Kilmister Ethan J, Paterson Claudia, Brasch Helen D, Davis Paul F, Tan Swee T
Gillies McIndoe Research Institute, Wellington, New Zealand.
Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Wellington, New Zealand.
Front Surg. 2019 Nov 26;6:67. doi: 10.3389/fsurg.2019.00067. eCollection 2019.
Keloid disorder (KD) is a fibroproliferative condition characterized by excessive dermal collagen deposition in response to wounding and/or inflammation of the skin. Despite intensive research, treatment for KD remains empirical and unsatisfactory. Activation of the renin-angiotensin system (RAS) leads to fibrosis in various organs through its direct effect and the resultant hypertension, and activation of the immune system. The observation of an increased incidence of KD in dark-skinned individuals who are predisposed to vitamin D deficiency (VDD) and hypertension, and the association of KD with hypertension and VDD, all of which are associated with an elevated activity of the RAS, provides clues to the pathogenesis of KD. There is increasing evidence implicating embryonic-like stem (ESC) cells that express ESC markers within keloid-associated lymphoid tissues (KALTs) in keloid lesions. These primitive cells express components of the RAS, cathepsins B, D, and G that constitute bypass loops of the RAS, and vitamin D receptor (VDR). This suggests that the RAS directly, and through signaling pathways that converge on the RAS, including VDR-mediated mechanisms and the immune system, may play a critical role in regulating the primitive population within the KALTs. This review discusses the role of the RAS, its relationship with hypertension, vitamin D, VDR, VDD, and the immune system that provide a microenvironmental in regulating the ESC-like cells within the KALTs. These ESC-like cells may be a novel therapeutic target for the treatment of this enigmatic and challenging condition, by modulating the RAS using inhibitors of the RAS and its bypass loops and convergent signaling pathways.
瘢痕疙瘩病症（KD）是一种纤维增生性疾病，其特征是皮肤受伤和/或发炎后真皮胶原蛋白过度沉积。尽管进行了深入研究，但KD的治疗仍然是经验性的且不尽人意。肾素-血管紧张素系统（RAS）的激活通过其直接作用以及由此产生的高血压和免疫系统激活，导致各个器官发生纤维化。在易患维生素D缺乏症（VDD）和高血压的深色皮肤个体中，KD发病率增加，以及KD与高血压和VDD之间的关联，所有这些都与RAS活性升高有关，这为KD的发病机制提供了线索。越来越多的证据表明，瘢痕疙瘩相关淋巴组织（KALTs）内表达胚胎干细胞（ESC）标志物的类胚胎干细胞存在于瘢痕疙瘩病变中。这些原始细胞表达RAS的成分、组织蛋白酶B、D和G（它们构成RAS的旁路环）以及维生素D受体（VDR）。这表明RAS可能直接以及通过汇聚于RAS的信号通路（包括VDR介导的机制和免疫系统）在调节KALTs内的原始细胞群中起关键作用。本综述讨论了RAS的作用、其与高血压、维生素D、VDR、VDD以及免疫系统之间的关系，这些因素在调节KALTs内的类ESC细胞方面提供了一个微环境。通过使用RAS及其旁路环和汇聚信号通路的抑制剂调节RAS，这些类ESC细胞可能是治疗这种神秘且具有挑战性疾病的新治疗靶点。
