scholarly journals TRPV4 Mechanotransduction in Fibrosis

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3053
Author(s):  
Ravi K. Adapala ◽  
Venkatesh Katari ◽  
Lakshminarayan Reddy Teegala ◽  
Sathwika Thodeti ◽  
Sailaja Paruchuri ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Organ Failure ◽  
Therapeutic Target ◽  
Lung Fibrosis ◽  
Mechanical Factors

Fibrosis is an irreversible, debilitating condition marked by the excessive production of extracellular matrix and tissue scarring that eventually results in organ failure and disease. Differentiation of fibroblasts to hypersecretory myofibroblasts is the key event in fibrosis. Although both soluble and mechanical factors are implicated in fibroblast differentiation, much of the focus is on TGF-β signaling, but to date, there are no specific drugs available for the treatment of fibrosis. In this review, we describe the role for TRPV4 mechanotransduction in cardiac and lung fibrosis, and we propose TRPV4 as an alternative therapeutic target for fibrosis.

scholarly journals Subchondral Bone Remodeling: A Therapeutic Target for Osteoarthritis

2021 ◽  
Vol 8 ◽  
Author(s):  
Xiaobo Zhu ◽  
Yau Tsz Chan ◽  
Patrick S. H. Yung ◽  
Rocky S. Tuan ◽  
Yangzi Jiang
Keyword(s):  
Extracellular Matrix ◽  
Signaling Pathways ◽  
Bone Remodeling ◽  
Molecular Mechanism ◽  
Subchondral Bone ◽  
Therapeutic Target ◽  
Therapeutic Targets ◽  
Regenerative Therapies

There is emerging awareness that subchondral bone remodeling plays an important role in the development of osteoarthritis (OA). This review presents recent investigations on the cellular and molecular mechanism of subchondral bone remodeling, and summarizes the current interventions and potential therapeutic targets related to OA subchondral bone remodeling. The first part of this review covers key cells and molecular mediators involved in subchondral bone remodeling (osteoclasts, osteoblasts, osteocytes, bone extracellular matrix, vascularization, nerve innervation, and related signaling pathways). The second part of this review describes candidate treatments for OA subchondral bone remodeling, including the use of bone-acting reagents and the application of regenerative therapies. Currently available clinical OA therapies and known responses in subchondral bone remodeling are summarized as a basis for the investigation of potential therapeutic mediators.

scholarly journals The promise of mTOR as a therapeutic target pathway in idiopathic pulmonary fibrosis

2020 ◽  
Vol 29 (157) ◽  
pp. 200269
Author(s):  
Manuela Platé ◽  
Delphine Guillotin ◽  
Rachel C Chambers
Keyword(s):  
Extracellular Matrix ◽  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Therapeutic Target ◽  
Critical Role ◽  
Mammalian Target Of Rapamycin ◽  
Lung Parenchyma ◽  
Extracellular Signals ◽  
Novel Therapeutic Strategies ◽  
Novel Therapeutic

Idiopathic pulmonary fibrosis (IPF) is characterised by the progressive deposition of excessive extracellular matrix proteins within the lung parenchyma and represents the most rapidly progressive and fatal of all fibrotic conditions. Current anti-fibrotic drugs approved for the treatment of IPF fail to halt disease progression and have significant side-effect profiles. Therefore, there remains a pressing need to develop novel therapeutic strategies for IPF. Mammalian target of rapamycin (mTOR) forms the catalytic subunit of two complexes, mTORC1 and mTORC2. mTORC1 acts as critical cellular sensor which integrates intracellular and extracellular signals to reciprocally regulate a variety of anabolic and catabolic processes. The emerging evidence for a critical role for mTORC1 in influencing extracellular matrix production, metabolism, autophagy and senescence in the setting of IPF highlights this axis as a novel therapeutic target with the potential to impact multiple IPF pathomechanisms.

Three-dimensional investigation and scoring of extracellular matrix remodeling during lung fibrosis using multiphoton microscopy

2007 ◽  
Vol 70 (2) ◽  
pp. 162-170 ◽  
Author(s):  
Ana-Maria Pena ◽  
Aurélie Fabre ◽  
Delphine Débarre ◽  
Joëlle Marchal-Somme ◽  
Bruno Crestani ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Lung Fibrosis ◽  
Multiphoton Microscopy ◽  
Three Dimensional ◽  
Extracellular Matrix Remodeling ◽  
Matrix Remodeling

scholarly journals Type-1 IFN primed monocytes in pathogenesis of idiopathic pulmonary fibrosis

2020 ◽  
Author(s):  
Emily Fraser ◽  
Laura Denney ◽  
Karl Blirando ◽  
Chaitanya Vuppusetty ◽  
Agne Antanaviciute ◽  
...  
Keyword(s):  
Idiopathic Pulmonary Fibrosis ◽  
Pulmonary Fibrosis ◽  
Immune Cells ◽  
Therapeutic Target ◽  
Lung Fibrosis ◽  
Ex Vivo ◽  
Treatment Options ◽  
Gene Expression Signature ◽  
Severe Form

ABSTRACTIdiopathic pulmonary fibrosis (IPF) is the most severe form of lung fibrosis. It is progressive, and has an extremely poor outcome and limited treatment options. The disease exclusively affects the lungs, and thus less attention has been focused on blood-borne immune cells. which could be a more effective therapeutic target than lung-based cells. Here, we questioned if circulating monocytes, which has been shown to be increased in IPF, bore abnormalities that might contribute to its pathogenesis. We found that levels of circulating monocytes correlated directly with the extent of fibrosis in the lungs, and increased further during acute clinical deterioration. Monocytes in IPF were phenotypically distinct, displaying increased expression of CD64, a type 1 IFN gene expression signature and a greater magnitude of type 1 IFN response when stimulated. These abnormalities were accompanied by markedly raised CSF-1 levels in the serum, prolonged survival of monocytes ex vivo, and increased numbers of monocytes in lung tissue. Our study defines the key monocytic abnormalities in IPF, proposing type 1 IFN-primed monocytes as a potential driver of an aberrant repair response and fibrosis. It provides a rationale for targeting monocytes and identifies monocytic CD64 as a potential specific therapeutic target for IPF.

scholarly journals Organ engineering: promise, progress and perspective

2016 ◽  
Vol 38 (4) ◽  
pp. 20-23
Author(s):  
Michelle E. Scarritt ◽  
Stephen F. Badylak
Keyword(s):  
Extracellular Matrix ◽  
Organ Failure ◽  
Treatment Option ◽  
Curative Treatment ◽  
Microscopic Structure ◽  
Support Structures ◽  
Organ Engineering ◽  
Human Organs ◽  
End Stage ◽  
Donor Organs

The only curative treatment option for patients with end-stage organ failure is transplantation. Organ engineering offers an alternative to traditional transplantation that may address the critical shortage of donor organs and eliminate the need for recipient immunosuppression. Organ engineering may be accomplished through the use of scaffold – support structures that contain the architecture of an organ. As organs are exceedingly complex, creating an organ scaffold is a difficult task; however, organ scaffolds can be derived through a process known as decellularization, which is the mechanical, chemical and/or enzymatic removal of cells from a tissue or organ. Through decellularization of xenogenic (animal) organs, biocompatible extracellular matrix (ECM) scaffolds can be produced that retain the complex macroscopic and microscopic structure and composition of the native organ ECM. These 3D ECM scaffolds are ideal for engineering human organs.

Glutathione peroxidase 3 localizes to the epithelial lining fluid and the extracellular matrix in lung fibrosis

2016 ◽  
Author(s):  
Andrea Schamberger ◽  
Herbert Schiller ◽  
Isis Fernandez ◽  
Martina Sterclova ◽  
Katharina Heinzelmann ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Glutathione Peroxidase ◽  
Lung Fibrosis ◽  
Epithelial Lining ◽  
Epithelial Lining Fluid ◽  
Glutathione Peroxidase 3

Connective-Tissue Growth Factor (CTGF/CCN2) Contributes to TGF-β1-Induced Lung Fibrosis

2020 ◽  
Author(s):  
Toyoshi Yanagihara ◽  
Sy Giin Chong ◽  
Mahsa Gholiof ◽  
Kenneth E. Lipson ◽  
Quan Zhou ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Connective Tissue ◽  
Pulmonary Fibrosis ◽  
Connective Tissue Growth Factor ◽  
Lung Fibrosis ◽  
Adenovirus Vector ◽  
Tissue Growth ◽  
Inhibitory Antibody ◽  
Tgf Β1

AbstractIdiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by progressive and excessive accumulation of myofibroblasts and extracellular matrix in the lung. Connective-tissue growth factor (CTGF) is known to exacerbate pulmonary fibrosis in radiation-induced lung fibrosis, and in this study, we show the upregulation of CTGF from a rat lung fibrosis model induced by adenovirus vector encoding active TGF-β1 (AdTGF-β1), and also in patients with IPF. The expression of CTGF was upregulated in vascular smooth muscle cells cultured from fibrotic lungs on days 7 or 14 as well as endothelial cells sorted from fibrotic lungs on day 14 or 28 respectively. These findings suggest the role of different cells in maintaining the fibrotic phenotype during fibrogenesis. Treatment of fibroblasts with recombinant CTGF along with TGF-β increases pro-fibrotic markers in fibroblasts, confirming the synergistic effect of recombinant CTGF with TGF-β in inducing pulmonary fibrosis. Also, fibrotic extracellular matrix upregulated the expression of CTGF, as compared to normal extracellular matrix, suggesting that not only profibrotic mediators but also a profibrotic environment contributes to fibrogenesis. We also showed that pamrevlumab, a CTGF inhibitory antibody, partially attenuates fibrosis in the model. These results suggest that pamrevlumab could be an option for the treatment of pulmonary fibrosis.

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