Atopic Dermatitis Deteriorates Dextran Sodium Sulfate-Induced Ulcerative Colitis via Thymic Stromal Lymphopoietin in Mice

It has been reported that atopic dermatitis (AD) and ulcerative colitis are related. However, the mechanism underlying this association has not been clarified. We therefore explored how AD induces ulcerative colitis. We developed an AD mouse model (NC/Nga mice) with ulcerative colitis by administering dextran sodium sulfate (DSS) for five days. DSS-induced ulcerative colitis was deteriorated in our conventional AD mouse model compared with specific-pathogen-free (SPF) mice. The plasma levels of thymic stromal lymphopoietin (TSLP) and tumor necrosis factor-α increased the most in DSS-treated conventional mice. Furthermore, the expression of dendritic cells (DC), retinoid-related orphan receptor (ROR)γt (marker of T helper 17 cells [Th17]), interleukin (IL)-17, GATA binding protein 3 (GATA3) (marker of Th2), and IL-4 increased the most in the colon of the DSS-treated conventional mice compared with DSS-treated SPF mice. In addition, TSLP inhibitor (TSLP neutralizing antibody) did not exacerbate ulcerative colitis in DSS-treated conventional mice. These results indicate that TSLP/DC/Th2 and Th17 play major roles in the exacerbation of ulcerative colitis by AD.

Interactions of thymic stromal lymphopoietin with interleukin-4 in adaptive immunity during Aspergillus fumigatus keratitis

AIM:To investigate the potential interactions of thymic stromal lymphopoietin(TSLP)with interleukin-4(IL-4)in adaptive immunity during fungal keratitis(FK).METHODS:An FK mouse model was induced with Aspergillus fumigatus(AF)hyphal infection.Mice were divided into several groups:untreated,phosphate buffer saline(PBS),infected with AF,and pretreated with a scrambled siRNA,a TSLP-specific siRNA(TSLP siRNA),murine recombinant TSLP(rTSLP),immunoglobulin G(IgG),murine recombinant IFN(rIFN-γ),murine recombinant IL-4(rI L-4),rIL-13,murine recombinant IL-17A(rIL-17A),and murine recombinant IL-17F(rIL-17F)groups.Quantitative realtime reverse transcription-polymerase chain reaction(qRTPCR)and enzyme-linked immunosorbent assay(ELISA)or Western blot were performed to determine mRNA and protein levels in the inflamed cornea.Cytokine locations were observed by immunofluoresence staining after AF hyphal infection.RESULTS:Compared to those in the untreated group,TSLP and T helper type 1(Th1)cytokine levels in the AF group were upregulated at 24 h post infection(hpi),and those of T helper type 2(Th2)and T helper type 17(Th17)cytokines were increased at 5 d post infection(dpi).Th2 cytokine levels were decreased in the TSLP siRNA-pretreated group and increased in the rTSLP-pretreated group compared with the AF group.The TSLP level was increased in the rIL-4-pretreated group,but there were no significant changes among the other groups.Immunofluorescence staining showed cytokine locations after AF hyphal infection.CONCLUSION:TSLP induces a Th2 immune response and promots Th2 T cell differentiation in vivo.IL-4 promotes TSLP secretion.Therefore,TSLP with IL-4 regulates adaptive immunity in FK.

Thymic stromal lymphopoietin: Next research hotspot of carcinogenesis?

Thymic stromal lymphopoietin (TSLP) is an epithetlial cell derived cytokine which has been reported to be a master regulator in T helper (Th) 2 driven inflammation. Through acting on dentritic cells (DCs), granulocytes, natural killer T cells or directly on CD4+ T cells, TSLP plays significant roles in the pathogenesis of atopic diseases consisting of the triad of asthma, allergic rhinitis and atopic dermatitis. Recently mounting evidence demonstrated that cancer-related inflammation play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis. As a crucial regulator of Th2 driven inflammation, the involvement of TSLP in carcinogenesis have attracted researchers’ attention. However, the mechanisms of TSLP’s involvement in carcinogenesis are still largely unknown. In this review we first outline the roles of TSLP involved in allergic inflammation and then we further focus on the recent findings on TSLP’s tumor promoting activities hoping to provide hints on elucidation of the TSLP implication in carcinogenesis in future studies.

Reduction of natural regulatory T cells in thymomas accompanying myasthenia gravis and its possible association with Foxp3 and thymic stromal lymphopoietin

Objective: To investigate the expression of both thymic regulatory T cells (CD4+CD25+Foxp3+cells, Treg) and thymic stromal lymphopoietin (TSLP) in thymomas accompanying myasthenia gravis. Methods: We used immunohistochemistry and real-time reverse trancription polymerase chain reaction (real-time RT-PCR) techniques to determine Foxp3+ Treg counts and the expression levels of Foxp3 mRNA and TSLP mRNA in thymomas of 23 MG patients and thymuses of 4 healthy controls. Results: The CD4+ Foxp3+ nTreg (natural regulatory T cells) counts in thymomas were significantly lower than those in normal thymuses (P<0.01), and the expression levels of Foxp3 mRNA and TSLP mRNA were also lower in thymomas(P<0.01). Among the thymoma types, type B1 thymoma had the highest Foxp3+ nTreg count and standard values of Foxp3 mRNA and TSLP mRNA. There was a strong positive correlation between the mRNA transcriptional levels of Foxp3 and TSLP. Conclusion: The insufficient expression of Foxp3 in thymoma, which may be caused by decreased transcription of TSLP, may result in the reduction of Tregs and cause autoimmune disorders.

加味玉屏风散治疗气虚毒瘀型晚期肝癌的临床研究

目的观察加味玉屏风散治疗气虚毒瘀型晚期肝癌的临床疗效及对患者血清胸腺基质淋巴细胞生成素(TSLP)水平的影响。方法采用随机双盲法将120例气虚毒瘀型晚期肝癌患者分为加味玉屏风散组、玉屏风散组和安慰剂组各40例,3组患者均给予放疗、化疗、介入或靶向治疗等常规治疗,加味玉屏风散组加服加味玉屏风散颗粒,玉屏风散组加服玉屏风散颗粒,安慰剂组加服安慰剂,疗程均为2个月。治疗前后观察3组患者Karnofsky功能状态评分(KPS评分)、中医证候积分、瘤体大小及血清TSLP水平变化情况,并将肿瘤大小变化与TSLP变化进行相关性分析。结果治疗后,玉屏风散组及加味玉屏风散KPS评分均显著提高(P<0.05,P<0.01),中医证候总积分显著降低(P<0.01),同时明显延缓肿瘤的生长(P<0.05,P<0.01),显著降低血清中TSLP水平(P<0.05,P<0.01)。此外,肿瘤大小变化与TSLP变化呈轻度正相关(P<0.05)。在改善瘤体大小方面,加味玉屏风散组疗效优于玉屏风散组(P<0.05)。治疗期间,3组患者均未见明显不良反应。结论加味玉屏风散联合常规治疗可显著延缓气虚毒瘀型晚期肝癌患者的肿瘤生长,改善患者中医症状同时显著提高患者生存质量,其疗效机制可能为通过降低患者血清TSLP表达,改善机体免疫状态有关。

FeNO联合TSLP对儿童咳嗽变异性哮喘与感染后咳嗽的鉴别价值及与小气道功能的关系

目的探究呼出气一氧化氮(FeNO)联合胸腺基质淋巴细胞生成素(TSLP)对儿童咳嗽变异性哮喘(CVA)与感染后咳嗽(PIC)的鉴别价值,并分析FeNO、TSLP与CVA病情、小气道功能的关系,为临床诊疗提供有利依据。方法选取2021年6月至2023年4月郑州大学第一附属医院儿科诊治收治的90例CVA患儿作为CVA组,另选取同期90例PIC患儿作为PIC组。比较两组患儿的临床资料和FeNO、TSLP水平,绘制受试者工作特征(ROC)曲线及曲线下面积(AUC)分析FeNO联合TSLP对CVA与PIC的鉴别价值;比较CVA不同病情严重程度和病情阶段患儿的小气道功能[FEF25(%)、FEF50(%)、FEF75(%)、FEF25~75(%)]和FeNO、TSLP水平,采用Spearman和Pearson相关系数法分析FeNO、TSLP与CVA小气道功能、病情阶段、病情严重程度的相关性。结果CVA组患儿的FeNO、TSLP水平明显高于PIC组,差异均有统计学意义(P<0.05);ROC分析结果显示,FeNO联合TSLP鉴别CVA与PIC的AUC最大(0.934),敏感度、特异度为87.78%、82.22%,明显高于各指标单独诊断(P<0.05);轻度组患儿的FEF25、FEF50、FEF75和FEF25~75>中度组>重度组,差异均有统计学意义(P<0.05);轻度组患儿的FeNO、TSLP水平<中度组<重度组,差异均有统计学意义(P<0.05);临床缓解期组患儿的FEF25、FEF50、FEF75、FEF25~75明显高于急性发作期组,FeNO、TSLP水平明显低于急性发作期组,差异均有统计学意义(P<0.05);Pearson相关系数法分析结果显示,FeNO、TSLP与FEF25、FEF50、FEF75、FEF25~75均呈负相关(P<0.05);Spearman相关系数法分析结果显示,FeNO、TSLP与病情阶段、病情严重程度均呈正相关(P<0.05)。结论与PIC患儿比较,CVA患儿FeNO、TSLP水平异常升高,其联合鉴别诊断CVA与PIC具有较高价值,且FeNO、TSLP水平与患儿病情、小气道功能密切相关。

Potential Role of Interleukin-25/Interleukin-33/Thymic Stromal Lymphopoietin-Fibrocyte Axis in the Pathogenesis of Allergic Airway Diseases

Objective： Allergic airway diseases （AADs） are a group of heterogeneous disease mediated by T-helper type 2 （Th2） immune response and characterized with airway inflammation and remodeling, including allergic asthma, allergic rhinitis, and chronic rhinosinusitis with allergic background. This review aimed to discuss the abnormal epithelial-mesenchymal crosstalk in the pathogenesis of AADs. Data Sources： Articles referred in this review were collected from the database of PubMed published in English up to January 2018. Study Selection： We had done a literature search using the following terms ＂allergic airway disease OR asthma OR allergic rhinitis OR chronic sinusitis AND IL-25 OR IL-33 OR thymic stromal lymphopoietin OR fibrocyte＂. Related original or review articles were included and carefully analyzed. Results： It is now believed that abnormal epithelial-mesenchymal crosstalk underlies the pathogenesis of AADs. However, the key regulatory factors and molecular events involved in this process still remain unclear. Epithelium-derived triple cytokines, including interleukin （IL）-25, IL-33, and thymic stromal lymphopoietin （TSLP）, are shown to act on various target cells and promote the Th2 immune response. Circulating fibrocyte is an important mesenchymal cell that can mediate tissue remodeling. We previously found that IL-25-circulating fibrocyte axis was significantly upregulated in patients with asthma, which may greatly contribute to asthmatic airway inflammation and remodeling. Conclusions： In view of the redundancy ofcytokines and ＂united airway＂ theory, we propose a new concept that IL-25/IL-33/TSLP-fibrocyte axis may play a vital role in the abnormal epithelial-mesenchymal crosstalk in some endotypes of AADs. This novel idea will guide potential new intervention schema for the common treatment of AADs sharing common pathogenesis in the future.

Thymic stromal lymphopoietin expression is increased in nasal epithelial cells of patients with mugwort pollen sensitive-seasonal allergic rhinitis

Background Excessive expression of thymic stromal lymphopoietin （TSLP） has been demonstrated in asthmatic airway epithelia and in nasal epithelia from animal models of allergic rhinitis （AR）, but the evidence of expression of TSLP in nasal epithelial cells （NECs） of patients with AR is lacking. We aimed to investigate the expression of TSLP in NECs of patients with mugwort sensitive-seasonal AR and determine whether it is associated with severity of symptoms and the number of infiltrated eosinophils in nasal mucosa. Methods NECs specimens were obtained by scraping with plastic curettes from the nasal inferior turbinates of patients with mugwort pollen sensitive-seasonal AR （n=22） and nonallergic controls （n=11） during last peak mugwort pollen season. The severity of nasal symptom was assessed using a Visual Analog Scale （VAS）. In addition, serum mugwort pollen IgE levels were tested from each patient. In situ hybridization （ISH） was performed to test the messenger RNA （mRNA） of TSLP in the NECs. Furthermore, immunohistochemical staining （IHC） was scored to evaluate the expression of TSLP and eosinophil cell count was made by May-Grunwald/Giemsa staining. The correlation between expression of TSLP and all other parameters was analyzed in this study. Results The mRNA level of TSLP was significantly increased in NECs of patients with AR compared with the nonallergic control group （P 〈0.05）. In addition, IHC results showed that expression of TSLP in NECs from patients with AR was up-regulated which was correlated with VAS score （r=0.598; P 〈0.05） and nasal eosinophils count （r=0.702; P 〈0.05）, but it was unrelated with mugwort pollen specific IgE level. Conclusions These preliminary findings indicate a potential relationship between TSLP expression, severity of symptoms and nasal eosinophils count in pathogenesis of AR, but TSLP expression did not correlate with mugwort pollen specific IgE level. The elevated expression of TSLP might play a critical role in local atopical responses of AR. In the future, the TSLP has the potential to be one of the most important molecular markers for AR diagnoses and assessment.

Topical Tetracycline Improves MC903-induced Atopic Dermatitis in Mice through Inhibition of Inflammatory Cytokines and Thymic Stromal Lymphopoietin Expression

Background： Tetracycline （TET） has been found to have both antibiotic and anti-inflammatory properties. The anti-inflammatory effect of topical TET on atopic dermatitis （AD） has not been reported. The purpose of this study was to explore the potential role of topical TET and its anti-inflammatory effects in a mouse model of AD. Methods： The 2% TET was applied topically to ears of MC903-induced AD-like BALB/c mice once a day. AD-like symptoms and severity were evaluated by assessing skin scoring of dermatitis, ear thickness, and frequency of scratching. Serum lgE and thymic stromal lymphopoietin （TSLP） levels were measured by enzyme-linked immunosorbent assay. Western blot was used for analyzing the expressions of TSLP, protease-activated receptor 2 （PAR2）, and nuclear factor-kappa B （NF-~：B） in skin lesions. Real-time polymerase chain reaction was performed to assess the mRNA levels of TSLP and inflammatory cytokines including interleukin （IL）-4, IL-13, tumor necrosis factor （TNF）-α, and IL-1β in skin lesions. Results： Scoring of dermatitis （9.00 ± 0.63 vs. 6.67± 1.03, P = 0.001）, ear thickness （0.44± 0.02 mm vs. 0.40±0.03 mm, P = 0.018）, and serum IgE level （421.06 ± 212.13 pg/ml vs. 244.15±121.39 pg/ml, P 0.047） were all improved in the 2% TET treatment group compared with AD group. Topical TET significantly reduced the serum level of TSLP （119.04 ±38.92 pg/ml vs. 65.95± 54.61 μg/ml, P = 0.011） and both mRNA and protein expressions of TSLP in skin lesions compared with AD group （P = 0.003 and 0.011, respectively）, and NF-κB and PAR2 expression in skin lesions were also suppressed （P = 0.016 and 0.040, respectively）. Furthermore, expressions of inflammatory cytokines IL-4, IL- 13, and TNF-α in skin lesions were down-regulated in 2% TET group compared with AD group （P = 0.035, 0.008, and 0.044, respectively）. Conclusions： Topical TET exerted anti-inflammatory effects through suppression of TSLP and inflammatory cytokines in AD mouse model, suggesting TET as a potential agent for the topical treatment of AD in the future.

Effects of Honokiol on Activation of Transient Receptor Potential Channel V1 and Secretion of Thymic Stromal Lymphopoietin in HaCaT Keratinocytes

Objective::This study was performed to investigate the effects of honokiol on the activation of transient receptor potential channel V1(TRPV1)and the secretion of thymic stromal lymphopoietin(TSLP)in a human benign epidermal keratinocyte line(HaCaT).Methods::HaCaT keratinocytes were cultivated and divided into six groups:capsaicin-induced model control group,capsazepine control group,solvent control group,and three honokiol treatment groups(7.81,15.63,and 31.25 mg/L of honokiol).The effect of honokiol on calcium(Ca^(2+))influx was measured by a Ca^(2+)fluorescence imaging system.The fluorescence intensity(F)of cells was measured.The rate of change in F(ΔF/F0)was calculated,and theΔF/F0-time curve was constructed.HaCaT keratinocytes were stimulated with polyinosinic:polycytidylic acid,recombinant human tumor necrosis factorα,and recombinant human interleukin 4.Different concentrations of honokiol(15.63,7.81,and 3.91 mg/L)were added to the cells in the respective honokiol groups;20 mg/L of dexamethasone or 0.5%dimethyl sulfoxide was added to the cells in the positive control group or solvent control group.The TSLP concentration in the HaCaT keratinocytes of each group was detected by enzyme-linked immunosorbent assay.Statistical analysis was performed by one-way analysis of variance and Dunnett t test.Results::The capsaicin-induced Ca^(2+)fluorescence intensity in HaCaT keratinocytes was significantly inhibited in the 31.25 mg/L honokiol group;ΔF/F0 at 45 second was 0.76 in the model control group and 0 in the 31.25 mg/L honokiol group.The TSLP level in the 15.63 and 7.81 mg/L honokiol groups was lower than that in the solvent control group(t=7.382,P=0.003,and t=2.766,P=0.023,respectively),while the TSLP level in the 3.91 mg/L honokiol group was not significantly different from that in the solvent control group(t=1.872,P=0.124).Conclusions::Honokiol inhibited the Ca^(2+)influx induced by capsaicin(TRPV1 agonist)in HaCaT keratinocytes.Honokiol has an inhibitory effect on TSLP secretion in HaCaT keratinocytes.

泄热解毒汤联合氯雷他定治疗急性湿疹疗效及对CCL27、TSLP表达的影响

目的观察泄热解毒汤联合氯雷他定治疗急性湿疹(脾虚湿蕴证)疗效,并探讨其对CC型趋化因子27(CCL27)、胸腺基质淋巴生成素(TSLP)表达的影响。方法120例患者按随机数字表法分为对照组与研究组各60例。对照组予氯雷他定治疗,研究组在对照组基础上联用泄热解毒汤。观察两组疗效,并比较两组治疗前后皮损情况、肿瘤坏死因子-α(TNF-α)、白细胞介素6(IL-6)、白细胞介素4(IL-4)、T细胞亚群(CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+))及血清CCL27、TSLP水平。结果研究组总有效率93.33%,高于对照组的80.00%(P<0.05)。两组治疗前瘙痒、皮损形态、皮损面积评分、血清TNF-α、IL-6、IL-4、CD4^(+)、CD8^(+)、CD4^(+)/CD8^(+)、CCL27、TSLP水平比较,差异均无统计学意义(均P>0.05)。两组治疗后瘙痒、皮损形态、皮损面积评分与治疗前比较均降低,且研究组皮损情况评分均优于对照组(均P<0.05)。两组治疗后TNF-α、IL-6、IL-4水平与治疗前比较均降低,且研究组各炎症指标均低于对照组(均P<0.05)。两组治疗后CD4^(+)、CD4^(+)/CD8^(+)与治疗前比较均升高,CD8^(+)则低于治疗前,且研究组T细胞亚群各项指标均优于对照组(均P<0.05)。两组治疗后血清CCL27、TSLP水平与治疗前比较均降低,且研究组均低于对照组(均P<0.05)。结论泄热解毒汤联合氯雷他定治疗急性湿疹(脾虚湿蕴证)疗效确切,可明显改善患者皮损状况,减轻机体炎症反应,降低CCL27、TSLP表达。

基于TSLP-OX40L通路探讨麻黄附子细辛汤合肾四味汤对变应性鼻炎大鼠的影响

目的 观察麻黄附子细辛汤合肾四味汤对变应性鼻炎大鼠的保护作用及对胸腺基质淋巴细胞生成素-OX40配体(TSLP-OX40L)通路的影响。方法 将60只SD雄性大鼠随机分为正常组、模型组、麻黄附子细辛汤组、肾四味汤组、合方组和泼尼松龙组,每组10只。除正常组外,其余组大鼠均采用卵清蛋白+氢氧化铝腹腔注射结合卵清蛋白滴鼻方法建立变应性鼻炎模型。成模后,麻黄附子细辛汤组给予1.62 g/kg麻黄附子细辛汤灌胃,肾四味汤组给予10.80 g/kg肾四味汤灌胃,合方组给予12.42 g/kg麻黄附子细辛汤和肾四味汤灌胃,泼尼松龙组给予6.3 mg/kg醋酸泼尼松龙片悬液灌胃,正常组及模型组灌胃同等量的纯化水,均1次/d,连续灌胃14 d。观察大鼠一般情况,记录灌胃第7天和第14天大鼠鼻炎症状评分,HE染色观察鼻黏膜组织病理学形态,ELISA法检测血清白细胞介素-5(IL-5)、白细胞介素-4(IL-4)、白细胞介素-13(IL-13)水平,RT-PCR法和Western blot法分别检测鼻黏膜组织中TSLP、OX40L mRNA及蛋白表达情况。结果 灌胃第7天和第14天,模型组大鼠鼻炎症状评分均明显高于正常组(P均<0.05);病理观察显示鼻黏膜上皮细胞脱落,腺体和血管周围出现水肿和炎症;末次灌胃结束后,血清IL-5、IL-4、IL-13水平和鼻黏膜组织中TSLP、OX40L mRNA及蛋白相对表达量均明显高于正常组(P均<0.05)。灌胃第7天,合方组和泼尼松龙组大鼠鼻炎症状评分明显低于模型组、麻黄附子细辛汤组、肾四味汤组(P均<0.05);灌胃第14天,各药物组大鼠鼻炎症状评分均明显低于模型组(P均<0.05),且合方组、泼尼松龙组、麻黄附子细辛汤组均明显低于肾四味汤组(P均<0.05)。末次灌胃结束后,各药物组大鼠鼻黏膜组织病理变化均明显改善,血清IL-5、IL-4、IL-13水平和鼻黏膜组织中TSLP、OX40L mRNA及蛋白相对表达量均较模型组明显降低(P均<0.05),且合方组和泼尼松龙组血清IL-4、IL-5、IL-13水平及鼻黏膜组织中TSLP、OX40L mRNA和蛋白相对表达量均明显低于麻黄附子细辛汤组和肾四味汤组(P均<0.05)。麻黄附子细辛汤组TSLP mRNA和蛋白相对表达量均明显低于肾四味汤组(P均<0.05),OX40L mRNA和蛋白相对表达量均明显高于肾四味汤组(P均<0.05)。结论 麻黄附子细辛汤合肾四味汤可明显减轻变应性鼻炎大鼠的症状和鼻黏膜组织病变,其机制可能与调控TSLP-OX40L通路有关。

胸腺基质淋巴细胞生成素联合小气道肺功能指标诊断儿童咳嗽变异性哮喘的临床价值

目的:比较胸腺基质淋巴细胞生成素(TSLP)、小气道肺功能指标单独或联合检测对咳嗽变异性哮喘(CVA)的临床诊断价值。方法:选择2019年1月至2021年4月于漯河市中心医院就诊的85例CVA患者设为CVA组,慢性咳嗽患儿42例设为non-CVA组。ELISA检测外周血中TSLP水平,肺功能分析仪检测小气道肺功能指标[肺活量的最大中段呼气流量(MMEF)、75%肺活量的最大呼气流速(MEF 75)、MEF 50和MEF 25]。比较两组间的TSLP水平和小气道肺功能检测参数,分析TSLP值与小气道肺功能指标的相关性,比较TSLP、小气道肺功能指标单独或联合诊断CVA的临床价值。结果:CVA组TSLP水平高于non-CVA组,MMEF、MEF 75、MEF 50和MEF 25水平低于non-CVA组,两组间比较差异有统计学意义(P<0.05)。CVA组中TSLP值与MMEF、MEF 75、MEF 50和MEF 25均呈负相关(r=−0.551,P<0.001;r=−0.473,P<0.001;r=−0.685,P<0.001;r=−0.347,P=0.001)。TSLP联合MMEF诊断CVA的临床价值高于TSLP和MMEF单独检测(Z=3.415,P=0.014;Z=3.624,P=0.010),TSLP联合MEF 50诊断CVA的临床价值高于TSLP和MEF 50单独检测(Z=4.215,P=0.007;Z=4.523,P=0.003)。结论:TSLP联合MMEF或MEF 50诊断CVA的临床价值高于单独检测,具有一定的临床使用价值。

曲安奈德对特应性皮炎小鼠血清白细胞介素-33、白细胞介素-25、胸腺基质淋巴细胞生成素和Th1/Th2平衡影响的实验研究

目的:探讨曲安奈德对特应性皮炎小鼠白细胞介素-33(IL-33)、白细胞介素-25(IL-25)、胸腺基质淋巴细胞生成素(TSLP)和Th1/Th2平衡的影响。方法:选择ABLB/c雄性小鼠60只,分为对照组、模型组、阳性对照组、曲安奈德组高、中、低剂量,给予模型组、阳性对照组、高、中、低剂量组建立特应性皮炎小鼠模型。高剂量组腹腔注射3μl 60 mg/ml曲安奈德,中剂量组腹腔注射3μl 40 mg/ml曲安奈德,低剂量组腹腔注射3μl 20 mg/ml曲安奈德,模型组、对照组腹腔注射3μl的0.5%羧甲基纤维素钠蒸馏水,阳性组腹腔注射3μl 10 mg/ml泼尼松龙,每天1次,六组均给予15 d。对比六组小鼠的搔抓行为、特应性皮炎评分(SCORAD)指数评分、肥大细胞密度、皮肤组织厚度、小鼠血清中的IL-33、IL-25、TSLP水平及Th1/Th2细胞比例。结果:与对照组相比,阳性对照组、低、中、高剂量组、模型组的搔抓行为、SCORAD指数、肥大细胞密度、皮肤组织厚度、血清中的IL-33、IL-25、TSLP、Th2水平明显较高,Th1、Th1/Th2水平明显较低(均P<0.05);与阳性对照组相比,低、中、高剂量组、模型组的搔抓行为、SCORAD指数、肥大细胞密度、皮肤组织厚度、血清中的IL-33、IL-25、TSLP、Th2水平明显较高,Th1、Th1/Th2水平明显较低(均P<0.05);与高剂量组相比,中、低剂量组、模型组的搔抓行为、SCORAD指数、肥大细胞密度、皮肤组织厚度、血清中的IL-33、IL-25、TSLP、Th2水平明显较高,Th1、Th1/Th2水平明显较低(均P<0.05);与低剂量组相比,模型组的搔抓行为、SCORAD指数、肥大细胞密度、皮肤组织厚度、血清中的IL-33、IL-25、TSLP、Th2水平明显较高,Th1、Th1/Th2水平明显较低(均P<0.05)。结论:曲安奈德可以通过抑制小鼠的IL-33、IL-25、TSLP水平,维持Th1/Th2平衡来改善特应性皮炎的皮肤损伤。

抗胸腺基质淋巴细胞生成素治疗在2型炎症通路相关疾病的应用及展望

胸腺基质淋巴细胞生成素(TSLP)是IL-7家族成员,有两种亚型,长亚型(lfTSLP)作用于2型炎症通路上游,参与过敏性疾病级联反应,短亚型(sfTSLP)则起到维持稳态作用。长短两亚型还在炎症性肠病、肿瘤等疾病中发挥不同作用。TSLP单克隆抗体特泽鲁单抗被FDA批准用于中重度药物控制不良哮喘患者的附加治疗,临床试验证明特泽鲁单抗不仅针对2型炎症型哮喘,对其他表型的哮喘也有效,且有望应用于其他2型炎症相关疾病,如特应性皮炎的治疗。抗TSLP疗法在其他疾病的应用也正在开发中。目前大多数针对TSLP的药物研究并未区分lfTSLP和sfTSLP,理想状态下,用于中和TSLP的单克隆抗体不应相互作用或阻碍sfTSLP的稳态作用。此外,TSLP的不同亚型在肿瘤和自身免疫性疾病中的作用及机制尚存在争议。目前仍需要更多研究阐明TSLP对免疫系统的影响,并探讨如何拓宽抗TSLP临床应用和抗TSLP治疗潜在的不良反应。

外源性TSLP蛋白对脓毒症肝损伤小鼠的作用及肝细胞自噬的影响

目的探究外源性胸腺基质淋巴细胞生成素(thymic stromal lymphopietin,TSLP)蛋白对脓毒症肝损伤(sepsis-induced liver injury,SILI)小鼠的作用及肝细胞自噬的影响。方法采用盲肠结扎穿孔术(CLP)制作SILI模型,将30只C57BL/6J小鼠随机分为假手术组(Sham组)、模型组[CLP+磷酸缓冲盐溶液(PBS)组]及外源性TSLP蛋白(重组小鼠TSLP蛋白,rTSLP)干预组(CLP+rTSLP组)。造模10 h处死小鼠,采集成功造模标本(每组n=6),检测三组小鼠血清丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)及乳酸脱氢酶(LDH)水平;苏木精-伊红染色法(HE)观察肝组织损伤情况并评分;应用实时荧光定量PCR技术(qRT-PCR)及蛋白免疫印迹(Western blot)检测小鼠肝脏白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)炎症因子表达。Western blot检测小鼠苄氯素1(Beclin1)、微管相关蛋白(LC3)Ⅱ自噬相关标记物及PI3K/Akt信号通路表达情况。结果rTSLP蛋白能降低血清ALT、AST和LDH水平(P<0.05),改善肝脏组织损伤(P<0.05),同时也能降低IL-1β、IL-6和TNF-α炎症因子的mRNA和蛋白表达水平(P<0.05),增强肝细胞自噬与PI3K/Akt信号通路水平的表达(P<0.05)。结论外源性TSLP蛋白通过上调肝细胞自噬,改善小鼠SILI,其机制可能是通过激活PI3K/Akt信号通路发挥作用。

环孢素滴眼液联合聚乙二醇滴眼液治疗干眼症患者的效果

目的:观察环孢素滴眼液联合聚乙二醇滴眼液治疗干眼症患者的效果。方法:选取2020年2月至2021年12月该院收治的73例干眼症患者进行前瞻性研究,按照随机数字表法将其分为观察组37例与对照组36例。对照组给予聚乙二醇滴眼液治疗,观察组在对照组基础上联合环孢素滴眼液治疗,比较两组临床疗效、治疗前后干眼症状评分、泪河高度、眼表疾病指数(OSDI)评分、眼表功能指标[泪膜破裂时间(BUT)、泪液分泌试验(SIT)、角结膜荧光素染色(FL)]水平和泪液炎性因子[基质金属蛋白酶-9(MMP-9)、白细胞介素-1β(IL-1β)、胸腺基质淋巴细胞生成素(TSLP)]水平。结果:观察组治疗总有效率为94.59%,明显高于对照组的75.00%,差异有统计学意义(P<0.05);治疗后,观察组泪河高度、BUT、SIT水平高于对照组,干眼症状评分、OSDI评分、FL评分以及TSLP、MMP-9、IL-1β水平低于对照组,差异均有统计学意义(P<0.05)。结论:环孢素滴眼液联合聚乙二醇滴眼液治疗干眼症可提高治疗总有效率、泪河高度、BUT、SIT水平,降低干眼症状评分、OSDI评分、FL评分和炎性因子水平,效果优于单纯聚乙二醇滴眼液治疗。

植物复合舒缓剂(CAP)对外源性皮肤刺激的保护作用

作为抵御外部环境的第一道防线,皮肤不仅是一种物理屏障,而且是一种具有多种免疫细胞的免疫器官。这些免疫细胞在不同的皮肤层中组织结构良好,并与非免疫结构细胞(如角质形成细胞)建立通信网络,参与先天和适应性免疫反应,以确保皮肤免疫稳态。通过探讨皮肤免疫反应的起始感知、初始传递、初级效应阶段下不同类型细胞所产生的关键调节剂来研究植物复合舒缓剂(CAP)对外源性皮肤刺激的潜在保护作用及机制。同时,利用三维(3D)重建的人类表皮模型(EpiKutis)来模拟弱屏障下的皮肤免疫反应研究CAP在组织层面的作用。结果显示,在外源性刺激时,关键免疫调节因子如胸腺基质淋巴细胞生成素(TSLP)、白细胞介素-8(IL-8)、前列腺素E2(PGE-2)、白细胞介素-6(IL-6)和肿瘤坏死因子-α(TNF-α)在角质形成细胞、3D EpiKutis模型、THP-1衍生细胞和肥大细胞中含量均显著升高,而CAP同步处理下可显著降低这些因子的表达量。此外,CAP剂量依赖性地改善由Poly(I:C)和LPS诱导导致的丝聚蛋白降低。结果表明,CAP通过促进皮肤屏障修复,调控皮肤免疫反应的起始、传递和效应阶段发挥重要作用。

靶向警报素单克隆抗体治疗哮喘的研究进展

哮喘是一种以慢性气道炎症为主要特征的异质性疾病。变应原、空气污染物等触发呼吸道上皮细胞产生的警报素——胸腺基质淋巴生成素、白细胞介素(IL)-33和IL-25在哮喘发病中发挥重要作用。警报素可直接激活2型固有淋巴细胞、嗜酸粒细胞、嗜碱粒细胞和肥大细胞,也可刺激树突状细胞驱动辅助性T细胞(Th细胞)0向Th2细胞表型转化,参与2型哮喘的发生发展。目前靶向警报素单克隆抗体治疗哮喘的研究已进入临床试验阶段。未来人源性抗警报素单克隆抗体或可成为哮喘治疗的有效方案,为疾病的治疗提供新思路。

TSLP、SAA、IL-8在不同皮炎湿疹类疾病患者血清中的表达差异

目的探讨胸腺基质淋巴细胞生成素(TSLP)、淀粉样蛋白A(SAA)、白介素-8(IL-8)在不同皮炎湿疹类疾病患者血清中的表达差异及其与糖皮质激素类外用药治疗效果的相关性。方法选取2020年6月—2022年9月在本院确诊与治疗的86例皮炎湿疹类疾病患者为疾病组,其中接触性皮炎46例、湿疹22例、特异性皮炎18例;另选取同期在本院体检的健康志愿者43例为对照组,检测所有纳入对象的血清TSLP、SAA、IL-8水平,分析不同皮炎湿疹类疾病患者血清中的各项指标的水平变化。所有患者行糠酸莫米松乳膏外用治疗2周后进行治疗效果评价,检测患者治疗前后的血清TSLP、SAA、IL-8水平,采用受试者工作特征(ROC)曲线评价血清TSLP、SAA、IL-8水平对皮炎湿疹类疾病治疗效果的评估价值。结果与对照组比较,病例组患者治疗前血清TSLP、SAA、IL-8水平明显较高(P<0.05)。接触性皮炎、湿疹、特异性皮炎的临床总有效率分别为67.39%、59.09%、61.11%,组间比较差异无统计学意义(P>0.05)。治疗2周后,各组患者血清TSLP、SAA、IL-8水平均显著下降(P<0.05),但各组间比较差异无统计学意义(P>0.05)。治疗2周后,有效组与无效组患者的血清TSLP、SAA、IL-8水平均下降,且有效组各指标水平更低(P<0.05)。ROC曲线分析,结果显示血清TSLP、SAA、IL-8水平对皮炎湿疹类疾病的治疗效果均有较好的评估价值(P<0.05)。结论不同皮炎湿疹类疾病患者血清中的TSLP、SAA、IL-8水平均显著升高,且其水平变化与糖皮质激素类外用药治疗效果存在一定的关联。