Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease whose molecular pathogenesis remainsunclear. In a recent paper, we demonstrated a key role for the PI3K pathway in both proliferation and differentiation intomyofibroblasts of normal human lung fibroblasts treated with TGF-b. In this research, we assessed the expression of classI PI3K p110 isoforms in IPF lung tissue as well as in tissue-derived fibroblast cell lines. Moreover, we investigated thein vitro effects of the selective inhibition of p110 isoforms on IPF fibroblast proliferation and fibrogenic activity. IHC wasperformed on normal and IPF lung tissue. Expression levels of PI3K p110 isoforms were evaluated by western blot andflow cytometry analysis. Fibroblast cell lines were established from both normal and IPF tissue and the effects of selectivepharmacological inhibition as well as specific gene silencing by small interfering RNAs were studied in vitro. No significantdifferences between normal and IPF tissue/tissue-derived fibroblasts were observed for the expression of PI3K p110 a, band d isoforms whereas p110g was more greatly expressed in both IPF lung homogenates and ex vivo fibroblast cell lines.Myofibroblasts and bronchiolar basal cells in IPF lungs exhibited strong immunoreactivity for p110g. Positive staining forthe markers of proliferation proliferating cell nuclear antigen and cyclin D1 was also shown in cells of fibrolastic foci.Furthermore, both p110g pharmacological inhibition and gene silencing were able to significantly inhibit proliferationrate as well as a-SMA expression in IPF fibroblasts. Our data suggest that PI3K p110g isoform may have an important rolein the etio-pathology of IPF and can be a specific pharmacological target.Laboratory Investigation advance online publication, 25 February 2013; doi:10.1038/labinvest.2013.6

PI3K p110γ overexpression in idiopathic pulmonary fibrosis lung tissue and fibroblast cells: in vitro effects of its inhibition

Fagone E;LO FURNO, DEBORA;GIUFFRIDA, Rosario;CRIMI, Nunzio;VANCHERI, CARLO
2013-01-01

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease whose molecular pathogenesis remainsunclear. In a recent paper, we demonstrated a key role for the PI3K pathway in both proliferation and differentiation intomyofibroblasts of normal human lung fibroblasts treated with TGF-b. In this research, we assessed the expression of classI PI3K p110 isoforms in IPF lung tissue as well as in tissue-derived fibroblast cell lines. Moreover, we investigated thein vitro effects of the selective inhibition of p110 isoforms on IPF fibroblast proliferation and fibrogenic activity. IHC wasperformed on normal and IPF lung tissue. Expression levels of PI3K p110 isoforms were evaluated by western blot andflow cytometry analysis. Fibroblast cell lines were established from both normal and IPF tissue and the effects of selectivepharmacological inhibition as well as specific gene silencing by small interfering RNAs were studied in vitro. No significantdifferences between normal and IPF tissue/tissue-derived fibroblasts were observed for the expression of PI3K p110 a, band d isoforms whereas p110g was more greatly expressed in both IPF lung homogenates and ex vivo fibroblast cell lines.Myofibroblasts and bronchiolar basal cells in IPF lungs exhibited strong immunoreactivity for p110g. Positive staining forthe markers of proliferation proliferating cell nuclear antigen and cyclin D1 was also shown in cells of fibrolastic foci.Furthermore, both p110g pharmacological inhibition and gene silencing were able to significantly inhibit proliferationrate as well as a-SMA expression in IPF fibroblasts. Our data suggest that PI3K p110g isoform may have an important rolein the etio-pathology of IPF and can be a specific pharmacological target.Laboratory Investigation advance online publication, 25 February 2013; doi:10.1038/labinvest.2013.6
2013
fibroblasts; IPF; lung tissue; myofibroblasts; PI3K p110g
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11769/39655
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