Publication Date
1-1-2024
Journal
PLoS One
DOI
10.1371/journal.pone.0306624
PMID
39240940
PMCID
PMC11379285
PubMedCentral® Posted Date
9-6-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Fibroblasts, Humans, p38 Mitogen-Activated Protein Kinases, Mice, Fibrosis, Scleroderma, Systemic, Bleomycin, Transforming Growth Factor beta1, Pyrimidines, Cell Differentiation, Pyridines, Enzyme Activation, Phosphoinositide-3 Kinase Inhibitors, Skin, Lung
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-β1)-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-β1-stimulated dermal fibroblasts. Finally, PIK-III administration significantly attenuated dermal and lung fibrosis in bleomycin-injured mice.
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Critical Care Commons, Internal Medicine Commons, Medical Sciences Commons, Pulmonology Commons, Sleep Medicine Commons
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