Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury

Douglass, Angela; Wallace, Karen; Parr, Rebecca D.; Park, Jennifer; Durward, Elaine; Broadbent, Ian D.; Barelle, Caroline; Porter, A.J.; Wright, Matthew C.

doi:10.1016/j.jhep.2008.01.032

Cited by 83 publications

(59 citation statements)

References 37 publications

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“…Coupling proapoptotic gliotoxin to a single-chain antibody against synaptophysin, which is expressed in activated HSC-induced apoptosis of activated HSC, and thus reduced fibrosis in the CCl 4 model. 67 Alternatively, vitamin A-modified liposomes increased delivery of small interfering RNA (siRNA) directed against the putative collagen-specific chaperone HSP47 to vitamin A-storing HSC, causing a pronounced antifibrotic effect in the CCl 4 and BDL-induced liver fibrosis. 68 Once effective targeted delivery of siRNA to activated HSC is confirmed, the versatility of this platform holds promise, because it permits the silencing of any known profibrogenic gene.…”

Section: Antifibrotic Drug Developmentmentioning

confidence: 99%

Targeting Liver Fibrosis

2009

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We have made striking progress in our understanding of the biochemistry and cell biology that underlies liver fibrosis and cirrhosis, including the development of strategies and agents to prevent and reverse fibrosis. However, translation of this knowledge into clinical practice has been hampered by (1) the limitation of many in vitro and in vivo models to confirm mechanisms and to test antifibrotic agents, and (2) the lack of sensitive methodologies to quantify the degree of liver fibrosis and the dynamics of fibrosis progression or reversal in patients. Furthermore, whereas cirrhosis and subsequent decompensation are accepted hard clinical endpoints, fibrosis and fibrosis progression alone are merely plausible surrogates for future clinical deterioration. In this review we focus on an optimized strategy for preclinical antifibrotic drug development and highlight the current and future techniques that permit noninvasive assessment and quantification of liver fibrosis and fibrogenesis. The availability of such noninvasive methodologies will serve as the pacemaker for the clinical development and validation of potent antifibrotic agents. (HEPATOLOGY 2009;50:1294-1306

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Section: Antifibrotic Drug Developmentmentioning

confidence: 99%

Targeting Liver Fibrosis

2009

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“…In a recent in vitro study, the pyrimidine synthesis inhibitor leflunomide was shown to enhance HSC apoptosis by upregulating TRAIL expression by Kupffer cells (25). Gliotoxin and sulfasalazine both exert their proapoptotic effect via NF-B inhibition in HSCs and have been shown to accelerate spontaneous resolution of bridging fibrosis in animal models (3,14,15). Gliotoxin has toxic effects on other cell types, but coupling to a single-chain antibody against synaptophysin (which is expressed in activated HSCs) conferred selectivity and reduced fibrosis in a CCl 4 rat model (3).…”

Section: Stimulating Hsc-mfb Apoptosismentioning

confidence: 99%

Therapeutic targets in liver fibrosis

Fallowfield

2011

American Journal of Physiology-Gastrointestinal and Liver Physi

116

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Detailed analysis of the cellular and molecular mechanisms that mediate liver fibrosis has provided a framework for therapeutic approaches to prevent, slow down, or even reverse fibrosis and cirrhosis. A pivotal event in the development of liver fibrosis is the activation of quiescent hepatic stellate cells (HSCs) to scar-forming myofibroblast-like cells. Consequently, HSCs and the factors that regulate HSC activation, proliferation, and function represent important antifibrotic targets. Drugs currently licensed in the US and Europe for other indications target HSC-related components of the fibrotic cascade. Their deployment in the near future looks likely. Ultimately, treatment strategies for liver fibrosis may vary on an individual basis according to etiology, risk of fibrosis progression, and the prevailing pathogenic milieu, meaning that a multiagent approach could be required. The field continues to develop rapidly and starts to identify exciting potential targets in proof-of-concept preclinical studies. Despite this, no antifibrotics are currently licensed for use in humans. With epidemiological predictions for the future prevalence of viral, obesity-related, and alcohol-related cirrhosis painting an increasingly gloomy picture, and a shortfall in donors for liver transplantation, the clinical urgency for new therapies is high. There is growing interest from stakeholders keen to exploit the market potential for antifibrotics. However, the design of future trials for agents in the developmental pipeline will depend on strategies that enable equal patient stratification, techniques to reliably monitor changes in fibrosis over time, and the definition of clinically meaningful end points. antifibrotic therapy; hepatic stellate cell MECHANISMS AND MEDIATORS OF LIVER FIBROGENESIS AND FIBROSIS REGRESSIONAs our understanding of the complex biological processes that regulate liver scarring increases, points of intervention in the fibrotic cascade are relentlessly uncovered. Key mechanisms and mediators are outlined below, to highlight emerging therapeutic targets (Fig. 1). Liver Fibrogenesis and the Role of the Hepatic Stellate Cell-MyofibroblastLiver fibrogenesis is orchestrated by a heterogeneous population of profibrogenic myofibroblasts (MFBs), the majority originating from hepatic stellate cells (HSCs), following a process termed "activation." Other sources of fibrogenic cells have recently been implicated, including portal fibroblasts and cells derived from the bone marrow (including fibrocytes) (7). A more controversial phenomenon is epithelial-to-mesenchymal transition, whereby epithelial cells (hepatocytes or cholangiocytes) undergo transdifferentiation to MFBs driven by bone morphogenic protein 7 and the hedgehog pathway, respectively, as well as a series of proinflammatory mediators. The relative contribution of these diverse precursors to fibrogenesis and the timing of their recruitment are unclear but may vary by disease etiology. In normal liver, quiescent HSCs store vitamin A in lipid droplets, but i...

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“…In early liver fibrosis, macrophages can act in a profibrogenic fashion through the production of profibrotic mediators, such as TGF-β, leading to HSC activation. In contrast, macrophages have been implicated in liver fibrosis resolution as well, possibly through the production of matrix metalloproteinases (MMPs), induction of apoptosis in HSCs, elimination of apoptotic cells, or secretion of IL-10 [41,42,43,44,45,46,47]. Hepatic recruitment of macrophages also plays a pivotal role in the fibrosis progression of experimental steatohepatitis [48,49].…”

Section: Innate Immunitymentioning

confidence: 99%

Intestinal Fibrosis and Liver Fibrosis: Consequences of Chronic Inflammation or Independent Pathophysiology?

Rieder¹,

Bettenworth²,

Imai³

et al. 2016

Inflamm Intest Dis

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Background: Intestinal fibrosis and liver fibrosis represent a significant burden for our patients and health-care systems. Despite the severe clinical problem and the observation that fibrosis is reversible, no specific antifibrotic therapies exist. Summary: In this review, using an ‘East-West' scientific collaboration, we summarize the current knowledge on principal mechanisms shared by intestinal fibrosis and liver fibrosis. We furthermore discuss inflammation as the cause of fibrogenesis in both entities, depict unique features of intestinal and hepatic fibrosis, and provide a future outlook on the development of antifibrotic therapies. Key Messages: A collaborative effort in the field of fibrosis, covering multiple organ systems, will have the highest chance of leading to the development of a successful antifibrotic intervention.

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Antibody-targeted myofibroblast apoptosis reduces fibrosis during sustained liver injury

Cited by 83 publications

References 37 publications

Targeting Liver Fibrosis

Targeting Liver Fibrosis

Therapeutic targets in liver fibrosis

Intestinal Fibrosis and Liver Fibrosis: Consequences of Chronic Inflammation or Independent Pathophysiology?

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