Abstract：
Hypertrophic scar (HS) formation is a cutaneous fibroproliferative disease that occurs after skin injuries and results in severe functional and esthetic disability. To date, few drugs have shown satisfactory outcomes for the treatment of HS formation. Transforming growth factor-beta (TGF-β)/Notch interaction via small mothers against decapentaplegic 3 (Smad3) could facilitate HS formation; therefore, targeting TGF-β/ Notch interaction via Smad3 is a potential therapeutic strategy to attenuate HS formation. In addition, optic atrophy 1 (OPA1)-mediated mitochondrial fusion contributes to fibroblast proliferation, and TGF-β/Smad3 axis and the Notch1 pathway facilitate OPA1-mediated mitochondrial fusion. Thus, the aim of this study was to investigate whether drugs targeting TGF-β/Notch interaction via Smad3 suppressed fibroblast proliferation to attenuate HS formation through OPA1-mediated mitochondrial fusion. We found that the TGF-β pathway, Notch pathway, and TGF-β/Notch interaction via Smad3 were inhibited by pirfenidone, the gamma- secretase inhibitor DAPT, and SIS3 in human keloid fibroblasts (HKF) and an HS rat model, respectively. Protein interaction was detected by co-immunoprecipitation, and mitochondrial morphology was determined by electron microscopy. Our results indicated that pirfenidone, DAPT, and SIS3 suppressed the proliferation of HKFs and attenuated HS formation in the HS rat model by inhibiting TGF-β/Notch interaction via Smad3. Moreover, pirfenidone, DAPT, and SIS3 hindered OPA1-mediated mitochondrial fusion through inhibiting TGF-β/Notch interaction, thereby suppressing the proliferation of HS fibroblasts and HS formation. In summary, these findings investigating the effects of drugs targeting TGF-β/Notch interaction on HS formation might lead to novel drugs for the treatment of HS formation.
摘要：
肥厚性瘢痕（HS）形成是一种皮肤纤维增生性疾病，发生在皮肤损伤后，并导致严重的功能和美学残疾。迄今为止,很少有药物显示出治疗HS形成的满意结果.转化生长因子-β（TGF-β）/Notch通过小母亲对抗十骨截瘫3（Smad3）的相互作用可以促进HS形成；因此，通过Smad3靶向TGF-β/Notch相互作用是减弱HS形成的潜在治疗策略。此外,视神经萎缩1（OPA1）介导的线粒体融合有助于成纤维细胞增殖，TGF-β/Smad3轴和Notch1途径促进OPA1介导的线粒体融合。因此，这项研究的目的是研究通过Smad3靶向TGF-β/Notch相互作用的药物是否通过OPA1介导的线粒体融合抑制成纤维细胞增殖以减弱HS形成。我们发现TGF-β通路,缺口通道,吡非尼酮抑制TGF-β/Notch通过Smad3的相互作用，γ-分泌酶抑制剂DAPT，和SIS3在人瘢痕疙瘩成纤维细胞（HKF）和HS大鼠模型中，分别。通过免疫共沉淀检测蛋白质相互作用，电镜观察线粒体形态。我们的结果表明，吡非尼酮，DAPT,SIS3通过Smad3抑制TGF-β/Notch相互作用抑制HS大鼠模型中HKFs的增殖并减弱HS的形成。此外，吡非尼酮,DAPT,SIS3通过抑制TGF-β/Notch相互作用阻碍OPA1介导的线粒体融合，从而抑制HS成纤维细胞的增殖和HS的形成。总之,这些研究结果研究了靶向TGF-β/Notch相互作用的药物对HS形成的影响，可能导致治疗HS形成的新药。
