Progressive Pulmonary Fibrosis Is Caused by Elevated Mechanical Tension on Alveolar Stem Cells

Wu, Huijuan; Yu, Yuanyuan; Huang, Huanwei; Hu, Yucheng; Fu, Siling; Zheng, Wei; Shi, Mengting; Zhao, Xi; Yuan, Jie; Li, Jiao; Yang, Xueyi; Bin, Ennan; Dong, Wei; Zhang, Hongbin; Zhang, Jin; Yang, Chun; Cai, Tao; Dai, Huaping; Chen, Jingyu; Tang, Nan

doi:10.1016/j.cell.2019.11.027

Cited by 245 publications

(207 citation statements)

References 50 publications

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“…In one respect, the inability of AT2 cells to carry out proper repair of the injured alveolus can lead to scar formation [85]. In fact, AT2 cells play a central role in the activation of TGFβ, which may be self-perpetuating through the rising tension within a fibrotic lung [91]. Additionally, AT2 cells have diminished capacity for transdifferentiation into AT1 cells in the IPF lungs [5].…”

Section: At2 Dysfunction In Ipfmentioning

confidence: 99%

“…This epithelial-mesenchymal crosstalk is clearly disrupted in IPF such that AT2 cells acquire a profibrotic phenotype to aberrantly secrete profibrotic mediators as paracrine factors that stimulate and activate fibroblasts [24]. In fact, TGFβ is predominantly produced by the epithelium where the integrins needed for activation of the latent form is primarily expressed, and abrogation of TGFβ signaling within the lung epithelium can attenuate lung fibrosis [91,[161][162][163][164]. CTGF is produced by the lung epithelium in response to TGFβ signaling and plays a vital profibrotic role by stimulating collagen deposition by fibroblasts [165][166][167].…”

Section: Altered At2-fibroblast Signaling In Ipfmentioning

confidence: 99%

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Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Parimon

Yao

Stripp

et al. 2020

IJMS

216

135

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: Alveolar epithelial type II cells (AT2) are a heterogeneous population that have critical secretory and regenerative roles in the alveolus to maintain lung homeostasis. However, impairment to their normal functional capacity and development of a pro-fibrotic phenotype has been demonstrated to contribute to the development of idiopathic pulmonary fibrosis (IPF). A number of factors contribute to AT2 death and dysfunction. As a mucosal surface, AT2 cells are exposed to environmental stresses that can have lasting effects that contribute to fibrogenesis. Genetical risks have also been identified that can cause AT2 impairment and the development of lung fibrosis. Furthermore, aging is a final factor that adds to the pathogenic changes in AT2 cells. Here, we will discuss the homeostatic role of AT2 cells and the studies that have recently defined the heterogeneity of this population of cells. Furthermore, we will review the mechanisms of AT2 death and dysfunction in the context of lung fibrosis.

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Section: At2 Dysfunction In Ipfmentioning

confidence: 99%

Section: Altered At2-fibroblast Signaling In Ipfmentioning

confidence: 99%

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Parimon

Yao

Stripp

et al. 2020

IJMS

216

135

View full text Add to dashboard Cite

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“…TGFβ1 is also an important index of brosis and in ammation 28 . Despite this, pulmonary brosis in ARDS mice was also detected after MSCs transplantation 29 .…”

Section: Discussionmentioning

confidence: 99%

Overexpression of TGFβ1 in murine mesenchymal stem cells improves lung inflammation by impacting the Th17/Treg balance in LPS-induced ARDS mice

Chen

Zhang

Xie

et al. 2020

Preprint

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Abstract Background: T helper 17 cells (Th17) /regulatory T cells (Treg), as subtypes of CD4 + T cells, play an important role in the inflammatory response of acute respiratory distress syndrome (ARDS). However, there is still a lack of effective methods to regulate the differentiation balance of Th17/Treg. It was proven that mesenchymal stem cells (MSCs) could regulate the differentiation of CD4 + T cells, but the mechanism is still unclear. TGFβ1, a paracrine cytokine of MSCs, could also regulate the differentiation of Th17/Treg but is lowly expressed in MSCs. Therefore, mouse MSCs (mMSCs) overexpressing TGFβ1 were constructed by lentivirus transfection and intratracheally transplanted into LPS-induced ARDS mice in our study. The aim of this study was to evaluate the therapeutic effects of mMSCs overexpressing TGFβ1 on inflammation and immunoregulation by impacting the Th17/Treg balance in LPS-induced ARDS mice. Methods: mMSCs overexpressing TGFβ1 were constructed using lentiviral vectors. Then, mouse bone-marrow-derived MSCs (mBM-MSC) and mBM-MSC-TGFβ1 (mBM-MSC overexpressing TGFβ1) were transplanted intratracheally into ARDS mice induced by lipopolysaccharide. At 3 d and 7 d after transplantation, the mice were sacrificed, and the homing of the mMSCs was assayed by ex vivo optical imaging. The relative numbers of Th17 and Treg in the lungs and spleens of mice were detected by FCM. IL-17A and IL-10 levels in the lungs of mice were analysed by western blot. Permeability and inflammatory cytokines were evaluated by analysing the protein concentration of BALF using ELISA. Histopathology of the lungs was assessed by haematoxylin and eosin staining and lung injury scoring. Alveolar lung fibrosis was assessed by Masson’s trichrome staining and Ashcroft scoring. The mortality of ARDS mice was followed until 7 days after transplantation. Results: The transduction efficiencies mediated by the lentiviral vectors ranged from 82.3-88.6%. Overexpressing TGF-β1 inhibited the proliferation of mMSCs during days 5-7 ( p <0.05) but had no effect on mMSCs differentiation or migration ( p >0.05). Compared to that in the LPS+mBM-MSC-NC group mice, engraftment of mMSCs overexpressing TGFβ1 led to much more differentiation of T cells into Th17 or Treg ( p <0.05), improved permeability of injured lungs ( p <0.05) and ameliorative histopathology of lung tissue in ARDS mice ( p <0.05). Moreover, IL-17A content was also decreased while IL-10 content was increased in the LPS+mBM-MSC-TGFβ1 group compared with those in the LPS+mBM-MSC-NC group ( p <0.05). Finally, mMSCs overexpressing TGFβ1 did not aggravate lung fibrosis in ARDS mice ( p >0.05). Conclusion: MSCs overexpressing TGFβ1 could regulate lung inflammation and attenuate lung injuries by modulating the imbalance of Th17/Treg in the lungs of ARDS mice.

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“…Controlling extracellular LOXL2 activity is important for decreasing microenvironmental mechanical tension and ECM stiffening in fibrotic alveoli. A recent study demonstrated that elevated mechanical tension in alveoli activates a TGF-β1 signaling loop in alveolar type 2 cells, which drives periphery-tocenter progression of lung fibrosis [38]. Barry-Hamilton and colleagues [21] reported that treatment with LOXL2 inhibitory monoclonal antibody (AB0023) decreased lung fibrosis and the number of activated fibroblasts in murine lungs.…”

Section: Discussionmentioning

confidence: 99%

Significance of nuclear upregulation of LOXL2 in fibroblasts and myofibroblasts in the fibrotic process of acute respiratory distress syndrome

Matsuo

Yanagi

Tsubouchi

et al. 2020

Preprint

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Background: Fibrotic scarring is an important prognostic factor for acute respiratory distress syndrome (ARDS). Lysyl oxidase-like 2 (LOXL2), an amine oxidase, is thought to make an integral contribution to fibrotic scarring by facilitating collagen cross-linking. LOXL2 has also been proposed to epigenetically regulate gene expression to direct cell fate. Recent clinical outcomes demonstrated the ineffectiveness of an inhibitory monoclonal antibody against LOXL2 in patients with organ fibrosis, including fibrosis of the lungs, suggesting that sole targeting of the extracellular activity of LOXL2 is insufficient to prevent fibrotic scarring. Moreover, the involvement of LOXL2 in human ARDS remains unknown. Methods: Expressiondynamics of LOXL2 during the pathological process of bleomycin (BLM)-induced lung injury model were measured by qRT-PCR and western blotting. The principal cell types expressing LOXL2 and its cellular localization were determined by immunohistochemistry and confocal microscopy. Mlg 2908, a murine lung fibroblast line, was transfected with LOXL2 siRNA or control siRNA, and then assessed for transforming growth factor (TGF)-β1-induced Axin2+ myofibrogenic progenitor (AMP) marker expression, actin filament expression, myofibroblast differentiation, collagen expression, and alteration of the TGF-β1/Smad/Snail pathway by phalloidin staining, qRT-PCR, western blotting, and immunocytochemistry. Levels of LOXL2 in bronchoalveolar lavage fluid (BALF) in patients with ARDS and control subjects were measured by enzyme-linked immunosorbent assay.Results: LOXL2 expression was elevated in lung tissue in the fibrotic phase after injury. Nuclear upregulation of LOXL2 in fibroblasts and myofibroblasts, as well as nuclear upregulation of Snail in myofibroblasts, was evident in fibrotic lung tissue after injury. LOXL2 knockdown blocked TGF-β1induced AMP marker expression, appearance of proto-myofibroblasts, evolution of differentiated myofibroblasts, collagen expression, and pSmad2/Snail induction in lung fibroblasts. We detected high levels of LOXL2 protein in the BALF from patients with ARDS, specifically during the fibrotic phase.Conclusions: Our results revealed that nuclear LOXL2 is upregulated in lung fibroblasts and myofibroblasts after injury and is required for generation of myofibroblast and maintenance of AMP.

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Progressive Pulmonary Fibrosis Is Caused by Elevated Mechanical Tension on Alveolar Stem Cells

Cited by 245 publications

References 50 publications

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Alveolar Epithelial Type II Cells as Drivers of Lung Fibrosis in Idiopathic Pulmonary Fibrosis

Overexpression of TGFβ1 in murine mesenchymal stem cells improves lung inflammation by impacting the Th17/Treg balance in LPS-induced ARDS mice

Significance of nuclear upregulation of LOXL2 in fibroblasts and myofibroblasts in the fibrotic process of acute respiratory distress syndrome

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