A Profibrotic Phenotype in Naïve and in Fibrotic Lung Myofibroblasts Is Governed by Modulations in Thy-1 Expression and Activation

Cohen, Pazit Y.; Breuer, Raphael; Wallach-Dayan, Shulamit B.

doi:10.1155/2018/4638437

Cited by 8 publications

(9 citation statements)

References 73 publications

(96 reference statements)

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“…In bleomycin-induced pulmonary fibrosis, integrin β3 expression is particularly enhanced in mesenchymal stromal cells. In normal Thy-1(+) lung fibroblasts, Thy-1 interacts with integrin αvβ3 to inhibit collagen-induced cell activation [31,32]. Meanwhile, studies have confirmed that loss of Thy-1 expression leads to the activation of integrin β3 and the downstream FAK/ PI3K/ Rac1 signaling pathway [35,36].…”

Section: Discussionmentioning

confidence: 98%

“…As a membrane-bound glycoprotein, Thy-1 is also an important regulator of cell-cell and cell-matrix interactions, activates intracellular signaling pathways, and affects a variety of cellular functions such as cell proliferation, differentiation, and survival [29,30]. Thy-1 is inversely associated with phenotypic characteristics in fibrosis and considered a "fibrosis suppressor gene" [31]. Several studies have suggested that the absence of Thy-1 in lung fibroblasts correlates with pulmonary fibrosis [32,33], Fig.…”

Section: Discussionmentioning

confidence: 99%

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Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis

Wan

Xie

et al. 2019

Laboratory Investigation

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ARTICLEThy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis Abstract Lipopolysaccharide (LPS)-induced autophagy inhibition in lung fibroblasts is closely associated with the activation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K-Akt-mTOR) pathway. However, the underlying mechanism remains unknown. In this study, we demonstrated that LPS activated the PI3K-Akt-mTOR pathway and inhibited lung fibroblast autophagy by depleting thymocyte differentiation antigen-1 (Thy-1) and upregulating integrin β3 (Itgb3). Challenge of the human lung fibroblast MRC-5 cell line with LPS resulted in significant upregulation of integrin β3, activation of the PI3K-Akt-mTOR pathway and inhibition of autophagy, which could be abolished by integrin β3 silencing by specific shRNA or treatment with the integrin β3 inhibitor cilengitide. Meanwhile, LPS could inhibit Thy-1 expression accompanied with PI3K-Akt-mTOR pathway activation and lung fibroblast autophagy inhibition; these effects could be prevented by Thy-1 overexpression. Meanwhile, Thy-1 downregulation with Thy-1 shRNA could mimic the effects of LPS, inducing the activation of PI3K-Akt-mTOR pathway and inhibiting lung fibroblast autophagy. Furthermore, protein immunoprecipitation analysis demonstrated that LPS reduced the binding of Thy-1 to integrin β3. Thy-1 downregulation, integrin β3 upregulation and autophagy inhibition were also detected in a mouse model of LPS-induced pulmonary fibrosis, which could be prohibited by intratracheal injection of Thy-1 overexpressing adeno-associated virus (AAV) or intraperitoneal injection of the integrin β3 inhibitor cilengitide. In conclusion, this study demonstrated that Thy-1 depletion and integrin β3 upregulation are involved in LPS-induced pulmonary fibrosis, and may serve as potential therapeutic targets for pulmonary fibrosis.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis

Wan

Xie

et al. 2019

Laboratory Investigation

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“…Myofibroblast isolation from fibrotic mouse lungs has been described by us in detail previously [37,38]. As detailed, the myofibroblast profile was confirmed by the elevated expression of α-smooth muscle actin [39]. The cells were cultured in RPMI 1640 Medium supplemented with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts

Nareznoi

Konikov-Rozenman

Petukhov

et al. 2020

Cells

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A prominent feature of obstructed tissue regeneration following injury in general, and fibrotic lung tissue in particular, is fibroblast proliferation and accumulation. The Fas/FasL apoptotic pathway has been shown to be involved in human idiopathic pulmonary fibrosis (IPF) and bleomycin-induced lung fibrosis in rodents. We previously showed that in normal injury repair, myofibroblasts’ accumulation is followed by their decline by FasL+ T cell-induced cell death. In pathological lung fibrosis, myofibroblasts resist cell death and accumulate. Like other members of the tumor necrosis factor (TNF) family, membrane-bound FasL can be cleaved from the cell surface to generate a soluble form (sFasL). Metalloproteinases (MMPs) are known to convert the membrane-bound form of FasL to sFasL. MMP-7 knockout (KO) mice were shown to be protected from bleomycin (BLM)-induced lung fibrosis. In this study, we detected increased levels of sFasL in their blood serum, as in the lungs of patients with IPF, and IPF-lung myofibroblast culture medium. In this study, using an MMP-inhibitor, we showed that sFasL is decreased in cultures of IPF-lung myofibroblasts and BLM-treated lung myofibroblasts, and in the blood serum of MMP-7KO mice. Moreover, resistant fibrotic-lung myofibroblasts, from the lungs of humans with IPF and of BLM-treated mice, became susceptible to T-cell induced cell death in a co-culture following MMP-inhibition- vs. control-treatment or BLM-treated MMP-7KO vs. wild-type mice, respectively. sFasL may be an unrecognized mechanism for MMP-7-mediated decreased tissue regeneration following injury and the evolution of lung fibrosis.

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“…As we described previously, we sorted out by FACS cell sorter [19], annexin-V-negative, bleomycin-treated MLEs [1] and quantified proliferation by BrdU uptake [23]. Briefly, FITC-conjugated annexin-V (BD Pharmingen, Franklin Lakes, NJ, USA), was added to 0.5 × 10 6 MLE adherent cells in the culture flask (1 μg, 30 min).…”

Section: Methodsmentioning

confidence: 99%

Increased Regeneration Following Stress-Induced Lung Injury in Bleomycin-Treated Chimeric Mice with CD44 Knockout Mesenchymal Cells

Petukhov

Richter-Dayan

Fridlender

et al. 2019

Cells

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CD44, an adhesion-molecule promoting cell-migration, is shown here to increase in stress conditions following bleomycin-induced apoptosis in alveolar epithelial cells (AECs), a main target of lung injury. In vivo, it inhibits tissue regeneration and leads to fibrosis. We show that some AECs survive by the ataxia-telangiectasia mutated kinase/ATM pathway, and undergo a CD44-mediated epithelial-mesenchymal transdifferentiation (EMT) with migratory capacities in vitro, and in vivo. We assessed apoptosis vs. proliferation of AECs following bleomycin, ATM/P53 signaling pathway in AECs, and CD44 involvement in EMT, cell motility and tissue regeneration in vitro and in vivo. Expression of survival genes, CD44, and ATM/p53 pathway was elevated in AECs surviving bleomycin injury, as were the markers of EMT (downregulation of E-cadherin, upregulation of N-cadherin and vimentin, nuclear translocation of β-catenin). Inhibition of CD44 decreased AECs transdifferentiation. Bleomycin-treated chimeric CD44KO-mice had decreased EMT markers, ATM, and mesenchymal cells (α-SMA+) accumulation in lung, increased surfactant-b, diminished lung mesenchymal cell motility, and increased lung tissue regenerative capacity following bleomycin injury, as indicated by lung collagen content and semiquantitave morphological index scoring. Thus, AECs surviving lung injury are plastic and undergo ATM-mediated, CD44-dependent transdifferentiation, preventing tissue regeneration and promoting fibrosis. Synthetic or natural compounds that downregulate CD44 may improve tissue regeneration following injury.

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A Profibrotic Phenotype in Naïve and in Fibrotic Lung Myofibroblasts Is Governed by Modulations in Thy-1 Expression and Activation

Cited by 8 publications

References 73 publications

Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis

Thy-1 depletion and integrin β3 upregulation-mediated PI3K-Akt-mTOR pathway activation inhibits lung fibroblast autophagy in lipopolysaccharide-induced pulmonary fibrosis

Matrix Metalloproteinases Retain Soluble FasL-mediated Resistance to Cell Death in Fibrotic-Lung Myofibroblasts

Increased Regeneration Following Stress-Induced Lung Injury in Bleomycin-Treated Chimeric Mice with CD44 Knockout Mesenchymal Cells

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