scholarly journals Baseline Stiffness Modulates the Non-Linear Response to Stretch of the Extracellular Matrix in Pulmonary Fibrosis

2021 ◽  
Vol 22 (23) ◽  
pp. 12928
Author(s):  
Constança Júnior ◽  
Maria Narciso ◽  
Esther Marhuenda ◽  
Isaac Almendros ◽  
Ramon Farré ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Pulmonary Fibrosis ◽  
Strain Hardening ◽  
Mechanical Behaviour ◽  
Cyclic Stretch ◽  
In Vivo Model ◽  
Micromechanical Properties ◽  
Order Of Magnitude ◽  
Mechanical Homeostasis

Pulmonary fibrosis (PF) is a progressive disease that disrupts the mechanical homeostasis of the lung extracellular matrix (ECM). These effects are particularly relevant in the lung context, given the dynamic nature of cyclic stretch that the ECM is continuously subjected to during breathing. This work uses an in vivo model of pulmonary fibrosis to characterize the macro- and micromechanical properties of lung ECM subjected to stretch. To that aim, we have compared the micromechanical properties of fibrotic ECM in baseline and under stretch conditions, using a novel combination of Atomic Force Microscopy (AFM) and a stretchable membrane-based chip. At the macroscale, fibrotic ECM displayed strain-hardening, with a stiffness one order of magnitude higher than its healthy counterpart. Conversely, at the microscale, we found a switch in the stretch-induced mechanical behaviour of the lung ECM from strain-hardening at physiological ECM stiffnesses to strain-softening at fibrotic ECM stiffnesses. Similarly, we observed solidification of healthy ECM versus fluidization of fibrotic ECM in response to stretch. Our results suggest that the mechanical behaviour of fibrotic ECM under stretch involves a potential built-in mechanotransduction mechanism that may slow down the progression of PF by steering resident fibroblasts away from a pro-fibrotic profile.

Closure of Fetoscopic Access Sites with Amniotic Extracellular Matrix Scaffolds in an In Vivo Model

2006 ◽  
Vol 66 (S 01) ◽  
Author(s):  
N Ochsenbein-Kölble ◽  
J Jani ◽  
G Verbist ◽  
L Lewi ◽  
K Marquardt ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
In Vivo Model ◽  
Extracellular Matrix Scaffolds

scholarly journals Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-κB/NLRP3-mediated epithelial–mesenchymal transition and inflammation

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Ling Peng ◽  
Li Wen ◽  
Qing-Feng Shi ◽  
Feng Gao ◽  
Bin Huang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Pulmonary Fibrosis ◽  
Epithelial Mesenchymal Transition ◽  
Matrix Metalloproteinase 2 ◽  
Mesenchymal Transition ◽  
The Impact ◽  
Anti Inflammation ◽  
Iκbα Degradation

AbstractIdiopathic pulmonary fibrosis (IPF) is featured with inflammation and extensive lung remodeling caused by overloaded deposition of extracellular matrix. Scutellarin is the major effective ingredient of breviscapine and its anti-inflammation efficacy has been reported before. Nevertheless, the impact of scutellarin on IPF and the downstream molecular mechanism remain unclear. In this study, scutellarin suppressed BLM-induced inflammation via NF-κB/NLRP3 pathway both in vivo and in vitro. BLM significantly elevated p-p65/p65 ratio, IκBα degradation, and levels of NLRP3, caspase-1, caspase-11, ASC, GSDMDNterm, IL-1β, and IL-18, while scutellarin reversed the above alterations except for that of caspase-11. Scutellarin inhibited BLM-induced epithelial–mesenchymal transition (EMT) process in vivo and in vitro. The expression levels of EMT-related markers, including fibronectin, vimentin, N-cadherin, matrix metalloproteinase 2 (MMP-2) and MMP-9, were increased in BLM group, and suppressed by scutellarin. The expression level of E-cadherin showed the opposite changes. However, overexpression of NLRP3 eliminated the anti-inflammation and anti-EMT functions of scutellarin in vitro. In conclusion, scutellarin suppressed inflammation and EMT in BLM-induced pulmonary fibrosis through NF-κB/NLRP3 signaling.

scholarly journals Lysyl oxidase directly contributes to extracellular matrix production and fibrosis in systemic sclerosis

2021 ◽  
Vol 320 (1) ◽  
pp. L29-L40
Author(s):  
Xinh-Xinh Nguyen ◽  
Tetsuya Nishimoto ◽  
Takahisa Takihara ◽  
Logan Mlakar ◽  
Amy D. Bradshaw ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Systemic Sclerosis ◽  
Pulmonary Fibrosis ◽  
Nuclear Localization ◽  
Amine Oxidase ◽  
Ex Vivo ◽  
Lysyl Oxidase ◽  
Lung Fibroblasts ◽  
Transcriptional Level

Pulmonary fibrosis is one of the important causes of morbidity and mortality in fibroproliferative disorders such as systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Lysyl oxidase (LOX) is a copper-dependent amine oxidase whose primary function is the covalent crosslinking of collagens in the extracellular matrix (ECM). We investigated the role of LOX in the pathophysiology of SSc. LOX mRNA and protein levels were increased in lung fibroblasts of SSc patients compared with healthy controls and IPF patients. In vivo, bleomycin induced LOX mRNA expression in lung tissues, and LOX activity increased in the circulation of mice with pulmonary fibrosis, suggesting that circulating LOX parallels levels in lung tissues. Circulating levels of LOX were reduced upon amelioration of fibrosis with an antifibrotic peptide. LOX induced ECM production at the transcriptional level in lung fibroblasts, human lungs, and human skin maintained in organ culture. In vivo, LOX synergistically exacerbated fibrosis in bleomycin-treated mice. Further, LOX increased the production of interleukin (IL)-6, and the increase was mediated by LOX-induced c-Fos expression, the nuclear localization of c-Fos, and its engagement with the IL-6 promoter region. Our findings demonstrate that LOX expression and activity correlate with fibrosis in vitro, ex vivo, and in vivo. LOX induced ECM production via upregulation of IL-6 and nuclear localization of c-Fos. Thus, LOX has a direct pathogenic role in SSc-associated fibrosis that is independent of its crosslinking function. Our findings also suggest that measuring circulating LOX levels and activity can be used for monitoring response to antifibrotic therapy.

Enhanced β-Catenin/Foxo1 Activity Alleviates Pulmonary Fibrosis by Inhibiting β-Catenin/T Cell Factor Signaling

2020 ◽  
Vol 10 (2) ◽  
pp. 182-188
Author(s):  
Kun Gui ◽  
Yu Huang ◽  
Meijin Wang ◽  
Jun Yang
Keyword(s):  
Extracellular Matrix ◽  
Pulmonary Fibrosis ◽  
Inflammatory Cytokines ◽  
Underlying Mechanism ◽  
Control Group ◽  
Kidney Fibrosis ◽  
Mrc5 Cell

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia, resulting in chronic respiratoryfailure and eventually death. β-catenin/Foxo1 showed a protective property in kidney fibrosis, but the role of β-catenin/Foxo1 in IPF was unclear. Our study aimed to investigate the role of β-catenin/Foxo1 in IPF and explore its underlying mechanism. The IPF model was established by injection of bleomycin (BLM) in vivo and stimulation by TGF-β1 in MRC5 cell in vitro. Haematoxylin-eosin staining and Masson’s trichrome staining were performed to examine histopathological injury in lung. Protein expression of corresponding genes was detected using western blot. Immunofluorescence staining assay was carried out to detect the expression of β-catenin, Foxo1, TCF and α-SMA. The expression levels of inflammatory cytokines were determined using ELISA kit assay. The results showed that BLM induced a serious pulmonary injury and proliferated fibroblasts. A higher interaction of β-catenin with TCF and a lower interaction of β-catenin with Foxo1 was found in BLM group compared to the control group. TGF-β1 promoted β-catenin/TCF, whereas ICG-001 inhibited β-catenin/TCF, and promoted β-catenin/Foxo1. Furthermore, ICG-001 reversed TGF-β1 induced largely production of inflammatory cytokines and accumulation of extracellular matrix, as well as high expression of α-SMA. However, AS1842856, a FOXO1 antagonist, strengthened the effects induced by TGF-β1. In summary, our study revealed that β-catenin/Foxo1 protected against IPF through inhibiting inflammatory response and extracellular matrix accumulation, providing an alternative approach to explain the potential mechanism of IPF and seek for more effective therapeutic drugs.

scholarly journals NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis

2020 ◽  
pp. 1901949
Author(s):  
Ruy Andrade Louzada ◽  
Raphaël Corre ◽  
Rabii Ameziane El Hassani ◽  
Lydia Meziani ◽  
Madeleine Jaillet ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Pulmonary Fibrosis ◽  
Nadph Oxidase ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Lung Fibroblasts ◽  
Mouse Lung ◽  
Epithelial Surface ◽  
Tgf Β1

Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of pulmonary fibrosis, and is governed by transforming growth factor (TGF-β1)/Smad signalling. TGF-β1 and oxidative stress cooperate to drive fibrosis. Cells can produce reactive oxygen species (ROS) through activation and/or induction of NADPH oxidases, such as dual oxidase (DUOX1/2). Since DUOX enzymes, as extracellular H2O2-generating systems, are involved in extracellular matrix formation and in wound healing in different experimental models, we hypothesised that DUOX-based NADPH oxidase plays a role in the pathophysiology of pulmonary fibrosis.Our in vivo data (IPF patients and mouse models of lung fibrosis) showed that the NADPH oxidase DUOX1 is induced in response to lung injury. DUOX1-deficient mice (DUOX1+/- and DUOX1-/-) had an attenuated fibrotic phenotype. In addition to being highly expressed at the epithelial surface of airways, DUOX1 appears to be also well expressed in the fibroblastic foci of remodelled lungs. By using primary human and mouse lung fibroblasts, we showed that TGF-β1 upregulates DUOX1 and its maturation factor DUOXA1 and that DUOX1-derived H2O2 promoted the duration of TGF-β1-activated Smad3 phosphorylation by preventing phospho-Smad3 degradation. Analysis of the mechanism revealed that DUOX1 inhibited the interaction between phospho-Smad3 and the ubiquitin ligase NEDD4L, preventing NEDD4L-mediated ubiquitination of phospho-Smad3 and its targeting for degradation.These findings highlight a role for DUOX1-derived H2O2 in a positive feedback that amplifies the signalling output of the TGF-β1 pathway and identify DUOX1 as a new therapeutic target in pulmonary fibrosis.

scholarly journals microRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis

2018 ◽  
Author(s):  
Albertomaria Moro ◽  
Tristan Discroll ◽  
William Armero ◽  
Liana C. Boraas ◽  
Dionna M. Kasper ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Tissue Stiffness ◽  
Matrix Synthesis ◽  
Tissue Properties ◽  
Multiple Systems ◽  
Regulatory Pathways ◽  
Genome Wide ◽  
Mechanical Homeostasis

SummaryThe mechanical properties of tissues, which are determined primarily by their extracellular matrix (ECM), are largely stable over time despite continual turnover of ECM constituents 1,2. These observations imply active homeostasis, where cells sense and adjust rates of matrix synthesis, assembly and degradation to keep matrix and tissue properties within the optimal range. However, the regulatory pathways that mediate this process are essentially unknown3. Genome-wide analyses of endothelial cells revealed abundant microRNA-mediated regulation of cytoskeletal, adhesive and extracellular matrix (CAM) mRNAs. High-throughput assays showed co-transcriptional regulation of microRNA and CAM genes on stiff substrates, which buffers CAM expression. Disruption of global or individual microRNA-dependent suppression of CAM genes induced hyper-adhesive, hyper-contractile phenotypes in multiple systems in vitro, and increased tissue stiffness in the zebrafish fin-fold during homeostasis and regeneration in vivo. Thus, a network of microRNAs and CAM mRNAs mediate tissue mechanical homeostasis.

Extracellular proteolysis in the development and progression of atherosclerosis

2002 ◽  
Vol 30 (2) ◽  
pp. 163-167 ◽  
Author(s):  
H. R. Lijnen
Keyword(s):  
Extracellular Matrix ◽  
Vessel Wall ◽  
Structural Integrity ◽  
In Vivo Model ◽  
Aneurysm Formation ◽  
Clinical Complications ◽  
Extracellular Matrix Components ◽  
Unstable Plaques ◽  
Combined Deficiency

Clinical complications of atherosclerosis are often triggered by the rupture of unstable plaques, while thinning of the atherosclerotic vessel wall owing to elastin and collagen degradation and media necrosis may result in aneurysm formation and bleeding. Proteolysis, mediated via the plasminogen/ plasmin and/or matrix metalloproteinase (MMP) systems may contribute to neovascularization and rupture of plaques, or to ulceration and rupture of aneurysms. In an in vivo model of atherosclerosis, using mice that had a combined deficiency of apolipoprotein E (ApoE) and urokinase-type plasminogen activator (u-PA) and that were maintained on a cholesterol-rich diet, it was observed that u-PA deficiency protects against aneurysm formation. This was explained by the findings that plasmin, generated from plasminogen by u-PA, activates several macrophage-secreted proMMPs (e.g. proMMP-3, −9, −12 and −13), which in turn cause extracellular matrix degradation. A potential role for MMP-3 (stromelysin-1) was confirmed in a subsequent study using mice with a combined deficiency of ApoE and MMP-3, that were kept on a cholesterol-rich diet. The results suggest that MMP-3 contributes to plaque destabilization, possibly by degrading extracellular matrix components, but also promotes aneurysm formation by degrading the elastic lamina. These effects may be mediated by MMP-3 directly or by activation of other proMMPs or other (proteolytic) systems. A functional role of MMPs is further supported by the finding that deficiency in TIMP-1 (tissue inhibitor of MMPs type 1) reduces atherosclerotic plaque size but enhances aneurysm formation. Taken together, these results suggest that u-PA has an important role in the structural integrity of the atherosclerotic vessel wall, which is likely to involve triggering the activation of MMPs and, furthermore, they suggest that increased u-PA levels are a risk factor for aneurysm formation.

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