PIK-III exerts anti-fibrotic effects in activated fibroblasts by regulating p38 activation

• Published in: PloS one 2024-09, Vol.19 (9), p.e0306624
• Main Authors: Sanchez, Santiago, McDowell-Sanchez, Aaron K, Al-Meerani, Sharaz B, Cala-Garcia, Juan D, Waich Cohen, Alan R, Ochsner, Scott A, McKenna, Neil J, Celada, Lindsay J, Wu, Minghua, Assassi, Shervin, Rosas, Ivan O, Tsoyi, Konstantin
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Analysis; Animals; Antibodies; Biopsy; Bleomycin; Bone morphogenetic proteins; Care and treatment; Cell differentiation; Cell Differentiation - drug effects; Collagen; Connective tissue diseases; Connective tissues; Diagnosis; Diamines; Differentiation; Effector cells; Enzyme Activation - drug effects; Extracellular matrix; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - pathology; Fibrosis; Gene expression; Growth factors; Health aspects; Humans; Kinases; Lung - drug effects; Lung - metabolism; Lung - pathology; Lungs; Mice; Mortality; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Phosphorylation; Proteins; Pulmonary fibrosis; Pyridines - pharmacology; Pyrimidines - pharmacology; Scleroderma; Scleroderma (Disease); Scleroderma, Systemic - genetics; Scleroderma, Systemic - metabolism; Scleroderma, Systemic - pathology; Signal transduction; Skin; Skin - drug effects; Skin - metabolism; Skin - pathology; Systemic scleroderma; Systemic sclerosis; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Transforming growth factors
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0306624

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.