Table 4.

Biological functions of PTEN in the development of pulmonary fibrosis.

Study type	Model/sample	Impact on PTEN	Additional signaling	Biological process	Ref.
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]