atopic asthma[J]. Am J Respir Crit Care Med, 2008, 178(5):476-482.
[5] Martin Alonso A, Saglani S. Mechanisms mediating pediatric severe asthma and potential novel therapies[J]. Front Pediatr, 2017, 5:154.
[6] Bertelsen RJ, Rava M, Carsin AE, et al. Clinical markers of asthma and IgE assessed in parents before conception predict asthma and hayfever in the offspring[J]. Clin Exp Allergy, 2017, 47(5):627-638.
[7] Lockett GA, Soto-Ramírez N, Ray MA, et al. Association of season of birth with DNA methylation and allergic disease[J]. Allergy, 2016, 71(9):1314-1324.
[8] Chawes BL. Low-grade disease activity in early life precedes childhood asthma and allergy[J]. Dan Med J, 2016, 63(8). pii:B5272.
[9] Wang RS, Jin HX, Shang SQ, et al. Associations of IL-2 and IL-4 expression and polymorphisms with the risks of mycoplasma pneumoniae infection and asthma in children[J]. Arch Bronconeumol, 2015, 51(11):571-578.
[10] Xia Y, Cai PC, Yu F, et al. IL-4-induced caveolin-1-containing lipid rafts aggregation contributes to MUC5AC synthesis in bronchial epithelial cells[J]. Respir Res, 2017, 18(1):174.
[11] Medrek SK, Parulekar AD, Hanania NA. Predictive biomarkers for asthma therapy[J]. Curr Allergy Asthma Rep, 2017, 17(10):69.
[12] Singhania A, Wallington JC, Smith CG, et al. Multitissue transcriptomics delineates the diversity of airway T cell functions in asthma[J]. Am J Respir Cell Mol Biol, 2018, 58(2):261-270.
[13] Costa RD, Figueiredo CA, Barreto ML, et al. Effect of polymorphisms on TGFB1 on allergic asthma and helminth infection in an African admixed population[J]. Ann Allergy Asthma Immunol, 2017, 118(4):483-488.
[14] Gon Y, Ito R, Maruoka S, et al. Long-term course of serum total and free IgE levels in severe asthma patients treated with omalizumab[J]. Allergol Int, 2018, 67(2):283-285.
[15] Chkhaidze I, Zirakishvili D, Shavshvishvili N, et al. Prognostic value of TH1/TH2 cytokines in infants with wheezing in a three year follow-up study[J]. Pneumonol Alergol Pol, 2016, 84(3):144-150.
[16] Abrahamsson TR, Sandberg Abelius M, Forsberg A, et al. A Th1/Th2-associated chemokine imbalance during infancy in children developing eczema, wheeze and sensitization[J]. Clin Exp Allergy, 2011, 41(12):1729-1739.
[17] 郁志伟, 钱俊, 顾晓虹, 等. 婴幼儿喘息性社区获得性肺炎患儿血清炎症因子的变化[J]. 中国当代儿科杂志, 2015, 17(8):815-818.
[18] Pitrez PM, Machado DC, Jones MH, et al. Th-1 and Th-2 cytokine production in infants with virus-associated wheezing[J]. Braz J Med Biol Res, 2005, 38(1):51-54.
[19] 胡亚美, 江载芳. 诸福棠实用儿科学[M]. 第7版. 北京:人民卫生出版社, 2002:1171-1204.
[20] Ducharme FM, Tse SM, Chauhan B. Diagnosis, management, and prognosis of preschool wheeze[J]. Lancet, 2014, 383(9928):1593-1604.
[21] Ng MC, How CH. Recurrent wheeze and cough in young children:is it asthma?[J]. Singapore Med J, 2014, 55(5):236-241.
[22] Grad R, Morgan WJ. Long-term outcomes of early-onset wheeze and asthma[J]. J Allergy Clin Immunol, 2012, 130(2):299-307.
[23] Beigelman A, Chipps BE, Bacharier LB. Update on the utility of corticosteroids in acute pediatric respiratory disorders[J]. Allergy Asthma Proc, 2015, 36(5):332-338.
[24] Belhassen M, De Blic J, Laforest L, et al. Recurrent wheezing in infants:apopulation-based study[J]. Medicine (Baltimore), 2016, 95(15):e3404.
[25] Ozdogan S, Tabakci B, Demirel AS, et al. The evaluation of risk factors for recurrent hospitalizations resulting from wheezing attacks in preschool children[J]. Ital J Pediatr, 2015, 41:91.
[26] Østergaard MS, Nantanda R, Tumwine JK, et al. Childhood asthma in low income countries:an invisible killer?[J]. Prim Care Respir, 2012, 21(2):214-219.
[27] Wen T, Besse JA, Mingler MK, et al. Eosinophil adoptive transfer system to directly evaluate pulmonary eosinophil trafficking in vivo[J]. Proc Natl Acad Sci U S A, 2013, 110(15):6067-6072.
[28] Fulkerson PC, Rothenberg ME. Targeting eosinophils in allergy, inflammation and beyond[J]. Nat Rev Drug Discov, 2013, 12(2):117-129.
[29] D'Agostino B, Gallelli L, Falciani M, et al. Endothelin-1 induced bronchial hyperresponsiveness in the rabbit:an ET(A) receptor-mediated phenomenon[J]. Naunyn Schmiedebergs Arch Pharmacol, 1999, 360(6):665-669.
[30] Van der Pouw Kraan TC, Van der Zee JS, Boeije LC, et al. The role of IL-13 in IgE synthesis by allergic asthma patients[J]. Clin Exp Immunol, 1998, 111(1):129-135.
[31] Hamelmann E, Tadeda K, Oshiba A, et al. Role of IgE in the development of allergic airway inflammation and airway hyperresponsiveness -a murine model[J]. Allergy, 1999, 54(4):297-305.
[32] Ierodiakonou D, Postma DS, Koppelman GH, et al. TGF-β1 polymorphisms and asthma severity, airway inflammation, and remodeling[J]. J Allergy Clin Immunol, 2013, 131(2):582-585.
[33] Das S, Miller M, Beppu AK, et al. GSDMB induces an asthma phenotype characterized by increased airway responsiveness and remodeling without lung inflammation[J]. Proc Natl Acad Sci USA, 2016, 113(46):13132-13137.
[34] Ma Y, Huang W, Liu C, et al. Immunization against TGF-β1 reduces collagen deposition but increases sustained inflammation in a murine asthma model[J]. Hum Vaccin Immunother, 2016, 12(7):1876-1885.
[35] Szefler SJ, Wenzel S, Brown R, et al. Asthma outcomes:biomarkers[J]. J Allergy Clin Immunol, 2012, 129(3 Suppl):S9-S23.
[36] Tu YL, Chang SW, Tsai HJ, et al. Total serum IgE in a population-based study of Asian children in Taiwan:reference value and significance in the diagnosis of allergy[J]. PLoS One, 2013, 8(11):e80996.
[37] Eggo RM, Scott JG, Galvani AP, et al. Respiratory virus transmission dynamics determine timing of asthma exacerbation peaks:evidence from a population-level model[J]. Proc Natl Acad Sci U S A, 2016, 113(8):2194-2199.
国家自然科学基金(81873851);湖南省自然科学基金(2018JJ6141);湖南省卫生计生委项目(B20180881)。