Phosphodiesterase 4 is overexpressed in human keloids and its inhibition reduces fibroblast activation and skin fibrosis.
Chem Biol Interact
; 402: 111211, 2024 Oct 01.
Article
en En
| MEDLINE
| ID: mdl-39197814
ABSTRACT
There is a pressing medical need for improved treatments in skin fibrosis including keloids and hypertrophic scars (HTS). This study aimed to characterize the role of phosphodiesterase 4 (PDE4), specifically PDE4B in fibrotic skin remodeling in vitro and in vivo. In vitro, effects of PDE4A-D (Roflumilast) or PDE4B (siRNA) inhibition on TGFß1-induced myofibroblast differentiation and dedifferentiation were studied in normal (NHDF) and keloid (KF) human dermal fibroblasts. In vivo, the role of PDE4 on HOCl-induced skin fibrosis in mice was addressed in preventive and therapeutic protocols. PDE4B (mRNA, protein) was increased in Keloid > HTS compared to healthy skin and in TGFß-stimulated NHDF and KF. In Keloid > HTS, collagen Iα1, αSMA, TGFß1 and NOX4 mRNA were all elevated compared to healthy skin confirming skin fibrosis. In vitro, inhibition of PDE4A-D and PDE4B similarly prevented TGFß1-induced Smad3 and ERK1/2 phosphorylation and myofibroblast differentiation, elevated NOX4 protein and proliferation in NHDF. PDE4A-D inhibition enabled myofibroblast dedifferentiation and curbed TGFß1-induced reactive oxygen species and fibroblast senescence. In KF PDE4A-D inhibition restrained TGFß1-induced Smad3 and ERK1/2 phosphorylation, myofibroblast differentiation and senescence. Mechanistically, PDE4A-D inhibition rescued from TGFß1-induced loss in PPM1A, a Smad3 phosphatase. In vivo, PDE4 inhibition mitigated HOCl-induced skin fibrosis in mice in preventive and therapeutic protocols. The current study provides novel evidence evolving rationale for PDE4 inhibitors in skin fibrosis (including keloids and HTS) and delivered evidence for a functional role of PDE4B in this fibrotic condition.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piel
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Fibrosis
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Factor de Crecimiento Transformador beta1
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Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4
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Inhibidores de Fosfodiesterasa 4
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Fibroblastos
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Queloide
Límite:
Animals
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Female
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Humans
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Male
Idioma:
En
Revista:
Chem Biol Interact
Año:
2024
Tipo del documento:
Article
Pais de publicación:
Irlanda