αv integrins: key regulators of tissue fibrosis

Conroy, Kylie P.; Kitto, Laura; Henderson, Neil C.

doi:10.1007/s00441-016-2407-9

Cited by 118 publications

(102 citation statements)

References 55 publications

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“…Because the severity of NASH-induced liver fibrosis is the main predictor of liver-related mortality in NASH, (7) it is critically important to identify the mechanisms responsible for fibrosis development in NASH and to develop treatments that are effective in the prevention and reversal of fibrosis. Recently, RGD-binding integrins were found to play an important role in the development of organ fibrosis, (35) and several studies, including a study from our laboratory, demonstrated the efficacy of a potent small-molecule synthetic analog of the RGD peptide (CWHM-12) in mouse-injury models of liver, lung, muscle, and pancreatic fibrosis. (14,20,21) Here, by assessing CWHM-12 in a mouse model of NASH, we provide evidence supporting the role of RGD-binding integrins in the pathogenesis of NASH-induced liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis

et al. 2018

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The presence and stage of liver fibrosis in patients with nonalcoholic steatohepatitis (NASH) is strongly associated with mortality. Thus, both preventing and reversing fibrosis are critically important approaches to prevent death or the need for liver transplantation from NASH. Recently, fibrosis in several mouse models of organ injury was shown to be prevented and reversed with the potent small molecule, arginine‐glycine‐aspartic acid tripeptide (RGD)‐binding, integrin antagonist (3S)‐3‐(3‐bromo‐5‐(tert‐butyl)phenyl)‐3‐(2‐(3‐hydroxy‐5‐((5‐hydroxy‐1,4,5,6‐tetrahydropyrimidin‐2‐yl)amino)benzamido)acetamido)propanoic acid (Center for World Health and Medicine [CWHM]‐12). We hypothesized that RGD‐binding integrins may play an important role in fibrosis progression in NASH. We assessed the efficacy of CWHM‐12 in a choline deficient, amino‐acid defined, high‐fat diet (CDAHFD) mouse model of NASH. Mice were kept on the CDAHFD or a control diet for 10 weeks, and CWHM‐12 was delivered by continuous infusion for the final 4 weeks. The parameters of NASH and liver fibrosis were evaluated before and after drug treatment. Hepatic steatosis, liver injury, and inflammation were significantly induced by the CDAHFD at week 6 and did not change by week 10. Hepatic profibrogenic gene expression was induced by the CDAHFD at week 6, further increased at week 10, and decreased by CWHM‐12. Fibrosis measured by analysis of liver collagen was reduced by CWHM‐12 to levels significantly less than found at 6 weeks, demonstrating the possibility of reversing already established fibrosis despite ongoing injury. Demonstrated mechanisms of the antifibrotic effect of CWHM‐12 included loss of activated hepatic stellate cells through apoptosis and suppression of hepatic profibrotic signal transduction by transforming growth factor β. Conclusion: RGD‐binding integrins may be critical in the development of fibrosis in NASH and may represent potential targets for treating patients with NASH to reverse advanced liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis

et al. 2018

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“…ASC treatment prevented BLM-induced upregulation of TNF-α expression in both lung and skin wound tissue (Table 1; p < 0.05). Expression of α v -integrin mRNA, a transmembrane cell adhesion molecule that modulates tissue fibrosis (Conroy, Kitto, & Henderson, 2016), was also increased in lung and skin from BLM-treated mice compared to saline controls (…”

Section: Molecular Markers Of Inflammation and Fibrosis Are Upregulmentioning

confidence: 99%

Mesenchymal stromal cells prevent bleomycin‐induced lung and skin fibrosis in aged mice and restore wound healing

Rubio

Elliot

Wikramanayake

et al. 2018

Journal Cellular Physiology

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Fibrosis can develop in nearly any tissue leading to a wide range of chronic fibrotic diseases. However, current treatment options are limited. In this study, we utilized an established aged mouse model of bleomycin-induced lung fibrosis (BLM) to test our hypothesis that fibrosis may develop simultaneously in multiple organs by evaluating skin fibrosis and wound healing. Fibrosis was induced in lung in aged (18-22-month-old) C57BL/6 male mice by intratracheal BLM administration. Allogeneic adipose-derived mesenchymal stromal cells (ASCs) or saline were injected intravenously 24 hr after BLM administration. Full thickness 8-mm punch wounds were performed 7 days later to study potential systemic anti-fibrotic and wound healing effects of intravenously delivered ASCs. Mice developed lung and skin fibrosis as well as delayed wound closure. Moreover, we observed similar changes in the expression of known pro-fibrotic factors in both lung and skin wound tissue, including miR-199 and protein expression of its corresponding target, caveolin-1, as well as phosphorylation of protein kinase B. Importantly, ASC-treated mice exhibited attenuation of BLM-induced lung and skin fibrosis and accelerated wound healing, suggesting that ASCs may prime injured tissues and prevent end-organ fibrosis.

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“…Integrins are the primary mechanosensors and transducers of tissue stiffness and several integrins have been identified as key drivers of profibrotic signaling in various organs. Some of these integrins, in particular αv subunit integrins, such as αvβ1 and αvβ6, have been shown to control the activation of latent TGF-β1 complex and targeting these integrins with small molecule inhibitors can block or reverse fibrosis progression in mouse models (Henderson and Sheppard, 2013; Henderson et al, 2013; Reed et al, 2015; Conroy et al, 2016). Given that BRD4 is critical for TGF-β-dependent profibrotic gene expression, BRD4 activity may be one of the downstream targets of integrin and TGF-β action.…”

Section: Conclusion and Future Prospectsmentioning

confidence: 99%

Targeting Mechanotransduction at the Transcriptional Level: YAP and BRD4 Are Novel Therapeutic Targets for the Reversal of Liver Fibrosis

et al. 2016

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Liver fibrosis is the result of a deregulated wound healing process characterized by the excessive deposition of extracellular matrix. Hepatic stellate cells (HSCs), which are activated in response to liver injury, are the major source of extracellular matrix and drive the wound healing process. However, chronic liver damage leads to perpetual HSC activation, progressive formation of pathological scar tissue and ultimately, cirrhosis and organ failure. HSC activation is triggered largely in response to mechanosignaling from the microenvironment, which induces a profibrotic nuclear transcription program that promotes HSC proliferation and extracellular matrix secretion thereby setting up a positive feedback loop leading to matrix stiffening and self-sustained, pathological, HSC activation. Despite the significant progress in our understanding of liver fibrosis, the molecular mechanisms through which the extracellular matrix promotes HSC activation are not well understood and no effective therapies have been approved to date that can target this early, reversible, stage in liver fibrosis. Several new lines of investigation now provide important insight into this area of study and identify two nuclear targets whose inhibition has the potential of reversing liver fibrosis by interfering with HSC activation: Yes-associated protein (YAP), a transcriptional co-activator and effector of the mechanosensitive Hippo pathway, and bromodomain-containing protein 4 (BRD4), an epigenetic regulator of gene expression. YAP and BRD4 activity is induced in response to mechanical stimulation of HSCs and each protein independently controls waves of early gene expression necessary for HSC activation. Significantly, inhibition of either protein can revert the chronic activation of HSCs and impede pathological progression of liver fibrosis in clinically relevant model systems. In this review we will discuss the roles of these nuclear co-activators in HSC activation, their mechanism of action in the fibrotic process in the liver and other organs, and the potential of targeting their activity with small molecule drugs for fibrosis reversal.

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αv integrins: key regulators of tissue fibrosis

Cited by 118 publications

References 55 publications

An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis

An Inhibitor of Arginine‐Glycine‐Aspartate‐Binding Integrins Reverses Fibrosis in a Mouse Model of Nonalcoholic Steatohepatitis

Mesenchymal stromal cells prevent bleomycin‐induced lung and skin fibrosis in aged mice and restore wound healing

Targeting Mechanotransduction at the Transcriptional Level: YAP and BRD4 Are Novel Therapeutic Targets for the Reversal of Liver Fibrosis

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