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《陕西医学杂志》[ISSN:1000-7377/CN:61-1281/TN]

卷:

54

期数:

2025年2期

页码:

164-169

栏目:

基础研究

出版日期:

2025-02-05

文章信息/Info

Title:

Therapeutic effects and mechanism of crisaborole ointment on psoriasis in mice

作者:

马磊磊¹; 苏 琪¹; 封三花²

(1.邢台市中医院皮肤科,河北 邢台 054001; 2.河北中医药大学第一附属医院中医内科,河北 石家庄 061199)

Author(s):

MA Leilei¹; SU Qi¹; FENG Sanhua²

(1.Department of Dermatology,Xingtai Hospital of Traditional Chinese Medicine,Xingtai 054001,China; 2.Department of Chinese Internal Medicine,First Affiliated Hospital of Hebei University of Traditional Chinese Medicine,Shijiazhuang 061199,China)

关键词:

银屑病;  克立硼罗软膏;  磷脂酰肌醇3-激酶/蛋白激酶B信号通路;  皮肤损害;  炎症反应;  小鼠

Keywords:

Psoriasis;  Crisaborole ointment;  Phosphatidylinositol 3-kinase/protein kinase B signaling pathway;  Skin damage;  Inflammatory response;  Mice

分类号:

R -33

DOI:

DOI:10.3969/j.issn.1000-7377.2025.02.004

文献标志码:

A

摘要:

目的:探讨克立硼罗软膏对小鼠银屑病的治疗作用及其可能的机制。方法:选取40只雄性BALB/c裸鼠随机分为空白组、模型组、阳性药组和克立硼罗软膏组,每组各10只。空白组备皮处涂抹凡士林软膏62.5 mg,其余组建立银屑病小鼠模型。建模成功后,于造模成功当天同时给药,模型组不做处理,阳性药组涂抹丁酸氢化可的松乳膏,克立硼罗软膏组涂抹克立硼罗软膏,均连续给药7 d。于给药第0、3、5、7天采用银屑病面积与严重性指数(PASI)评分评估小鼠皮损程度。采用ELISA法检测血清肿瘤坏死因子-α(TNF-α)、白细胞介素(IL)-1β、IL-6、干扰素-γ(IFN-γ)水平。采用流式细胞仪检测外周血辅助性T细胞17(Th17)和调节性T细胞(Treg)比例。采用HE染色观察皮肤组织病理学变化。Western blot检测小鼠皮肤组织中磷脂酰肌醇3-激酶(PI3K)、蛋白激酶B(AKT)、p-AKT蛋白表达。结果:与模型组比较,阳性药组和克立硼罗软膏组小鼠给药第0、3、5、7天PASI评分降低,且克立硼罗软膏组低于阳性药组(均P<0.05)。与空白组比较,模型组血清TNF-α、IL-1β、IL-6、IFN-γ水平升高(均P<0.05)。模型组血清TNF-α、IL-1β、IL-6、IFN-γ水平高于阳性药组和克立硼罗软膏组,且阳性药组高于克立硼罗软膏组(均P<0.05)。与空白组比较,模型组外周血Th17细胞比例、Th17/Treg比值升高,Treg细胞比例下降(均P<0.05)。阳性药组Th17细胞比例、Th17/Treg比值高于克立硼罗软膏组,Treg细胞比例低于克立硼罗软膏组(均P<0.05)。HE染色结果显示,空白组小鼠皮肤结构完整,表皮颗粒层清晰,真皮区域未见炎症细胞,且无角化过度或不全情况。模型组小鼠表皮层过度角化,可见棘层变厚,真皮层出现新生血管,呈扩张和充血状态,且有炎症细胞浸润严重。阳性药组和克立硼罗软膏组小鼠皮肤角化状态趋于正常,角质层受损程度缓解,棘层变薄,真皮内少量新生血管,炎症反应轻微,且克立硼罗软膏组更明显。与空白组比较,模型组PI3K、p-AKT蛋白表达水平增加(均P<0.05)。阳性药组和克立硼罗软膏组PI3K、p-AKT蛋白表达水平较模型组降低,且克立硼罗软膏组低于阳性药组(均P<0.05)。结论:克立硼罗软膏可改善银屑病小鼠皮肤损害,减轻炎症反应,调节免疫功能,其机制可能与抑制PI3K/AKT信号通路有关。

Abstract:

Objective:To investigate the therapeutic effects of crisaborole ointment on psoriasis in mice and explore its potential mechanisms.Methods:Forty male BALB/c nude mice were randomly divided into four groups:blank group,model group,positive drug group and crisaborole ointment group,with 10 mice in each group.The blank group was treated with 62.5 mg of petrolatum ointment,while the other groups were subjected to the establishment of a psoriasis mouse model.After successful modeling,treatment was initiated on the same day,with the model group receiving no treatment,the positive drug group treated with hydrocortisone butyrate cream,and the crisaborole ointment group treated with crisaborole ointment for 7 consecutive days.The severity of skin lesions in mice was assessed using the Psoriasis Area and Severity Index(PASI)scores on days 0,3,5 and 7 post-treatment.ELISA was used to detect serum levels of tumor necrosis factor-alpha(TNF-α),interleukin(IL)-1β,IL-6,and interferon-gamma(IFN-γ).Flow cytometry was employed to measure the proportions of peripheral blood helper T cells 17(Th17)and regulatory T cells(Treg).HE staining was used to observe pathological changes in skin tissue.Western blot was performed to detect the expression of phosphatidylinositol 3-kinase(PI3K),protein kinase B(AKT)and p-AKT proteins in mouse skin tissue.Results:Compared with the model group,both the positive drug group and the crisaborole ointment group showed reduced PASI scores on days 0,3,5 and 7 post-treatment,with the crisaborole ointment group showing lower scores than the positive drug group(all P<0.05).Compared with the blank group,the model group had increased serum levels of TNF-α,IL-1β,IL-6 and IFN-γ(all P<0.05).The model group had higher levels of TNF-α,IL-1β,IL-6 and IFN-γ than both the positive drug group and the crisaborole ointment group,with the positive drug group having higher levels than the crisaborole ointment group(all P<0.05).Compared with the blank group,the model group had increased proportions of peripheral blood Th17 cells and Th17/Treg ratio,and decreased proportion of Treg cells(all P<0.05).The positive drug group had higher Th17 cell proportions and Th17/Treg ratio,and lower Treg cell proportion than the crisaborole ointment group(all P<0.05).HE staining showed that the blank group mice had intact skin structure,clear epidermal granular layer,no inflammatory cells in the dermis,and no hyperkeratosis or hypokeratosis.The model group mice exhibited excessive epidermal keratinization,thickened spinous layer,neovascularization in the dermis with dilation and congestion,and severe inflammatory cell infiltration.The positive drug group and crisaborole ointment group mice showed a trend towards normalization of skin keratinization,alleviation of stratum corneum damage,thinning of the spinous layer,few neovascularizations in the dermis,mild inflammatory response,and the crisaborole ointment group showed more significant improvements.Compared with the blank group,the model group had increased expression levels of PI3K and p-AKT proteins(all P<0.05).Both the positive drug group and the crisaborole ointment group had reduced PI3K and p-AKT protein expression levels compared to the model group,with the crisaborole ointment group showing lower levels than the positive drug group(all P<0.05).Conclusion:Crisaborole ointment can improve skin damage in psoriasis mice,alleviate inflammatory responses and regulate immune function.Its mechanism may be related to the inhibition of the PI3K/AKT signaling pathway.

备注/Memo

备注/Memo:

[基金项目]河北省中医药管理局科研计划项目(2021453); 河北省邢台市科技计划自筹经费项目(2022ZC128)

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更新日期/Last Update: 2025-02-04