TY - JOUR T1 - Role of phosphatidylinositol-3-kinase (PI3K) in TGF-β-induced proliferation and differentiation of human lung fibroblasts into myofibroblasts JF - European Respiratory Journal JO - Eur Respir J VL - 38 IS - Suppl 55 SP - p2005 AU - Enrico Conte AU - Mary Fruciano AU - Evelina Fagone AU - Elisa Gili AU - Maria Iemmolo AU - Nunzio Crimi AU - Carlo Vancheri Y1 - 2011/09/01 UR - http://erj.ersjournals.com/content/38/Suppl_55/p2005.abstract N2 - Molecular mechanisms and pathogenesis of idiopathic pulmonary fibrosis (IPF) remain unclear yet TGF-β-induced differentiation and proliferation of fibroblasts/myofibroblasts are recognized as primary events.We investigated the role of PI3K/Akt pathway in TGF-β-induced proliferation of human lung fibroblasts and their differentiation into myofibroblasts. Moreover, we evaluated the expression of all PI3K class I p100 isoforms (α, β, δ and γ). By using selective inhibitors, we also dissected the functional role of these isoforms.Ex-vivo human lung fibroblasts were stimulated with TGF-β in the presence or absence of PI3Ks pan-inhibitor LY294002 as well as of selective inhibitors. Cell proliferation was evaluated by cell counts and WST-1 proliferation assay. Western blot analysis and the Sircol assay were used for assessing a-Smooth Actin (SMA) expression and collagen production, respectively. RNA messenger and protein levels of p100 isoforms were evaluated by Q-RT-PCR and western blot analysis, respectively.Here we show that LY294002 was able to abrogate the TGF-β-induced increase in cell proliferation,α-SMA expression and collagen production besides to inhibit Akt phosphorylation, thus demonstrating the central role of PI3K/Akt pathway in TGF-β-induced lung fibroblast proliferation and differentiation. Moreover, we show that PI3K p110δ and p100γ are functionally expressed in human lung fibroblasts, in addition to the ubiquitously expressed p100α and p110β. Finally, we demonstrate a major role of p110γ and p100α in the fibrotic process.Overall, these results suggest that specific class I PI3K isoforms can be pharmacological targets in IPF. ER -