Lysyl oxidase promotes bleomycin-induced lung fibrosis through modulating inflammation

Cheng, Tao; Liu, Qingbo; Zhang, Rui; Zhang, Ying; Chen, Jianfeng; Yu, Ronghuan; Ge, Gaoxiang

doi:10.1093/jmcb/mju039

Cited by 60 publications

(38 citation statements)

References 38 publications

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“…A recent study in muscular fiber development identified LOXL3 as an enhancer and key regulator of integrin signaling, supporting the role of LOXL3 in pro-fibrotic signaling pathways 34 . Moreover, LOX inhibition was shown to be efficacious in early inflammatory phases of the Bleomycin-induced fibrosis model, suggesting that a LOX inhibitory component in an anti-fibrotic treatment approach could be beneficial 35 . Therefore, a detailed evaluation of the potential of dual LOX/LOXL2 or LOXL2/LOXL3 targeting should be conducted in future studies.…”

Section: Discussionmentioning

confidence: 99%

Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis

Aumiller

Strobel

Romeike

et al. 2017

Sci Rep

110

101

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Extracellular matrix (ECM) composition and stiffness are major driving forces for the development and persistence of fibrotic diseases. Lysyl oxidase (LOX) and LOX-like (LOXL) proteins play crucial roles in ECM remodeling due to their collagen crosslinking and intracellular functions. Here, we systematically investigated LOX/L expression in primary fibroblasts and epithelial cells under fibrotic conditions, Bleomycin (BLM) induced lung fibrosis and in human IPF tissue. Basal expression of all LOX/L family members was detected in epithelial cells and at higher levels in fibroblasts. Various pro-fibrotic stimuli broadly induced LOX/L expression in fibroblasts, whereas specific induction of LOXL2 and partially LOX was observed in epithelial cells. Immunohistochemical analysis of lung tissue from 14 IPF patients and healthy donors revealed strong induction of LOX and LOXL2 in bronchial and alveolar epithelium as well as fibroblastic foci. Using siRNA experiments we observed that LOXL2 and LOXL3 were crucial for fibroblast-to-myofibroblast transition (FMT). As FMT could only be reconstituted with an enzymatically active LOXL2 variant, we conclude that LOXL2 enzymatic function is crucial for fibroblast transdifferentiation. In summary, our study provides a comprehensive analysis of the LOX/L family in fibrotic lung disease and indicates prominent roles for LOXL2/3 in fibroblast activation and LOX/LOXL2 in IPF.

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Section: Discussionmentioning

confidence: 99%

Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis

Aumiller

Strobel

Romeike

et al. 2017

Sci Rep

110

101

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“…38 Notably, previous studies have uncovered that LOX expression is significantly elevated in bleomycin-induced pulmonary fibrosis and inhibition of LOX activity alleviates the pulmonary fibrosis. 39,40 However, the involvement of LOX in bleomycin-based sclerotherapy is undetermined. Herein, we observed that bleomycin not only markedly upregulated the expression and activity of LOX, but increased the mRNA expression of multiple ECM components in HUVEC, which was reversed by LOX suppression with BAPN.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of lysyl oxidase in venous malformations: Association with vascular destabilization and sclerotherapy

Zhu

Shao

Guo

et al. 2020

The Journal of Dermatology

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Venous malformations (VM) are localized defects in vascular morphogenesis manifested by dilated venous channels with reduced perivascular cell coverage. As a vital enzyme for extracellular matrix (ECM) deposition, lysyl oxidase (LOX) plays important roles in vascular development and diseases. However, the expression and significance of LOX are unknown in VM. Herein, 22 VM specimens and eight samples of normal skin tissues were evaluated immunohistochemically for the expression of LOX, α-smooth muscle cell actin (α-SMA) and transforming growth factor-β (TGF-β). In vitro studies on human umbilical vein endothelial cells (HUVEC) were employed for determining potential mechanisms. Our results showed that LOX expression was significantly reduced in VM compared with normal skin tissues, in parallel with attenuated perivascular α-SMA + cell coverage and TGF-β downregulation in VM. Further correlation analysis indicated that LOX expression was positively correlated with perivascular α-SMA + cell coverage and TGF-β expression in VM. Moreover, marked elevation of LOX, TGF-β and α-SMA was observed in bleomycin-treated VM samples. Furthermore, our in vitro data demonstrated that both recombinant TGF-β and bleomycin induced obvious increase of LOX expression and activity and a concomitant increase in ECM components in HUVEC, which could be reversed by LOX inhibition. To our best knowledge, this study revealed for the first time the downregulation of LOX in VM and its correlation with vascular destabilization and TGF-β-induced endothelial ECM deposition. Moreover, our results highlighted that LOX may be implicated in the sclerotherapy of VM and holds promise as a therapeutic target.

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“…B, Cell apoptosis was performed by flow cytometry analysis, and representative plots were shown. 37 Additionally, TGF-β 1 increases LOX expression and activity in vascular smooth muscle cell, which is critical in vascular remodelling. Values shown are mean ± SD from at least three independent experiments.…”

Section: Discussionmentioning

confidence: 99%

“…35,36 Inhibition of LOX impairs TGF-β 1 signalling and myofibroblast accumulation in bleomycin-induced lung fibrosis. 37 Additionally, TGF-β 1 increases LOX expression and activity in vascular smooth muscle cell, which is critical in vascular remodelling. 38 In the present study, we showed that siRNA TGF-β 1 could completely abolish the expression of LOX and inhibit hypoxia-induced PASMCs proliferation, suggesting that LOX may be a direct target of TGF-β 1 .…”

Section: Discussionmentioning

confidence: 99%

Hypercapnia downregulates hypoxia‐induced lysyl oxidase expression in pulmonary artery smooth muscle cells via inhibiting transforming growth factor β₁ signalling

Xia

Peng

Liú

et al. 2019

Cell Biochemistry & Function

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Hypoxic pulmonary arterial hypertension is characterized by elevated pulmonary vascular resistance and remodelling. Transforming growth factor-β 1 (TGF-β 1 ) is the master regulator in cellular response to hypoxia which can directly target lysyl oxidase (LOX). This study aimed to determine whether hypercapnia attenuates hypoxic pulmonary hypertension via regulating TGF-β 1 and LOX signalling. We found that exposure to hypercapnia ameliorated the increase in mean pulmonary artery pressure (mPAP) and ratio of right ventricle to left ventricle plus septum (RV/(LV + S)) induced by hypoxia but had no effect on mPAP and RV/(LV + S) in normoxia-exposed control.In addition, exposure to hypoxia upregulated the mRNA and protein levels of LOX and TGF-β 1 in rat PASMCs both in vivo and in vitro, but these effects were abrogated by concurrent exposure to hypercapnia. The downregulation of LOX in rat PASMCs induced by hypercapnia was reversed by the administration with TGF-β 1 , while TGF-β 1 knockdown repressed the upregulation of LOX in hypoxia-exposed rat PASMCs. In conclusion, hypoxia upregulates LOX and TGF-β 1 expression in PASMCs and contributes to pulmonary hypertension. Hypercapnia downregulates hypoxiainduced LOX expression and alleviates hypoxia-associated pulmonary hypertension via inhibiting TGF-β 1 signalling.Significance of the Study: Hypoxia-induced upregulation of TGF-β 1 , PDGF, and HIF-1α plays a pivotal role in PAH, but molecular mechanism of how hypoxia regulates LOX expression is not clear. In the present study, we showed that mRNA and protein expression levels of LOX were substantially increased when TGF-β 1 was induced by hypoxia, and the effects were reversed by TGF-β 1 knockdown. Our study indicates that TGF-β 1 is implicated in the regulation of LOX.

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Lysyl oxidase promotes bleomycin-induced lung fibrosis through modulating inflammation

Cited by 60 publications

References 38 publications

Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis

Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis

Downregulation of lysyl oxidase in venous malformations: Association with vascular destabilization and sclerotherapy

Hypercapnia downregulates hypoxia‐induced lysyl oxidase expression in pulmonary artery smooth muscle cells via inhibiting transforming growth factor β₁ signalling

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Lysyl oxidase promotes bleomycin-induced lung fibrosis through modulating inflammation

Cited by 60 publications

References 38 publications

Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis

Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis

Downregulation of lysyl oxidase in venous malformations: Association with vascular destabilization and sclerotherapy

Hypercapnia downregulates hypoxia‐induced lysyl oxidase expression in pulmonary artery smooth muscle cells via inhibiting transforming growth factor β1 signalling

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Hypercapnia downregulates hypoxia‐induced lysyl oxidase expression in pulmonary artery smooth muscle cells via inhibiting transforming growth factor β₁ signalling