TGF-β drives myofibroblast activation and inflammatory mediator production in vulvar lichen sclerosus

Sarah A. Fischer BS , Zahra Mahamed MS , Ashley Updike BS , Briana Boachie BS , Caitriona Greene BS , Ruth Agwaze BS , Kira Parr BS , Tanzy Love PhD , Adrienne D. Bonham MD , Mitchell A. Linder MD , Megan L. Falsetta PhD
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Abstract

Objective

Vulvar lichen sclerosus (VLS) is a chronic inflammatory skin condition characterized by whitening of the external genitalia, debilitating pruritus (itching), and pain. As disease advances, loss of labia, burying of vulvar anatomy (ie, clitoris, urethra, vaginal opening), and vulvar cancer can occur, yet mechanistic understanding of these events remains limited. VLS lesions appear visibly similar to scars and are frequently referred to as such. Therefore, we investigated the role of fibrosis in the VLS disease mechanism with the goal of identifying targets for new therapeutic and diagnostic strategies.

Study design

6-mm biopsies were collected from 8 participants with VLS from regions of the vulva visibly affected by lichen sclerosus (“scarred”) and adjacent unaffected areas (“unscarred”), allowing each patient to serve as their own control thus diminishing biological noise. Specimens were also used to establish fibroblast strains, and cells were stimulated with TGF-β to assess fibroblast-to-myofibroblast transitions, extracellular matrix (ECM) production, and inflammatory responses in scarred versus unscarred areas.

Results

Fibroblasts from scarred areas expressed higher levels of cytoskeletal proteins (alpha-smooth muscle actin) and inflammatory mediators (interleukin 6, prostaglandin E2) upon TGF-β stimulation compared to their unscarred counterparts. Treatment with SB-431542, a TGF-β receptor inhibitor, quelled these responses (P≤.05), indicating that these effects are mediated through the TGF-β pathway. Fibroblasts isolated from scarred tissues exhibit myofibroblast morphologies, but so do fibroblasts from unscarred areas.

Conclusion

TGF-β activates myofibroblasts and exacerbates inflammation in VLS cells from scarred areas. However, fibroblasts from both scarred and unscarred areas show similarities in morphology and ECM production, suggesting molecular changes may occur in VLS skin before visible changes are detected, which could lead to new diagnostic strategies to treat disease before irreversible architectural changes occur.
TGF-β驱动外阴硬化地衣肌成纤维细胞活化和炎症介质产生
目的:硬化性地衣(VLS)是一种慢性炎症性皮肤病,其特征是外生殖器变白,虚弱性瘙痒(瘙痒)和疼痛。随着疾病的进展,可能发生阴唇丧失、外阴解剖(即阴蒂、尿道、阴道口)埋藏和外阴癌,但对这些事件的机制了解仍然有限。VLS病变看起来与疤痕明显相似,经常被称为疤痕。因此,我们研究了纤维化在VLS疾病机制中的作用,目的是确定新的治疗和诊断策略的靶点。研究设计从8名VLS患者的外阴明显受硬化地衣影响的区域(“瘢痕”)和邻近未受影响的区域(“未瘢痕”)收集6毫米活检,允许每个患者作为自己的对照,从而减少生物噪音。标本也用于建立成纤维细胞株,并用TGF-β刺激细胞,以评估疤痕区与未疤痕区成纤维细胞向肌成纤维细胞的转变、细胞外基质(ECM)的产生和炎症反应。结果疤痕区成纤维细胞在TGF-β刺激下表达更高水平的细胞骨架蛋白(α -平滑肌肌动蛋白)和炎症介质(白细胞介素6、前列腺素E2)。TGF-β受体抑制剂SB-431542可以抑制这些反应(P≤0.05),表明这些作用是通过TGF-β途径介导的。从瘢痕组织分离的成纤维细胞表现为肌成纤维细胞形态,但从未瘢痕组织分离的成纤维细胞也表现为肌成纤维细胞形态。结论tgf -β可激活瘢痕区VLS细胞的肌成纤维细胞并加重炎症反应。然而,疤痕和未疤痕区域的成纤维细胞在形态和ECM产生方面表现出相似性,这表明在检测到可见变化之前,VLS皮肤可能发生了分子变化,这可能导致在不可逆的结构变化发生之前治疗疾病的新诊断策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
AJOG global reports
AJOG global reports Endocrinology, Diabetes and Metabolism, Obstetrics, Gynecology and Women's Health, Perinatology, Pediatrics and Child Health, Urology
CiteScore
1.20
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