PIK-III exerts anti-fibrotic effects in activated fibroblasts by regulating p38 activation.
PLoS One
; 19(9): e0306624, 2024.
Article
in En
| MEDLINE
| ID: mdl-39240940
ABSTRACT
Systemic sclerosis (SSc), also known as scleroderma, is an autoimmune-driven connective tissue disorder that results in fibrosis of the skin and internal organs such as the lung. Fibroblasts are known as the main effector cells involved in the progression of SSc through the induction of extracellular matrix (ECM) proteins and myofibroblast differentiation. Here, we demonstrate that 4'-(cyclopropylmethyl)-N2-4-pyridinyl-[4,5'-bipyrimidine]-2,2'-diamine (PIK-III), known as class III phosphatidylinositol 3-kinase (PIK3C3/VPS34) inhibitor, exerts potent antifibrotic effects in human dermal fibroblasts (HDFs) by attenuating transforming growth factor-beta 1 (TGF-ß1)-induced ECM expression, cell contraction and myofibroblast differentiation. Unexpectedly, neither genetic silencing of PIK3C3 nor other PIK3C3 inhibitors (e.g., SAR405 and Autophinib) were able to mimic PIK-III-mediated antifibrotic effect in dermal fibroblasts, suggesting that PIK-III inhibits fibroblast activation through another signaling pathway. We identified that PIK-III effectively inhibits p38 activation in TGF-ß1-stimulated dermal fibroblasts. Finally, PIK-III administration significantly attenuated dermal and lung fibrosis in bleomycin-injured mice.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Fibrosis
/
P38 Mitogen-Activated Protein Kinases
/
Fibroblasts
Limits:
Animals
/
Humans
Language:
En
Journal:
PLoS ONE (Online)
/
PLoS One
/
PLos ONE
Journal subject:
CIENCIA
/
MEDICINA
Year:
2024
Document type:
Article
Affiliation country:
Estados Unidos
Country of publication:
Estados Unidos