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4 results on '"Miku Okawara"'

1. Cluster of Differentiation 44 Promotes Liver Fibrosis and Serves as a Biomarker in Congestive Hepatopathy

Author

Yosuke Osawa, Hironari Kawai, Tomoyuki Tsunoda, Haruki Komatsu, Miku Okawara, Yuriko Tsutsui, Yuichi Yoshida, Shiori Yoshikawa, Taizo Mori, Taiji Yamazoe, Sachiyo Yoshio, Takashi Oide, Ayano Inui, and Tatsuya Kanto

Subjects
Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Congestive hepatopathy (CH) with chronic passive congestion is characterized by the progression of liver fibrosis without prominent inflammation and hepatocellular damage. Currently, the lack of reliable biomarkers for liver fibrosis in CH often precludes the clinical management of patients with CH. To explore fibrosis biomarkers, we performed proteome analysis on serum exosomes isolated from patients with CH after the Fontan procedure. Exosomal cluster of differentiation (CD)44 levels were increased in patients with CH compared to healthy volunteers and was accompanied by increases in serum levels of soluble CD44 and CD44 expression in the liver. To address the roles of CD44 in CH, we established a mouse model of chronic liver congestion by partial inferior vena cava ligation (pIVCL) that mimics CH by fibrosis progression with less inflammation and cellular damage. In the pIVCL mice, enhanced CD44 expression in hepatic stellate cells (HSCs) and deposition of its ligand hyaluronan were observed in the liver. Blood levels of soluble CD44 were correlated with liver fibrosis. The blockade of CD44 with specific antibody inhibited liver fibrosis in pIVCL mice and was accompanied by a reduction in S100 calcium‐binding protein A4 expression following activation of HSCs. Conclusion: Chronic liver congestion promotes fibrosis through CD44. This identifies CD44 as a novel biomarker and therapeutic target of liver fibrosis in patients with CH.

Published
2021
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2. Blood angiopoietin-2 predicts liver angiogenesis and fibrosis in hepatitis C patients

Author

Yosuke Osawa, Sachiyo Yoshio, Yoshihiko Aoki, Masaaki Korenaga, Masatoshi Imamura, Takashi Oide, Miku Okawara, Hironari Kawai, Yuriko Tsutsui, Yuichi Yoshida, Shiori Yoshikawa, Taizo Mori, Taiji Yamazoe, and Tatsuya Kanto

Subjects
Angiogenesis, Angiopoietin-2, Carbon tetrachloride, Chronic hepatitis C, Endothelin-1, Liver fibrosis, Diseases of the digestive system. Gastroenterology, RC799-869
Abstract

Abstract Background Pathological angiogenesis is involved in the development of hepatocellular carcinoma. In patients with chronic hepatitis C (CHC), the level of angiogenic factor angiopoietin (ANGP)-2 is reported to be increased in the blood, correlating with fibrosis. In this study, we aimed to clarify whether blood ANGP-2 is useful as a biomarker for liver angiogenesis and fibrosis in CHC patients and to further reveal the relationship between such pathology in a carbon tetrachloride (CCl4)-treated liver fibrosis mouse model. Methods Plasma levels of ANGP-2, expression of a liver sinusoidal endothelial cell (LSEC) marker (CD31), collagen deposition (Sirius Red staining) in the liver, clinical fibrosis markers (Mac-2 binding protein glycosylation isomer, virtual touch quantification, and liver stiffness measurement), and liver function (albumin bilirubin score) were examined in CHC patients. To determine the effects of an anti-angiogenic agent on liver fibrosis in vivo, sorafenib was administered to the CCl4-treated mice (BALB/c male). Results The plasma levels of ANGP-2 were increased in CHC patients compared to healthy volunteers and decreased by the eradication of hepatitis C with direct-acting antivirals. In addition, plasma ANGP-2 levels were correlated with CD31 expression, collagen deposition, clinical fibrosis markers, and liver function. Sorafenib inhibited liver angiogenesis and fibrosis in the CCl4-treated mice and was accompanied by decreased ANGP-2 expression in LSECs. Conclusions ANGP-2 may serve as a useful biomarker for liver angiogenesis and fibrosis in CHC patients. In addition, angiogenesis and fibrosis may be closely related.

Published
2021
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3. Peripheral-dominant liver fibrosis and tumor distribution in a mouse model of congestive hepatopathy

Author

Hironari Kawai, Yosuke Osawa, Tomoyuki Tsunoda, Michitaka Matsuda, Miku Okawara, Yuzuru Sakamoto, Tomonari Shimagaki, Yuriko Tsutsui, Yuichi Yoshida, Shiori Yoshikawa, Hiroyoshi Doi, Taizo Mori, Taiji Yamazoe, Sachiyo Yoshio, Tadashi Okamura, Masaya Sugiyama, Daisuke Okuzaki, Haruki Komatsu, Ayano Inui, Katsuhiko Yanaga, Toru Ikegami, and Tatsuya Kanto

Subjects
Infectious Diseases, Hepatology
Abstract

Congestive hepatopathy often leads to liver fibrosis and hepatocellular carcinoma. Imaging modalities provided clinical evidence that elevation of liver stiffness and tumor occurrence are mainly induced in liver periphery of patients with congestive hepatopathy. However, clinical relevance of liver stiffness and liver fibrosis is unclear because liver congestion itself increases liver stiffness in congestive hepatopathy. It also unclear which factors configure such regional disparity of tumor development in patients with congestive hepatopathy. To answer these questions, we evaluated the macroscopic spatial distribution of liver fibrosis and tumors in murine model of congestive hepatopathy.Chronic liver congestion was induced by partial ligation of the suprahepatic inferior vena cava (pIVCL). Distribution of liver congestion, fibrosis, and tumors in pIVCL mice was assessed by histological findings, laser microdissection (LMD)-based qPCR and enhanced computed tomography. LMD-based RNA-seq was performed to identify causal factors which promotes tumor development in congestive hepatopathy.Liver fibrosis was mainly induced in liver periphery and co-localized with distribution of liver congestion. Liver tumors were also induced in liver periphery where liver congestion and fibrosis occurred. LMD-based RNA-seq revealed the upregulation of extracellular matrix/collagen fibril related-, wound healing related-, angiogenesis related-, morphogenesis related-, and cell motility-related signaling pathways in liver periphery compared to liver center.Our findings showed experimental relevance of liver congestion, fibrosis and tumor development in congestive hepatopathy, and may provide important locational information. Macroscopic regional disparity observed in this murine model should be considered to manage patients with congestive hepatopathy. This article is protected by copyright. All rights reserved.

Published
2022

4. Sphingosine-1-phosphate promotes tumor development and liver fibrosis in mouse model of congestive hepatopathy

Author

Miku Okawara, Katsuhiko Yanaga, Hiroyoshi Doi, Shiori Yoshikawa, Keisuke Yanagida, Hironori Kusano, Masaya Sugiyama, Yuriko Tsutsui, Yosuke Osawa, Tomoyuki Tsunoda, Tomonari Shimagaki, Taizo Mori, Yuichi Yoshida, Kana Hashi, Ayano Inui, Daisuke Okuzaki, Daisuke Hishikawa, Hideo Shindou, Sachiyo Yoshio, Taiji Yamazoe, Toru Ikegami, Masayoshi Kage, Yuzuru Sakamoto, Hironari Kawai, Tatsuya Kanto, Chinatsu Oyama, Michitaka Matsuda, Haruki Komatsu, and Miwa Tamura-Nakano

Subjects
Lipopolysaccharides, Liver Cirrhosis, Liver tumor, Carcinoma, Hepatocellular, Inferior vena cava, Liver disease, Mice, Fibrosis, Sphingosine, medicine, Animals, Humans, Vascular Diseases, Heart Failure, Hepatology, biology, business.industry, Liver Neoplasms, medicine.disease, Disease Models, Animal, Receptors, Lysosphingolipid, Congestive hepatopathy, medicine.vein, Sphingosine kinase 1, Hepatocellular carcinoma, Cancer research, biology.protein, Lysophospholipids, Liver cancer, business
Abstract

Background & aims Chronic liver congestion reflecting right-sided heart failure (RHF), Budd-Chiari syndrome, or Fontan-associated liver disease (FALD) is involved in liver fibrosis and hepatocellular carcinoma (HCC). However, molecular mechanisms of fibrosis and HCC in chronic liver congestion remain poorly understood. Approach & results Here, we first demonstrated that chronic liver congestion promoted HCC and metastatic liver tumor growth using murine model of chronic liver congestion by partial inferior vena cava ligation (pIVCL). As the initial step triggering HCC promotion and fibrosis, gut-derived lipopolysaccharide (LPS) appeared to induce liver sinusoidal endothelial cells (LSECs) capillarization in mice and in vitro. LSECs capillarization was also confirmed in FALD patients. Mitogenic factor, sphingosine-1-phosphate (S1P) was increased in congestive liver and expression of sphingosine kinase 1 (SphK1), a major synthetase of S1P, was increased in capillarized LSECs after pIVCL. Inhibition of S1P receptor (S1PR)1 (Ex26) and S1PR2 (JTE013) mitigated HCC development and liver fibrosis, respectively. Antimicrobials treatment lowered portal blood LPS concentration, LSECs capillarization, and liver S1P concentration accompanied by reduction of HCC development and fibrosis in the congestive liver. Conclusions In conclusion, chronic liver congestion promotes HCC development and liver fibrosis by S1P production from LPS-induced capillarized LSECs. Careful treatment of both RHF and liver cancer might be necessary for RHF patients with primary or metastatic liver cancer.

Published
2021

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