Promising Therapy Candidates for Liver Fibrosis

Wang, Ping; Koyama, Yukinori; Liu, Xiao; Xu, Jun; Yen, Hsiao; Liang, Shuang; Kim, In H.; Brenner, David A.; Kisseleva, Tatiana

doi:10.3389/fphys.2016.00047

Cited by 75 publications

(55 citation statements)

References 93 publications

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“…This study showed T1ρ MRI can differentiate BDL day-10 animals, when liver fibrosis (METAVIR stage-2) started to develop, from normal liver (33,34). Both animal experiments and clinical studies have revealed that liver fibrosis, even early cirrhosis, is reversible, treatment with combined therapies on underline etiology and fibrosis simultaneously might expedite the regression of liver fibrosis and promote liver regeneration (35)(36)(37).…”

Section: Bdl Is a Well Established Model For Liver Fibrosis Researchmentioning

confidence: 98%

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Black blood T1rho MR imaging may diagnose early stage liver fibrosis: a proof-of-principle study with rat biliary duct ligation model

Koon¹,

Zhang²,

Chen

et al. 2016

Quant. Imaging Med. Surg.

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Background: To explore black blood T1rho (T1ρ) liver imaging and investigate the earliest stage when biliary duct ligation (BDL) induced liver fibrosis can be diagnosed.Methods: MR was performed at 3 Tesla. A T1ρ prepared 2D fast spin echo (FSE) sequence with acquisition of four spin lock times (TSLs: 1, 10, 30, and 50 msec) and spin-lock frequency of 500 Hz was applied.Inherent black blood effect of FSE and double inversion recovery (DIR) achieved blood signal suppression, and 3 axial sections per liver were obtained. Male Sprague-Dawley rats were scanned at baseline (n=32), and on day-3 (n=13), day-5 (n=11), day-7 (n=10), day-10 (n=4) respectively after BDL. Hematoxylin-eosin (HE) and picrosirius red staining liver histology was obtained at these time points.Results: The physiological liver parenchyma T1ρ was 38.38±1.53 msec (range, 36.05-41.53 msec). Liver T1ρ value elevated progressively after BDL. On day-10 after BDL all experimental animals can be separated from normal liver based on T1ρ measurement with lowest value being 42.82 msec. Day-7 and day-10 liver resembled METAVIR stage-F1/F2 fibrosis, and fibrous area counted for 0.22%±0.13% and 0.38%±0.44% of liver parenchyma area, respectively. Conclusions:This study provides the first proof-of-principle that T1ρ might diagnose early stage liver fibrosis.

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Section: Bdl Is a Well Established Model For Liver Fibrosis Researchmentioning

confidence: 98%

“…Even when the underline etiology of liver fibrosis could not be eradicated, therapies on liver fibrosis might help restrict the disease progression to cirrhosis (37). Therefore early detection of liver fibrosis and treatment monitoring is of paramount importance.…”

Section: Bdl Is a Well Established Model For Liver Fibrosis Researchmentioning

confidence: 99%

Black blood T1rho MR imaging may diagnose early stage liver fibrosis: a proof-of-principle study with rat biliary duct ligation model

Koon¹,

Zhang²,

Chen

et al. 2016

Quant. Imaging Med. Surg.

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“…ROS have been implicated in promoting fibrosis in multiple organs, such as the lung, liver, and kidney, through a number of mechanisms, as have been discussed in several recent reviews [160–167]. Significantly, it has been established that ROS promote the transformation of fibroblasts to myofibroblasts by interacting with the TGF-β1 signaling pathway [168–172]. ROS can augment the expression and secretion of TGF-β1 and activate the latent TGF-β1 to become active and functional.…”

Section: Rosmentioning

confidence: 99%

Myofibroblasts and lung fibrosis induced by carbon nanotube exposure

Dong

2016

Part Fibre Toxicol

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Carbon nanotubes (CNTs) are newly developed materials with unique properties and a range of industrial and commercial applications. A rapid expansion in the production of CNT materials may increase the risk of human exposure to CNTs. Studies in rodents have shown that certain forms of CNTs are potent fibrogenic inducers in the lungs to cause interstitial, bronchial, and pleural fibrosis characterized by the excessive deposition of collagen fibers and the scarring of involved tissues. The cellular and molecular basis underlying the fibrotic response to CNT exposure remains poorly understood. Myofibroblasts are a major type of effector cells in organ fibrosis that secrete copious amounts of extracellular matrix proteins and signaling molecules to drive fibrosis. Myofibroblasts also mediate the mechano-regulation of fibrotic matrix remodeling via contraction of their stress fibers. Recent studies reveal that exposure to CNTs induces the differentiation of myofibroblasts from fibroblasts in vitro and stimulates pulmonary accumulation and activation of myofibroblasts in vivo. Moreover, mechanistic analyses provide insights into the molecular underpinnings of myofibroblast differentiation and function induced by CNTs in the lungs.In view of the apparent fibrogenic activity of CNTs and the emerging role of myofibroblasts in the development of organ fibrosis, we discuss recent findings on CNT-induced lung fibrosis with emphasis on the role of myofibroblasts in the pathologic development of lung fibrosis. Particular attention is given to the formation and activation of myofibroblasts upon CNT exposure and the possible mechanisms by which CNTs regulate the function and dynamics of myofibroblasts in the lungs. It is evident that a fundamental understanding of the myofibroblast and its function and regulation in lung fibrosis will have a major influence on the future research on the pulmonary response to nano exposure, particle and fiber-induced pneumoconiosis, and other human lung fibrosing diseases.

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“…Hydrophobic bile acids are particularly toxic and promote cholangiocyte/hepatocyte damage, liver fibrosis, cirrhosis, and formation of hepatocellular carcinoma (HCC) under cholestatic conditions [1–3]. Deposition of collagen and other extracellular matrix components is an orchestrated event in cholestatic liver fibrosis and involves several cell types including Kupffer cells and stellate cells.…”

Section: Introductionmentioning

confidence: 99%

Epidermal growth factor signaling protects from cholestatic liver injury and fibrosis

et al. 2016

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We have demonstrated that the signal transducer and activator of transcription 3 (STAT3) protects from cholestatic liver injury. Specific ablation of STAT3 in hepatocytes and cholangiocytes (STAT3∆hc) aggravated liver damage and fibrosis in the Mdr2−/− (multidrug resistance 2) mouse model for cholestatic disease. Upregulation of bile acid biosynthesis genes and downregulation of epidermal growth factor receptor (EGFR) expression were observed in STAT3∆hc Mdr2−/− mice but the functional consequences of these processes in cholestatic liver injury remained unclear. Here, we show normal canalicular architecture and bile flow but increased amounts of bile acids in the bile of STAT3∆hc Mdr2−/− mice. Moreover, STAT3-deficient hepatocytes displayed increased sensitivity to bile acid-induced apoptosis in vitro. Since EGFR signaling has been reported to protect hepatocytes from bile acid-induced apoptosis, we generated mice with hepatocyte/cholangiocyte-specific ablation of EGFR (EGFR∆hc) and crossed them to Mdr2−/− mice. Importantly, deletion of EGFR phenocopied deletion of STAT3 and led to aggravated liver damage, liver fibrosis, and hyperproliferation of K19+ cholangiocytes. Our data demonstrate hepatoprotective functions of the STAT3-EGFR signaling axis in cholestatic liver disease.Key message STAT3 is a negative regulator of bile acid biosynthesis.STAT3 protects from bile acid-induced apoptosis and regulates EGFR expression.EGFR signaling protects from cholestatic liver injury and fibrosis.

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Promising Therapy Candidates for Liver Fibrosis

Cited by 75 publications

References 93 publications

Black blood T1rho MR imaging may diagnose early stage liver fibrosis: a proof-of-principle study with rat biliary duct ligation model

Black blood T1rho MR imaging may diagnose early stage liver fibrosis: a proof-of-principle study with rat biliary duct ligation model

Myofibroblasts and lung fibrosis induced by carbon nanotube exposure

Epidermal growth factor signaling protects from cholestatic liver injury and fibrosis

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