Hepatic Stellate Cells Secrete Angiopoietin 1 That Induces Angiogenesis in Liver Fibrosis

Taura, Kojiro; Minicis, S. De; Seki, Ekihiro; Hatano, Etsuro; Iwaisako, Keiko; Österreicher, Christoph H.; Kodama, Yuzo; Miura, Kouichi; Ikai, Iwao; Üemoto, Shinji; Brenner, David A.

doi:10.1053/j.gastro.2008.07.065

Cited by 243 publications

(207 citation statements)

References 32 publications

Supporting

Mentioning

195

Contrasting

Unclassified

Order By: Relevance

“…Angiogenesis that is induced by hypoxia within an injured liver and appears to aggravate hepatic fibrogenesis. 25 Accordingly, using CD31 immunostaining, we noted significant neovascularization that was paralleled by an increased angiopoietin-1 and fibronectin expression 26,27 in livers of mice chronically treated with CCl 4 . All these parameters were ameliorated by IFNc and IFNc-PEG treatment, but most dramatically by IFNc-PEG-PPB (Fig.…”

Section: Ifnc-peg-ppb Inhibits Angiogenesis and Livermentioning

confidence: 83%

See 1 more Smart Citation

Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice

et al. 2011

View full text Add to dashboard Cite

Liver fibrogenesis is a process tightly controlled by endogenous anti-and pro-fibrogenic factors. Interferon gamma (IFNc) is a potent antifibrogenic cytokine in vitro and might therefore represent a powerful therapeutic entity. However, its poor pharmacokinetics and adverse effects, due to the presence of IFNc receptors on nearly all cells, prevented its clinical application so far. We hypothesized that delivery of IFNc specifically to the disease-inducing cells and concurrently avoiding its binding to nontarget cells might increase therapeutic efficacy and avoid side effects. We conjugated IFNc to a cyclic peptide recognizing the plateletderived growth factor beta receptor (PDGFbR) which is strongly up-regulated on activated hepatic stellate cells (HSC), the key effector cells responsible for hepatic fibrogenesis. The IFNc conjugates were analyzed in vitro for PDGFbR-specific binding and biological effects and in vivo in acute (early) and chronic (progressive and established) carbon-tetrachlorideinduced liver fibrosis in mice. The targeted-IFNc construct showed PDGFbR-specific binding to fibroblasts and HSC and inhibited their activation in vitro. In vivo, the targeted-IFNc construct attenuated local HSC activation in an acute liver injury model. In the established liver fibrosis model, it not only strongly inhibited fibrogenesis but also induced fibrolysis. In contrast, nontargeted IFNc was ineffective in both models. Moreover, in contrast to unmodified IFNc, our engineered targeted-IFNc did not induce IFNc-related side effects such as systemic inflammation, hyperthermia, elevated plasma triglyceride levels, and neurotropic effects. Conclusion: This study presents a novel HSC-targeted engineered-IFNc, which in contrast to systemic IFNc, blocked liver fibrogenesis and is devoid of side effects, by specifically acting on the key pathogenic cells within the liver. (HEPATOLOGY 2011;54:586-596)

show abstract

Section: Ifnc-peg-ppb Inhibits Angiogenesis and Livermentioning

confidence: 83%

“…Recent reports highlight the relevance of angiogenesis in the pathogenesis of liver fibrosis, [25][26][27] whereas the role of chronic inflammation was recognized earlier. 28 The significant inhibition of these processes by the targeted construct and not by native IFNc further highlights the potency of our targeting approach.…”

mentioning

confidence: 99%

Novel engineered targeted interferon-gamma blocks hepatic fibrogenesis in mice

et al. 2011

View full text Add to dashboard Cite

show abstract

“…In addition, a third unexpected finding was the absence of correlation between the expression of both ANGPTs and the variables associated with disease severity in BA (age at portoenterostomy, ACOL, and PCK7) because there are reports linking these angiogenic molecules to hepatic fibrogenesis and, hence, to disease aggravation (33). Specifically in the context of ACOL, this lack of association may be ascribed to inherent difficulties in the analysis of liver fibrosis, such as sampling errors and phenotypic idiosyncratic features in relation to fibrogenesis (2).…”

Section: Discussionmentioning

confidence: 99%

Angiopoietin 1 and angiopoietin 2 are associated with medial thickening of hepatic arterial branches in biliary atresia

et al. 2013

View full text Add to dashboard Cite

Background: Biliary atresia (BA) is an infantile disorder characterized by progressive sclerosing cholangiopathy leading to biliary obstruction. First-line treatment of BA is hepatoportoenterostomy, the prognosis of which is related to age at surgery and to histological variables such as extent of fibrosis and ductular reaction. Hepatic arterial medial thickening (MT) suggests an arteriopathy in BA pathogenesis. We evaluated the expression of angiopoietin (ANGPT)/tyrosine kinase with immunoglobulin-like and epidermal growth factorlike domains 2 (TIE2) system in liver samples obtained from patients with BA, correlating it with MT, variables associated with disease severity, and postoperative prognosis. Methods: ANGPT1, ANGPT2, and TIE2 expression levels were assessed by quantitative PCR in liver samples obtained from BA patients (n = 23) at portoenterostomy and age-matched infants with intrahepatic cholestasis (IHC; n = 7). Histological variables were morphometrically assessed. results: ANGPT1 and ANGPT2 were overexpressed in BA in comparison with IHC (P = 0.024 and P = 0.029, respectively). In BA, ANGPTs expression was positively correlated with MT (ANGPT1: r s = 0.59, P = 0.013; ANGPT2: r s = 0.52, P = 0.032), not with the variables associated with disease severity. TIE2 and ANGPTs expression levels were negatively correlated (ANGPT1: r s = −0.73, P < 0.001; ANGPT2: r s = −0.54, P = 0.007). conclusion: In BA, there is overexpression of both ANGPT1 and ANGPT2, which is correlated with MT but not with age at portoenterostomy or with the histological variables associated with disease severity at the time of procedure. Biliary atresia (BA) is an infantile hepatobiliary disorder characterized by the obstruction of bile ducts associated with a progressive sclerosing cholangiopathy. The primary treatment for BA is a hepatoportoenterostomy, which should be performed as soon as possible, because its chances of longterm success decrease when the age at surgery increases (1). In addition to age at portoenterostomy, histological findings observed in biopsies collected at the time of the procedure, such as the extents of fibrosis and ductular reaction, represent variables associated with disease severity and can help foresee the postoperative outcomes (2).Regardless of portoenterostomy, BA induces cirrhosis by the continuous sclerosing cholangiopathy process, thus making this entity the leading cause of liver transplantation in children.The etiology of such a cholangiopathy remains elusive, and BA seems to represent more a phenotype than a unique disease. Our group is interested in the putative role of an arteriopathy in the development of BA because there are arteriographic (3), ultrasonographic (4-6), computed tomographic (7), histological (8), and immunohistochemical (9) evidences of medial thickening (MT) in hepatic artery branches owing to a vascular remodeling associated with hypoxia-ischemia in the portal tracts and porta hepatis. Knowledge on the behavior of angiogenic molecules in the liver of the affected patients...

show abstract

“…4,5 The mechanistic basis for benefit is not fully elucidated; however, there is increasing and compelling evidence suggesting an intimate link between angiogenesis, fibrosis, and portal hypertension and, thus, it has been proposed that a part of the mechanism of action of these agents may be through an antiangiogenic mechanism. [6][7][8][9] In the current issue of HEPATOLOGY, the article by Mejias et al 10 demonstrates a beneficial effect of the receptor tyrosine kinase inhibitor, sorafenib, on splanchnic, intrahepatic, and portocollateral circulations in cirrhotic rats with portal hypertension; these observations are reminiscent of recent work with sunitinib in this model. 4 This work is exciting in many ways, especially given that sorafenib is presently approved and used in patients with existing cirrhosis and HCC.…”

mentioning

confidence: 88%