Chisholm Jessica, Gareau Alison J, Byun Stephanie, Paletz Justin L, Tang David, Williams Jason, LeVatte Terry, Bezuhly Michael
Halifax, Nova Scotia, Canada.
From the Department of Microbiology and Immunology and the Department of Surgery, Division of Plastic and Reconstructive Surgery, Dalhousie University; and the Izaak Walton Killam Health Centre.
Plast Reconstr Surg. 2017 Nov;140(5):686e-696e. doi: 10.1097/PRS.0000000000003800.
Although surgical excision and intralesional collagenase injection are mainstays in Dupuytren disease treatment, no effective medical therapy exists for recurrent disease. Compound 21, a selective agonist of the angiotensin II type 2 receptor, has been shown to protect against fibrosis in models of myocardial infarction and stroke. The authors investigated the potential use of compound 21 in the treatment of Dupuytren disease.
Human dermal fibroblasts were treated in vitro with compound 21 and assessed for viability using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, migration by means of scratch assay, and profibrotic gene transcription by means of quantitative reverse transcription polymerase chain reaction. Compound 21 effects in vivo were assessed using a xenograft model. Dupuytren disease cord specimens from patients undergoing open partial fasciectomy were divided into two segments. Segments were implanted under the dorsal skin of nude mouse pairs. Beginning on day 5, one mouse from each pair received daily intraperitoneal injections of compound 21 (10 μg/kg/day), and the other received vehicle. On day 10, segments were explanted and submitted for immunohistochemistry.
Human dermal fibroblasts treated with compound 21 displayed decreased migration and decreased gene expression of connective tissue growth factor, fibroblast specific protein-1, transforming growth factor-β1, Smad3, and Smad4. Dupuytren disease segments from compound 21-treated mice demonstrated significantly reduced alpha-smooth muscle actin and Ki67 staining, with increased density of CD31 staining vessels.
Compound 21 significantly decreases expression of profibrotic genes and decreases myofibroblast proliferation as indicated by reduced Ki67 and alpha-smooth muscle actin expression. These findings support compound 21 as a potential novel treatment modality for Dupuytren disease.
尽管手术切除和病灶内注射胶原酶是治疗掌腱膜挛缩症的主要方法，但对于复发性疾病尚无有效的药物治疗方法。化合物21是血管紧张素II 2型受体的选择性激动剂，已被证明在心肌梗死和中风模型中具有抗纤维化作用。作者研究了化合物21在掌腱膜挛缩症治疗中的潜在用途。
用化合物21体外处理人皮肤成纤维细胞，并使用3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐法评估细胞活力，通过划痕试验评估细胞迁移，并通过定量逆转录聚合酶链反应评估促纤维化基因转录。使用异种移植模型评估化合物21在体内的作用。将接受开放性部分筋膜切除术患者的掌腱膜挛缩症条索标本分成两段。将这些片段植入裸鼠对的背部皮肤下。从第5天开始，每对小鼠中的一只每天接受腹腔注射化合物21（10μg/kg/天），另一只接受赋形剂。在第10天，取出片段并进行免疫组织化学检查。
用化合物21处理的人皮肤成纤维细胞显示迁移减少，结缔组织生长因子、成纤维细胞特异性蛋白-1、转化生长因子-β1、Smad3和Smad4的基因表达降低。来自接受化合物21治疗小鼠的掌腱膜挛缩症片段显示α-平滑肌肌动蛋白和Ki67染色显著减少，CD31染色血管密度增加。
如Ki67和α-平滑肌肌动蛋白表达降低所示，化合物21显著降低促纤维化基因的表达并减少肌成纤维细胞增殖。这些发现支持化合物21作为掌腱膜挛缩症的一种潜在新治疗方式。
