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Study type | Model/sample | Impact on PTEN | Additional signaling | Biological process | Ref. |
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In vivo | Myeloid PTEN-deficient mice/bleomycin | Loss of PTEN expression | Sustained activation of PI3K pathway | Increased TGF-β1 activation, collagen deposition; reduced number of macrophages and T-cells | [93] |
In vivo/in vitro | Human IPF lung tissue; IPF lung tissue; C57BL/6 and A549 cells/bleomycin | Loss of PTEN | P21WAF1, P16ink4, and SA-β-gal overexpression; NF-κB and Akt activation | Alveolar epithelial cell senescence promotes lung fibrosis | [94, 95] |
In vivo/in vitro | Human lung tissue; C57BL/6 embryonic mouse fibroblasts and 3T3 murine fibroblasts/TGF-β1; C57BL/6 mice/bleomycin | Diminished PTEN expression and phosphatase activity | Inhibition of PTEN activity in IPF-derived fibroblasts | α-SMA expression, cell proliferation, collagen production, and myofibroblast differentiation | [97] |
In vivo/in vitro | Primary fibroblast cell lines from IPF and healthy lung/type I collagen–rich matrix; PTEN haploinsufficient and wild-type mice/bleomycin | High phosphatase activity in normal lung fibroblasts, but low activity in IPF-derived fibroblasts | Aberrant activation of the PI3K–Akt–S6K1 signaling pathway in IPF-derived fibroblasts | Enhanced the proliferation of primary lung fibroblasts | [99] |
In vitro | Fibroblasts and myofibroblasts from patients with IPF; MRC-5 cells/H2O2 | Loss of PTEN expression | Activated the TGF-β1 pathway and increased hyaluronan synthase 2 expression | Increased proliferation, apoptosis resistance, and migration/invasion activities | [100] |
In vivo/in vitro | Human IPF lung tissue; MRC-5 cells/TGF-β1 | PTEN ubiquitination and degradation | Downregulation of ubiquitin-specific peptidase 13 (USP13) | Enhanced proliferative, migratory, and invasive capacities of lung fibroblasts | [101] |
In vivo/in vitro | Human IPF lung tissue; HFL-I cells/TGF-β1 | Low expression of PTEN | Enhanced PI3K/Akt and TGF-β/Smad3 signaling | PTEN inhibited the proliferation and myofibroblast differentiation and promoted the apoptosis of fibroblasts | [102] |
In vitro | Human lung fibroblasts CCL-210/mechanical stretch | Increased PTEN activity | Decreased Akt phosphorylation | Promoted fibroblast apoptosis | [106] |
In vitro | Primary IPF-derived and normal fibroblasts/polymerized type I collagen | Low phosphatase activity | High Akt activity promoted the inactivation of FoxO3a and downregulation of p27 in IPF-derived fibroblasts | Facilitated fibroblast proliferation | [107] |
In vitro | Primary control and IPF-derived lung fibroblasts/polymerized type I collagen | Low phosphatase activity | Inactivation of FoxO3a, which downregulated caveolin-1 and Fas expression | Apoptosis-resistant phenotype of IPF-derived fibroblasts | [108] |
In vitro | Primary IPF-derived lung fibroblasts/polymerized type I collagen | Decreased phosphatase activity | Enhanced p-mTOR expression along with low expression of LC3-2 and FoxO3a | Suppressed autophagic activity | [109, 110] |
In vivo/in vitro | Primary human alveolar epithelial type II (AEII) cells; small-airway epithelial cells/mechanical stretch | Downregulation of PTEN | miR-19a overexpression | Development of the EMT phenotype and lung fibrosis | [111] |
In vitro | Murine embryonic fibroblasts/LPS | Low PTEN expression | Upregulation of TLR4 and PI3K/Akt pathway activation | Increased fibroblast proliferation | [112] |
In vitro | Primary IPF-derived lung fibroblasts; normal human fetal lung fibroblasts (IMR-90) | Low PTEN expression and phosphatase activity | Loss of α4β1 signaling | Migratory/invasive phenotype of fibroblasts | [113] |
In vitro | IMR-90 cells; murine embryonic fibroblasts/prostaglandin E2 | Increased PTEN phosphatase activity by decreasing the phosphorylation of PTEN | E-prostanoid (EP) 2 receptor | Inhibited fibroblast migration | [115] |
In vivo/in vitro | Human embryo lung fibroblasts/silica | Loss of PTEN expression due to hypermethylation of its promoter | MAPK and c-Jun methylation | | [116] |
In vitro | Deletion of PTEN or both PTEN and CCN2 in mouse fibroblasts | Loss of PTEN expression | Overproduction of collagen type I and connective tissue growth factor (CCN2) | Collagen deposition | [117] |
In vitro | Epithelial H358 cells; normal human adult lung fibroblasts CC2512 and primary mouse lung fibroblasts /unphosphorylated PTEN/TGF-β1 | Loss of PTEN enzymatic activity via phosphorylation of its C-terminus; retention of enzymatic activity in PTEN4A-treated cells | Suppression of β-catenin translocation by PTEN4A treatment | PTEN4A inhibits ECM production | [118] |
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