背景:瘢痕疙瘩组织含有炎性细胞和上调的促炎细胞因子。Janus激酶(JAK)-信号转导和转录激活因子(STAT)途径介导对这些细胞因子的细胞应答。
目的:对JAK-STAT通路在瘢痕疙瘩发病中的作用及JAK-STAT抑制剂在瘢痕疙瘩治疗中的作用进行系统评价。
方法:搜索将术语(1)瘢痕疙瘩和(2)JAK或TYK或STAT组合在一起,并包括MeSH术语和同义词。两名审稿人筛选了文章,并评估了有关资格的全文。收集了测试药物和分子的数据,实验中使用的细胞和组织的类型,并研究JAK-STAT通路与瘢痕疙瘩细胞和组织之间的相关性。
结果:共纳入20项临床前研究。11项临床前研究证明,STAT3在瘢痕疙瘩组织和瘢痕疙瘩成纤维细胞中的表达和磷酸化增强。研究了13种不同的JAK和/或STAT抑制剂。测试药物抑制瘢痕疙瘩的进展,如通过不同的过程证明,包括减少胶原蛋白的产生,细胞增殖和迁移,细胞周期停滞和凋亡增加,增强抗氧化反应,减少(旁分泌)信号,促纤维化基因表达降低。迄今为止,尚未发表临床研究。
结论:临床前研究表明JAK-STAT通路在瘢痕疙瘩发病机制中的作用以及JAK-STAT抑制剂在瘢痕疙瘩治疗中的潜在作用。在人类瘢痕疙瘩皮肤模型中,应进一步研究这些药物对相关生物标志物的影响,优选包括免疫细胞,除了瘢痕疙瘩成纤维细胞和角质形成细胞和临床研究。
Keloid tissues contain inflammatory cells and upregulated pro-inflammatory cytokines. The Janus kinase (JAK)-signal transducer and activator of transcription (
STAT) pathway mediate cellular responses to these cytokines. We performed a systematic
review on the role of the JAK-
STAT pathway in keloid pathogenesis and the evidence for JAK-
STAT inhibitors in keloid treatment. The search combined the terms (1) keloid and (2) JAK or TYK or STAT and included MeSH terms and synonyms. Two reviewers screened the articles and assessed the full texts on eligibility. Data were collected on the tested drugs and molecules, the type of cells and tissues used in the experiments, and study findings on the association between the JAK-STAT pathway and keloid cells and tissues. A total of twenty preclinical studies were included. Eleven preclinical studies proved that STAT3 expression and phosphorylation are enhanced in keloid tissue and keloid fibroblasts. Thirteen different JAK and/or
STAT inhibitors were investigated. Tested drugs inhibited keloid progression as demonstrated by different processes, including reduced collagen production, cell proliferation and migration, increased cell cycle arrest and apoptosis, enhanced antioxidant responses, decreased (paracrine) signalling, and decreased profibrotic gene expression. No clinical studies have been published to date. Preclinical studies indicate a role for the JAK-STAT pathway in keloid pathogenesis and a potential role for JAK-
STAT inhibitors in keloid treatment. The effect of these drugs should be further investigated on relevant biomarkers in a human keloid skin model, preferably including immune cells besides keloid fibroblasts and keratinocytes and in clinical studies.