磷酸二酯酶 4 在瘢痕表皮疤痕中过度表达,抑制磷酸二酯酶 4 可减少角质细胞纤维化改变。

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Medicine Pub Date : 2024-09-02 DOI:10.1186/s10020-024-00906-8
Javier Milara, Pilar Ribera, Severiano Marín, Paula Montero, Inés Roger, Julio Cortijo
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引用次数: 0

摘要

背景:表皮重塑和肥厚是皮肤纤维化疾病的特征,角质细胞向间充质(EMT)的类似转化推动了瘢痕疙瘩和增生性疤痕(HTS)等皮肤纤维化中表皮的改变。虽然磷酸二酯酶4(PDE4)抑制剂在各种纤维化疾病中显示出了有效性,但它们在皮肤纤维化中的作用还不完全清楚。本研究旨在探索 PDE4B 在皮肤纤维化过程中表皮重塑和肥厚中的特殊作用:体外实验研究了抑制 PDE4A-D(使用罗氟司特)或 PDE4B(使用 siRNA)对 TGFβ1 诱导的人三维表皮 EMT 分化和去分化的影响。体内研究采用预防和治疗方法调查了 PDE4 抑制对 HOCl 诱导的小鼠皮肤纤维化和表皮肥厚的影响:研究发现,与健康表皮相比,瘢痕疙瘩 > HTS 表皮中的 PDE4B(mRNA、蛋白质)水平以及 TGFβ 刺激的三维表皮中的 PDE4B(mRNA、蛋白质)水平均有所提高。瘢痕疙瘩和HTS表皮的胶原蛋白Iα1、纤连蛋白、αSMA、N-钙粘连蛋白和NOX4 mRNA水平升高,而E-钙粘连蛋白和ZO-1水平下降,证实了EMT过程。抑制 PDE4A-D 和 PDE4B 可阻止 TGFβ1 诱导的 Smad3 和 ERK1/2 磷酸化以及体外间质分化。抑制 PDE4A-D 还能促进间质的去分化,并通过挽救 Smad3 磷酸酶 PPM1A 减少 TGFβ1 诱导的 ROS 和角质形成细胞的衰老。在体内,PDE4抑制剂可在预防和治疗两种情况下减轻HOCl诱导的小鼠表皮肥厚:总之,该研究支持 PDE4 抑制剂(尤其是 PDE4B)在治疗皮肤纤维化(包括瘢痕疙瘩和 HTS)方面的潜力,并揭示了它们在这种情况下的功能性作用。
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Phosphodiesterase 4 is overexpressed in keloid epidermal scars and its inhibition reduces keratinocyte fibrotic alterations.

Background: Epidermal remodeling and hypertrophy are hallmarks of skin fibrotic disorders, and keratinocyte to mesenchymal (EMT)-like transformations drive epidermis alteration in skin fibrosis such as keloids and hypertrophic scars (HTS). While phosphodiesterase 4 (PDE4) inhibitors have shown effectiveness in various fibrotic disorders, their role in skin fibrosis is not fully understood. This study aimed to explore the specific role of PDE4B in epidermal remodeling and hypertrophy seen in skin fibrosis.

Methods: In vitro experiments examined the effects of inhibiting PDE4A-D (with Roflumilast) or PDE4B (with siRNA) on TGFβ1-induced EMT differentiation and dedifferentiation in human 3D epidermis. In vivo studies investigated the impact of PDE4 inhibition on HOCl-induced skin fibrosis and epidermal hypertrophy in mice, employing both preventive and therapeutic approaches.

Results: The study found increased levels of PDE4B (mRNA, protein) in keloids > HTS compared to healthy epidermis, as well as in TGFβ-stimulated 3D epidermis. Keloids and HTS epidermis exhibited elevated levels of collagen Iα1, fibronectin, αSMA, N-cadherin, and NOX4 mRNA, along with decreased levels of E-cadherin and ZO-1, confirming an EMT process. Inhibition of both PDE4A-D and PDE4B prevented TGFβ1-induced Smad3 and ERK1/2 phosphorylation and mesenchymal differentiation in vitro. PDE4A-D inhibition also promoted mesenchymal dedifferentiation and reduced TGFβ1-induced ROS and keratinocyte senescence by rescuing PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced epidermal hypertrophy in mice in both preventive and therapeutic settings.

Conclusions: Overall, the study supports the potential of PDE4 inhibitors, particularly PDE4B, in treating skin fibrosis, including keloids and HTS, shedding light on their functional role in this condition.

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来源期刊
Molecular Medicine
Molecular Medicine 医学-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
137
审稿时长
1 months
期刊介绍: Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.
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