Zhukov A S, Khairutdinov V R, Samtsov A V, Krasavin M, Garabadzhiu A V
Department of Dermatology S. M. Kirov Military Medical Academy Saint Petersburg Russia.
Saint Petersburg State University Saint Petersburg Russia.
Skin Health Dis. 2021 Dec 30;2(2):e90. doi: 10.1002/ski2.90. eCollection 2022 Jun.
Psoriasis is a chronic immune-mediated inflammatory skin disease manifested by an increased rate of keratinocyte division. Currently, it has been established that the cytokines of the IL-36 family play a significant role in the initiation and regulation of the inflammatory process in psoriasis. The IL-36 cytokine found in skin is inactive and its activation requires proteolytic processing that may occur via the involvement of neutrophil serine proteases such as human neutrophil elastase (HNE). The localization of these enzymes in the upper layers of the epidermis suggests that topical application of HNE inhibitors could be efficacious in the treatment of psoriasis. Sivelestat is an HNE inhibitor developed for systemic use towards the treatment of acute respiratory failure.
The present study focussed on the investigation of the effects of sivelestat formulated for topical use, in the imiquimod-induced model of psoriasis in mice.
The psoriasis-like state was induced by application of imiquimod (Aldara) 5% cream to mouse shaven skin. A group of 40 inbred mice of the BALB/c strain randomized into 4 groups of 10 was used in the experiment: Group 1 - no therapy (control), Group 2 - ointment (Vaseline) containing 1% sivelestat, Group 3 - cream (lanoline + olive oil + water in equal proportions) containing 1% sivelestat, Group 4 - 1% betamethasone dipropionate. Dermatological assessment of skin lesions was performed by means of the PASI method (mPASI), as well as histological and immunohistochemical evaluation.
Based on the evaluation of efficacy manifestations, it was established that the total mPASI index value decreased by 50% during therapy with sivelestat cream and by 36% during therapy with sivelestat ointment. Histological study revealed that the epidermal thickness in groups that underwent therapy was 2.4-3.6 times lower compared to the control group. Immunohistochemical study of the skin indicated that following sivelestat treatment, the quantity of CD3+cells in the skin was 1.8-2.2 times lower, and the level of proliferative activity (Ki-67+cells) was 2.3-2.9 lower compared to the non-therapy group. In contrast to topical corticosteroids where the more pronounced anti-inflammatory effect is typically seen with ointment formulations, with sivelestat we observed an opposite effect. The reasons for that reversal remain unclear.
Based on the results obtained using the animal model of imiquimod-induced psoriasis, it was established that the HNE inhibitor sivelestat demonstrated efficacy comparable to that of a strong topical glucocorticoid steroidal drug (betamethasone dipropionate 1%). Significant resolution of skin lesions, reduction of epidermal thickness, diminishing of the skin infiltration with T-lymphocytes and normalization of the cell division rate in epidermis and dermis were evident. Thus, suppression of IL-36 mediated inflammation activity in the skin by topical application of a HNE inhibitor represents a promising new direction in the treatment of psoriasis. Certainly, HNE has other targets; thus, molecular studies could be subject of future experiments beyond the scope of the present study.
银屑病是一种慢性免疫介导的炎症性皮肤病，表现为角质形成细胞分裂速率增加。目前已经确定，白细胞介素 - 36（IL - 36）家族的细胞因子在银屑病炎症过程的启动和调节中起重要作用。在皮肤中发现的IL - 36细胞因子是无活性的，其激活需要蛋白水解过程，这可能通过中性粒细胞丝氨酸蛋白酶如人中性粒细胞弹性蛋白酶（HNE）的参与而发生。这些酶在表皮上层的定位表明，局部应用HNE抑制剂可能对银屑病治疗有效。西维来司他是一种开发用于全身治疗急性呼吸衰竭的HNE抑制剂。
本研究聚焦于对局部用西维来司他在咪喹莫特诱导的小鼠银屑病模型中的作用进行研究。
通过将5%咪喹莫特（艾达乐）乳膏涂抹于小鼠剃毛皮肤上诱导出银屑病样状态。将一组40只BALB/c品系的近交小鼠随机分为4组，每组10只用于实验：第1组 - 不治疗（对照），第2组 - 含1%西维来司他的软膏（凡士林），第3组 - 含1%西维来司他的乳膏（羊毛脂 + 橄榄油 + 水按等比例混合），第4组 - 1%丙酸倍他米松。通过银屑病面积和严重程度指数（PASI）方法（改良PASI，mPASI）进行皮肤病变的皮肤病学评估，以及组织学和免疫组织化学评估。
基于疗效表现的评估，确定在使用西维来司他乳膏治疗期间，总mPASI指数值降低了50%，在使用西维来司他软膏治疗期间降低了36%。组织学研究显示，接受治疗的组的表皮厚度比对照组低2.4 - 3.6倍。皮肤的免疫组织化学研究表明，西维来司他治疗后，皮肤中CD3 +细胞数量比未治疗组低1.8 - 2.2倍，增殖活性水平（Ki - 67 +细胞）低2.3 - 2.9倍。与局部皮质类固醇不同，软膏制剂通常具有更明显的抗炎作用，而对于西维来司他，我们观察到了相反的效果。这种逆转的原因尚不清楚。
基于使用咪喹莫特诱导的银屑病动物模型获得的结果，确定HNE抑制剂西维来司他显示出与强效局部糖皮质甾体药物（1%丙酸倍他米松）相当的疗效。皮肤病变明显消退，表皮厚度降低，皮肤T淋巴细胞浸润减少，表皮和真皮细胞分裂速率恢复正常。因此，局部应用HNE抑制剂抑制皮肤中IL - 36介导的炎症活性代表了银屑病治疗中一个有前景的新方向。当然，HNE还有其他靶点；因此，分子研究可能是本研究范围之外未来实验的主题。
