Platelet‐derived adenosine 5′‐triphosphate suppresses activation of human hepatic stellate cell: <i>In vitro</i> study

Ikeda, Naoya; Murata, Soichiro; Maruyama, Takehito; Tamura, Takafumi; Nozaki, Reiji; Kawasaki, Takuya; Fukunaga, Kiyoshi; Oda, Tatsuya; Sasaki, Ryoko; Homma, Masato; Ohkohchi, Nobuhiro

doi:10.1111/j.1872-034x.2011.00893.x

Cited by 50 publications

(44 citation statements)

References 44 publications

(47 reference statements)

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“…When the liver is injured, platelets accumulate in the injured liver and actively translocate into Disse spaces Nakamura 1992, 1993;Nakamura et al 1998;Murata et al 2007;Myronovych et al 2008). The direct contact between platelets and hepatocytes or LSECs is necessary for hepatocyte proliferation (Matsuo et al 2008;Kawasaki et al 2010), and the direct contact between platelets and HSCs is essential for an anti-fibrotic effect (Ikeda et al 2011). Taken together, the previous and current data suggest that transfused platelets delivered to the portal vein accumulate in the damaged liver due to CLD; directly contact hepatocytes, LSECs, and HSCs; and finally improve liver function and reduce liver fibrosis.…”

Section: Discussionmentioning

confidence: 99%

“…Platelets promote hepatocyte proliferation and have an anti-fibrotic effect in vitro (Matsuo et al 2008;Kawasaki et al 2010;Ikeda et al 2011), and thrombocytosis promotes liver regeneration and reduces liver fibrosis in vivo (Murata et al 2007;Murata et al 2008b;Myronovych et al 2008;Watanabe et al 2009). We hypothesized that platelet increment therapy would improve liver function in humans.…”

Section: Discussionmentioning

confidence: 99%

“…Hepatic stellate cells (HSCs) play a major role in liver fibrosis (Friedman 2008). Platelets suppress the activation of HSCs by releasing adenosine 5′-triphosphate (Ikeda et al 2011), and thrombocytosis reduces liver fibrosis (Murata et al 2008b;Watanabe et al 2009). Taken together, these findings indicate that platelets promote liver regeneration and reduce liver fibrosis and that platelet increment therapy may be effective for patients with CLD and cirrhosis.…”

Section: Introductionmentioning

confidence: 99%

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Platelet Transfusion Improves Liver Function in Patients with Chronic Liver Disease and Cirrhosis

Maruyama

Murata

Takahashi

et al. 2013

Tohoku J. Exp. Med.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Platelet Transfusion Improves Liver Function in Patients with Chronic Liver Disease and Cirrhosis

Maruyama

Murata

Takahashi

et al. 2013

Tohoku J. Exp. Med.

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“…In a recent paper, it has been claimed that ATP released from human platelets contributes to suppression of both human HSC activation and type I collagen production in vitro [132]. It was suggested further that an adenosine-cAMP signalling pathway mediated this process.…”

Section: Fibrosis and Hscsmentioning

confidence: 99%

Purinergic signalling in the liver in health and disease

Burnstock

Vaughn

Robson

2013

Purinergic Signalling

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Purinergic signalling is involved in both the physiology and pathophysiology of the liver. Hepatocytes, Kupffer cells, vascular endothelial cells and smooth muscle cells, stellate cells and cholangiocytes all express purinoceptor subtypes activated by adenosine, adenosine 5′-triphosphate, adenosine diphosphate, uridine 5′-triphosphate or UDP. Purinoceptors mediate bile secretion, glycogen and lipid metabolism and indirectly release of insulin. Mechanical stress results in release of ATP from hepatocytes and Kupffer cells and ATP is also released as a cotransmitter with noradrenaline from sympathetic nerves supplying the liver. Ectonucleotidases play important roles in the signalling process. Changes in purinergic signalling occur in vascular injury, inflammation, insulin resistance, hepatic fibrosis, cirrhosis, diabetes, hepatitis, liver regeneration following injury or transplantation and cancer. Purinergic therapeutic strategies for the treatment of these pathologies are being explored.

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“…Platelets promote hepatocyte proliferation (Matsuo et al 2008) and exert anti-fibrotic effects in vitro (Ikeda et al 2012), and thrombocytosis promotes liver regeneration and reduces liver fibrosis in vivo (Murata et al 2007;Watanabe et al 2009). We hypothesized that platelet transfusion therapy would improve liver function in humans (Murata et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Stable Liver Function during Long-Term Administration of Eltrombopag, a Thrombopoietin Receptor Agonist, in Patients with Chronic Liver Disease

Kurokawa

Murata

Ohkohchi

2016

Tohoku J. Exp. Med.

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Liver cirrhosis is the end stage of chronic liver disease, but no definitive pharmacological treatment is currently available. It has been reported that thrombopoietin (TPO) promotes liver regeneration and improves liver cirrhosis by increasing platelet count. We have shown the direct effect of platelet transfusion on the improvement of liver function in patients with chronic liver disease. However, platelet transfusion often causes adverse events, such as platelet transfusion refractoriness and pruritus. Therefore, we conducted an exploratory clinical trial and administered eltrombopag, an orally bioavailable, small-molecule, non-peptide TPO receptor agonist that has been approved for the treatment of chronic idiopathic thrombocytopenic purpura. The study included five male patients, aged from 49 to 75 years (57.6 ± 10.4 years), with both chronic liver disease and hepatitis C virus infection, who presented with thrombocytopenia but without cancer. Eltrombopag, ranged from 6.25 to 50 mg/day (18.75 ± 18.22 mg/day), was administrated to the five patients during six months. All of the patients maintained platelet counts between 10 and 15 × 10 10 /L during the study. The indicators of liver function in patients were stable throughout the clinical trial, although we had predicted the same degree of the improvement of liver function, compared to platelet transfusion. Importantly, the liver volumes were also stable, and no cancerous lesions were observed. These results indicate the safety of long-term eltrombopag administration for patients with chronic liver disease and hepatitis C virus infection.

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Platelet‐derived adenosine 5′‐triphosphate suppresses activation of human hepatic stellate cell: In vitro study

Abstract: Activation of human HSC is suppressed by human platelets or platelet-derived ATP via adenosine-cAMP signaling pathway in vitro. Therefore, platelets have the possibility to be used in the treatment of liver cirrhosis.

Cited by 50 publications

References 44 publications

Platelet Transfusion Improves Liver Function in Patients with Chronic Liver Disease and Cirrhosis

Platelet Transfusion Improves Liver Function in Patients with Chronic Liver Disease and Cirrhosis

Purinergic signalling in the liver in health and disease

Stable Liver Function during Long-Term Administration of Eltrombopag, a Thrombopoietin Receptor Agonist, in Patients with Chronic Liver Disease

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