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Habu K, Akamoto S, Imura S, Fujiwara Y, Konishi Y, Fukuhara T, Nakagawa K, Okano K. Laparoscopic Distal Pancreatectomy for Lymph Node Metastasis around Splenic Artery from Hepatocellular Carcinoma in a Patient with Portal Annular Pancreas. Surg Case Rep 2025; 11:24-0130. [PMID: 40265139 PMCID: PMC12012305 DOI: 10.70352/scrj.cr.24-0130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Accepted: 03/27/2025] [Indexed: 04/24/2025] Open
Abstract
INTRODUCTION Lymph node metastases after hepatocellular carcinoma (HCC) resection exist, although they are not common. However, solitary metastasis to the splenic artery lymph node with suspected pancreatic invasion after HCC resection is rare. In certain cases, surgical resection is performed to improve patient outcomes. We report a case of lymph node metastasis resected by laparoscopic distal pancreatectomy (LDP) in a patient with a unique anatomical anomaly known as portal annular pancreas (PAP). CASE PRESENTATION A 79-year-old Japanese man underwent laparoscopic left lateral segmentectomy for HCC. Two months after the surgery, alpha-fetoprotein levels remained elevated. Plain computed tomography revealed a swollen lymph node along the splenic artery involving the pancreas and the PAP. We suspected a solitary metastasis to the lymph node around splenic artery with pancreatic invasion. LDP was performed for complete resection of lymph node metastasis. Although the patient developed a grade B postoperative pancreatic fistula, he was discharged on postoperative day 33 under conservative treatment of antibiotics. He has remained recurrence-free for 4 years and 3 months after surgery. CONCLUSIONS LDP was successfully performed for lymph node metastasis around the splenic artery in an HCC patient and resulted in long-term survival. Surgeons should be aware of the unique anatomical characteristics of PAP during LDP.
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Affiliation(s)
- Kyosuke Habu
- Department of Surgery, Sumitomo Besshi Hospital, Niihama, Ehime, Japan
| | - Shintaro Akamoto
- Department of Surgery, Sumitomo Besshi Hospital, Niihama, Ehime, Japan
| | - Shin Imura
- Department of Surgery, Sumitomo Besshi Hospital, Niihama, Ehime, Japan
| | - Yuta Fujiwara
- Department of Surgery, Sumitomo Besshi Hospital, Niihama, Ehime, Japan
| | - Yusuke Konishi
- Department of Surgery, Sumitomo Besshi Hospital, Niihama, Ehime, Japan
| | - Tetsuji Fukuhara
- Department of Surgery, Sumitomo Besshi Hospital, Niihama, Ehime, Japan
| | - Kazuhiko Nakagawa
- Department of Surgery, Sumitomo Besshi Hospital, Niihama, Ehime, Japan
| | - Keiichi Okano
- Department of Gastroenterological Surgery, Faculty of Medicine, Kagawa University, Miki, Kagawa, Japan
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Raspeño-García JF, González-Granero S, Herranz-Pérez V, Cózar-Cuesta A, Artacho-Pérula E, Insausti R, García-Verdugo JM, de la Rosa-Prieto C. Anatomy, histology and ultrastructure of the adult human olfactory peduncle: Blood vessel and corpora amylacea assessment. Tissue Cell 2025; 93:102737. [PMID: 39827708 DOI: 10.1016/j.tice.2025.102737] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2024] [Revised: 01/08/2025] [Accepted: 01/08/2025] [Indexed: 01/22/2025]
Abstract
The mammalian olfactory system is responsible for processing environmental chemical stimuli and comprises several structures, including the olfactory epithelium, olfactory bulb, olfactory peduncle (OP), and olfactory cortices. Despite the critical role played by the OP in the conduction of olfactory information, it has remained understudied. In this work, optical, confocal, and electron microscopy were employed to examine the anatomy, histology, and ultrastructure of six human OP specimens (ages 37-84 years). Three concentric layers were identified in coronal sections: the external layer (EL), the axonal layer (AL), and the internal layer (IL). Immunohistochemistry revealed the distribution of neurons and glial cells throughout the OP. Two neuronal morphologies were observed: granule cells and larger pyramidal cells, the latter associated with projection neurons of the anterior olfactory nucleus. Astrocytes were uniformly distributed with a more radial morphology in the EL. Oligodendrocytes were mainly located in the AL. Blood vessels (BVs) were evenly distributed along the OP, with a mean luminal area of 82.9 µm² and a density of 1.26 %, with a significant increase in the IL. Corpora amylacea (CA) were abundant, with an average size of 49.3 µm² and a density of 3.23 %. CA clustered near BVs, particularly at tissue edges, with both size and density increasing with age. Notably, CA showed strong associations with astrocytes. This study provides the first detailed qualitative and quantitative data on the internal organization of the human OP, which may contribute to a better understanding of the pathophysiology of some neuropathological disorders.
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Affiliation(s)
- J F Raspeño-García
- Neurogenesis and Neurostereology laboratory, Biomedicine Institute-UCLM, Institute of Health Research of Castilla-La Mancha (IDISCAM), University of Castilla-La Mancha, Albacete, Spain
| | - S González-Granero
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, Valencia, Spain
| | - V Herranz-Pérez
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, Valencia, Spain
| | - A Cózar-Cuesta
- Neurogenesis and Neurostereology laboratory, Biomedicine Institute-UCLM, Institute of Health Research of Castilla-La Mancha (IDISCAM), University of Castilla-La Mancha, Albacete, Spain
| | - E Artacho-Pérula
- Neurogenesis and Neurostereology laboratory, Biomedicine Institute-UCLM, Institute of Health Research of Castilla-La Mancha (IDISCAM), University of Castilla-La Mancha, Albacete, Spain
| | - R Insausti
- Human Neuroanatomy Laboratory, Biomedicine Institute-UCLM, Faculty of Medicine of Albacete, University of Castilla-La Mancha, Albacete, Spain
| | - J M García-Verdugo
- Laboratory of Comparative Neurobiology, Cavanilles Institute of Biodiversity and Evolutionary Biology, University of Valencia and CIBERNED-ISCIII, Valencia, Spain.
| | - C de la Rosa-Prieto
- Neurogenesis and Neurostereology laboratory, Biomedicine Institute-UCLM, Institute of Health Research of Castilla-La Mancha (IDISCAM), University of Castilla-La Mancha, Albacete, Spain.
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Chen M, Zhao JB, Wu GB, Wu ZH, Luo GQ, Zhao ZF, Zhang CH, Lin JY, Li HJ, Qi XL, Huo HZ, Tuersun A, Fan Q, Zheng L, Luo M. Platelet activation relieves liver portal hypertension via the lymphatic system though the classical vascular endothelial growth factor receptor 3 signaling pathway. World J Gastroenterol 2025; 31:100194. [PMID: 40093669 PMCID: PMC11886527 DOI: 10.3748/wjg.v31.i10.100194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Revised: 12/16/2024] [Accepted: 01/21/2025] [Indexed: 02/26/2025] Open
Abstract
BACKGROUND Liver cirrhosis and portal hypertension (PHT) can lead to lymphatic abnormalities and coagulation dysfunction. Because lymphangiogenesis may relieve liver cirrhosis and PHT, the present study investigated the gene expression alterations in the lymphatic system and the effectiveness of platelet-mediated lymphangiogenesis in improving liver cirrhosis and PHT. AIM To investigate the role of lymphangiogenesis in preclinical PHT models. METHODS Immunohistochemistry and transcriptome sequencing of bile duct ligation (BDL) and control lymphatic samples were conducted to reveal the indicated signaling pathways. Functional enrichment analyses were performed on the differentially expressed genes and hub genes. Adenoviral infection of vascular endothelial growth factor C (VEGF-C), platelet-rich plasma (PRP), and VEGF3 receptor (VEGFR) inhibitor MAZ-51 was used as an intervention for the lymphatic system in PHT models. Histology, hemodynamic tests and western blot analyses were performed to demonstrate the effects of lymphatic intervention in PHT patients. RESULTS Lymphangiogenesis was increased in the BDL rat model. Transcriptome sequencing analysis of the extrahepatic lymphatic system revealed its close association with platelet adherence, aggregation, and activation. The role of PHT in the rat model was investigated by activating (PRP) and inhibiting (MAZ-51) the lymphatic system. PRP promoted lymphangiogenesis, which increased lymphatic drainage, alleviated portal pressure, reduced liver fibrosis, inhibited inflammation, inhibited angiogenesis, and suppressed mesenteric artery remodeling. MAZ-51 reversed the above improvements. CONCLUSION Via VEGF-C/VEGFR-3, platelets impede fibrosis, angiogenesis, and mesenteric artery remodeling, ultimately alleviating PHT. Thus, platelet intervention is a therapeutic approach for cirrhosis and PHT.
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Affiliation(s)
- Min Chen
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
- Department of Urology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China
| | - Jin-Bo Zhao
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Guang-Bo Wu
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Zheng-Hao Wu
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Gu-Qing Luo
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Zhi-Feng Zhao
- Xijing Hospital of Digestive Diseases, Air Force Military Medical University, Xi’an 710032, Shaanxi Province, China
| | - Chi-Hao Zhang
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Jia-Yun Lin
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Hong-Jie Li
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Xiao-Liang Qi
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Hai-Zhong Huo
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Abudukadier Tuersun
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Qiang Fan
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Lei Zheng
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Meng Luo
- Department of General Surgery, Ninth People’s Hospital Affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Jiao Tong University, Shanghai 200011, China
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Arya R, Kumar R, Kumar T, Kumar S, Anand U, Priyadarshi RN, Maji T. Prevalence and risk factors of lymphatic dysfunction in cirrhosis patients with refractory ascites: An often unconsidered mechanism. World J Hepatol 2023; 15:1140-1152. [PMID: 37970615 PMCID: PMC10642429 DOI: 10.4254/wjh.v15.i10.1140] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Revised: 09/14/2023] [Accepted: 10/08/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND The lymphatic system is crucial in maintaining the body fluid homeostasis. A dysfunctional lymphatic system may contribute to the refractoriness of ascites and edema in cirrhosis patients. Therefore, assessment of lymphatic dysfunction in cirrhosis patients with refractory ascites (RA) can be crucial as it would call for using different strategies for fluid mobilization. AIM To assessing the magnitude, spectrum, and clinical associations of lymphatic dysfunction in liver cirrhosis patients with RA. METHODS This observational study included 155 consecutive cirrhosis patients with RA. The presence of clinical signs of lymphedema, such as peau d'orange appearance and positive Stemmer sign, intestinal lymphangiectasia (IL) on duodenal biopsy seen as dilated vessels in the lamina propria with strong D2-40 immunohistochemistry, and chylous ascites were used to diagnose the overt lymphatic dysfunctions. RESULTS A total of 69 (44.5%) patients out of 155 had evidence of lymphatic dysfunction. Peripheral lymphedema, found in 52 (33.5%) patients, was the most common manifestation, followed by IL in 42 (27.0%) patients, and chylous ascites in 2 (1.9%) patients. Compared to patients without lymphedema, those with lymphedema had higher mean age, median model for end-stage liver disease scores, mean body mass index, mean ascitic fluid triglyceride levels, and proportion of patients with hypoproteinemia (serum total protein < 5 g/dL) and lymphocytopenia (< 15% of total leukocyte count). Patients with IL also had a higher prevalence of lymphocytopenia and hypoproteinemia (28.6% vs. 9.1%, P = 0.004). Seven (13%) patients with lymphedema had lower limb cellulitis compared to none in those without it. On multivariate regression analysis, factors independently associated with lymphatic dysfunction included obesity [odds ratio (OR): 4.2, 95% confidence intervals (95%CI): 1.1-15.2, P = 0.027], lymphocytopenia [OR: 6.2, 95%CI: 2.9-13.2, P < 0.001], and hypoproteinemia [OR: 3.7, 95%CI: 1.5-8.82, P = 0.003]. CONCLUSION Lymphatic dysfunction is common in cirrhosis patients with RA. Significant indicators of its presence include hypoproteinemia and lymphocytopenia, which are likely due to the loss of lymphatic fluid from the circulation. Future efforts to mobilize fluid in these patients should focus on methods to improve lymphatic drainage.
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Affiliation(s)
- Rahul Arya
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
| | - Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India.
| | - Tarun Kumar
- Department of Pathology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
| | - Sudhir Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
| | - Utpal Anand
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
| | - Rajeev Nayan Priyadarshi
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Patna 801507, Bihar, India
| | - Tanmoy Maji
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
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Juneja P, Sharma A, Shasthry SM, Kumar G, Tripathi DM, Rajan V, Rastogi A, Sarin SK, Kaur S. Podoplanin-positive dilated lymphatic vessels in duodenum associates with three-month mortality in patients with cirrhosis. Front Physiol 2023; 14:1045983. [PMID: 37304826 PMCID: PMC10248415 DOI: 10.3389/fphys.2023.1045983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 05/16/2023] [Indexed: 06/13/2023] Open
Abstract
Dilated and dysfunctional gut lymphatic vessels (LVs) have been reported in experimental cirrhosis. Here, we studied LVs in duodenal (D2)-biopsies of liver cirrhosis patients and investigated the prognostic role of a LV marker, podoplanin (PDPN), in predicting the mortality of patients with cirrhosis. A prospective, single-center cohort study was performed in liver cirrhosis patients (n = 31) and matched healthy controls (n = 9). D2-biopsies were obtained during endoscopy procedure, immunostained with PDPN, and scored based on 1) intensity and 2) density of positively-stained LVs per high power field. Gut and systemic inflammation were estimated by quantifying duodenal CD3+ intraepithelial lymphocytes (IELs), CD68+ macrophages, and serum TNF-α and IL-6 levels, respectively. Gut permeability and inflammation as assessed by quantifying gene expression of TJP1, OCLN, TNF-α, and IL-6 in D2-biopsies. Gene expression of LV markers, PDPN (8-fold), and LYVE1 (3-fold) was enhanced in D2-biopsies of cirrhosis patients compared to control (p < 0.0001). The mean PDPN score in decompensated cirrhosis patients (6.91 ± 1.26, p < 0.0001) was significantly increased as compared to those with compensated (3.25 ± 1.60). PDPN score positively and significantly correlated with the number of IELs (r = 0.33), serum TNF-α (r = 0.35), and IL-6 (r = 0.48) levels, while inversely correlated with TJP1 expression (r = -0.46, p < 0.05 each). In Cox regression, the PDPN score was a significant and independent 3-month-mortality predictor in patients (HR: 5.61; 1.08-29.109; p = 0.04). The area under the curve for the PDPN score was 84.2, and cutoff value for predicting mortality was ≥6.5 with 100% sensitivity and 75% specificity. Collectively, dilated LVs with high PDPN expression in D2-biopsies is a characteristic feature of patients with decompensated cirrhosis. PDPN score correlates with enhanced gut and systemic inflammation and also associates with 3-month mortality in cirrhosis.
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Affiliation(s)
- Pinky Juneja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Aarti Sharma
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - S. M. Shasthry
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Guresh Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Dinesh M. Tripathi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - V. Rajan
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Savneet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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Sakamoto K, Ogawa K, Tamura K, Honjo M, Funamizu N, Takada Y. Prognostic Role of the Intrahepatic Lymphatic System in Liver Cancer. Cancers (Basel) 2023; 15:2142. [PMID: 37046803 PMCID: PMC10093457 DOI: 10.3390/cancers15072142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 03/30/2023] [Accepted: 04/03/2023] [Indexed: 04/08/2023] Open
Abstract
Although several prognosticators, such as lymph node metastasis (LNM), were reported for hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), the prognostic impact of intrahepatic lymphatic vessel invasion (LVI) in liver cancer has rarely been reported. We sought to clarify the prognostic impact of intrahepatic lymphatic system involvement in liver cancer. We systematically reviewed retrospective studies that described LVI and clinical outcomes of liver cancer and also included studies that investigated tumor-associated lymphangiogenesis. We conducted a meta-analysis using RevMan software (version 5.4.1; Cochrane Collaboration, Oxford, UK). The prognostic impact of intrahepatic LVI in HCC was not reported previously. However, tumor-associated lymphangiogenesis reportedly correlates with prognosis after HCC resection. The prognostic impact of intrahepatic LVI was reported severally for ICC and a meta-analysis showed that overall survival was poorer in patients with positive LVI than with negative LVI after resection of ICC. Lymphangiogenesis was also reported to predict unfavorable prognosis in ICC. Regarding colorectal liver metastases, LVI was identified as a poor prognosticator in a meta-analysis. A few reports showed correlations between LVI/lymphangiogenesis and LNM in liver cancer. LVI and lymphangiogenesis showed worse prognostic impacts for liver cancer than their absence, but further study is needed.
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Affiliation(s)
- Katsunori Sakamoto
- Department of Hepato-Biliary-Pancreatic and Breast Surgery, Ehime University Graduate School of Medicine, 454 Kou, Shitsukawa, Toon 791-0295, Ehime, Japan
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Hassan M, Juanola O, Keller I, Nanni P, Wolski W, Martínez-López S, Caparrós E, Francés R, Moghadamrad S. Paneth Cells Regulate Lymphangiogenesis under Control of Microbial Signals during Experimental Portal Hypertension. Biomedicines 2022; 10:biomedicines10071503. [PMID: 35884808 PMCID: PMC9313283 DOI: 10.3390/biomedicines10071503] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/15/2022] [Accepted: 06/22/2022] [Indexed: 11/16/2022] Open
Abstract
Intestinal microbiota can modulate portal hypertension through the regulation of the intestinal vasculature. We have recently demonstrated that bacterial antigens activate Paneth cells (PCs) to secrete products that regulate angiogenesis and portal hypertension. In the present work we hypothesized that Paneth cells regulate the development of lymphatic vessels under the control of intestinal microbiota during experimental portal hypertension. We used a mouse model of inducible PCs depletion (Math1Lox/LoxVilCreERT2) and performed partial portal vein ligation (PPVL) to induce portal hypertension. After 14 days, we performed mRNA sequencing and evaluated the expression of specific lymphangiogenic genes in small intestinal tissue. Intestinal and mesenteric lymphatic vessels proliferation was assessed by immunohistochemistry. Intestinal organoids with or without PCs were exposed to pathogen-associated molecular patterns, and conditioned media (CM) was used to stimulate human lymphatic endothelial cells (LECs). The lymphangiogenic activity of stimulated LECs was assessed by tube formation and wound healing assays. Secretome analysis of CM was performed using label-free proteomics quantification methods. Intestinal immune cell infiltration was evaluated by immunohistochemistry. We observed that the intestinal gene expression pattern was altered by the absence of PCs only in portal hypertensive mice. We found a decreased expression of specific lymphangiogenic genes in the absence of PCs during portal hypertension, resulting in a reduced proliferation of intestinal and mesenteric lymphatic vessels as compared to controls. In vitro analyses demonstrated that lymphatic tube formation and endothelial wound healing responses were reduced significantly in LECs treated with CM from organoids without PCs. Secretome analyses of CM revealed that PCs secrete proteins that are involved in lipid metabolism, cell growth and proliferation. Additionally, intestinal macrophages infiltrated the ileal mucosa and submucosa of mice with and without Paneth cells in response to portal hypertension. Our results suggest that intestinal microbiota signals stimulate Paneth cells to secrete factors that modulate the intestinal and mesenteric lymphatic vessels network during experimental portal hypertension.
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Affiliation(s)
- Mohsin Hassan
- Department of Hepatology & Gastroenterology, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany;
- Department for Biomedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
| | - Oriol Juanola
- Laboratories for Translational Research, Department of Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland;
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6900 Lugano, Switzerland
| | - Irene Keller
- Interfaculty Bioinformatics Unit, Swiss Institute of Bioinformatics, University of Bern, 3008 Bern, Switzerland;
| | - Paolo Nanni
- Functional Genomics Center Zurich, University/ETH Zurich, 8057 Zurich, Switzerland; (P.N.); (W.W.)
| | - Witold Wolski
- Functional Genomics Center Zurich, University/ETH Zurich, 8057 Zurich, Switzerland; (P.N.); (W.W.)
| | - Sebastián Martínez-López
- Hepatic and Intestinal Immunobiology Group, Departamento Medicina Clínica, Universidad Miguel Hernández, 03550 Alicante, Spain; (S.M.-L.); (E.C.); (R.F.)
- Instituto de Investigación Sanitaria ISABIAL, Hospital General Universitario, 03010 Alicante, Spain
| | - Esther Caparrós
- Hepatic and Intestinal Immunobiology Group, Departamento Medicina Clínica, Universidad Miguel Hernández, 03550 Alicante, Spain; (S.M.-L.); (E.C.); (R.F.)
- Instituto de Investigación Sanitaria ISABIAL, Hospital General Universitario, 03010 Alicante, Spain
| | - Rubén Francés
- Hepatic and Intestinal Immunobiology Group, Departamento Medicina Clínica, Universidad Miguel Hernández, 03550 Alicante, Spain; (S.M.-L.); (E.C.); (R.F.)
- Instituto de Investigación Sanitaria ISABIAL, Hospital General Universitario, 03010 Alicante, Spain
- Instituto de Investigación, Desarrollo e Innovación en Biotecnología Sanitaria de Elche (IDiBE), Universidad Miguel Hernández, 03207 Elche, Spain
- CIBERehd, Instituto Salud Carlos III, 28029 Madrid, Spain
| | - Sheida Moghadamrad
- Department for Biomedical Research (DBMR), University of Bern, 3008 Bern, Switzerland
- Laboratories for Translational Research, Department of Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, 6500 Bellinzona, Switzerland;
- Faculty of Biomedical Sciences, Università della Svizzera Italiana, 6900 Lugano, Switzerland
- University Clinic of Visceral Surgery and Medicine, Inselspital, 3008 Bern, Switzerland
- Correspondence: ; Tel.: +41-58-666-7117
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ASSATO AK, PASINATO APBF, CIRQUEIRA CDS, WAKAMATSU A, ALVES VAF. IMMUNOHISTOCHEMICAL ASSESSMENT OF LYMPHATIC VESSELS IN HUMAN LIVERS WITH CHRONIC HEPATITIS C - RELATION TO HISTOLOGICAL VARIABLES. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:58-64. [DOI: 10.1590/s0004-2803.202200001-11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 10/22/2021] [Indexed: 11/22/2022]
Abstract
ABSTRACT Background Viral hepatitis C is a significant public health challenge. The disease may remain clinically silent in both acute and chronic forms, and chronic infections may progress to advanced disease such as cirrhosis and hepatocellular carcinoma, requiring costly treatment, compromising the patient’s quality of life and even leading to death. For this reason, it is one of the most frequent indications for liver transplantation. Although treatment with direct-acting antivirals represents remarkable progress, many patients are still infected and even those who cleared the viral infection must be followed due to their previous hepatic lesions, especially regarding the disturbances of lobular architecture and the sanguineal and lymphatic vessels. Objective To assess immunohistochemical aspects of lymphatic sprouts and mature lymphatic vascularity with histological variables of liver injury attributable to hepatitis C virus (HCV) and fatty disease. Methods The present study included 72 liver biopsies of cases with chronic hepatitis C. Morphologic changes reflecting “staging” and “activity” were analyzed. Immunohistochemical reactions were performed with monoclonal antibody D2-40 anti-podoplanin. Major histological variables were also semiquantified so as to enable the search for possible associations among histological and Immunohistochemical criteria, as well as with genotypes 1 and 3 of HCV. Results Histological findings showed that the different degrees of strutural changes were well represented in this casuistic. Intralobular/parenchymal necro-inflammatory activity was predominantly mild to moderate. Most cases did not show major evidences of fatty disease, which was found significantly higher in cases infected with HCV genotype 3. The amount of portal lymphatic sprouts increased along with the progression of structural changes, maximal at cirrhosis. Portal lymphatic sprouts as well as portal mature lymphatic vessels also showed an increase parallel to the increase in the degree of portal/septal inflammatory infiltrate. In the present study, no significant association was found between the proportion of portal lymphatic sprouts or portal mature lymphatic vessels and the degree of periportal/periseptal activity. No significant relations were detected between lymphatic sprouts/mature vessels and periportal or parenchymal inflammatory activity, nor with infections due to HCV genotype 1 or 3. Conclusion Visualization and semiquantitation of sprouts and mature lymphatic vessels were clearly yielded by Immunohistochemical staining with monoclonal antibody D2-40. The amount of lymphatics was increased along fibrogenic process, significantly related to progression of liver disease and maximal at cirrhosis. No significant relations were detected with necro-inflammatory activity at interface or in the parenchyma.
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Roy S, Banerjee P, Ekser B, Bayless K, Zawieja D, Alpini G, Glaser SS, Chakraborty S. Targeting Lymphangiogenesis and Lymph Node Metastasis in Liver Cancer. THE AMERICAN JOURNAL OF PATHOLOGY 2021; 191:2052-2063. [PMID: 34509441 PMCID: PMC8647434 DOI: 10.1016/j.ajpath.2021.08.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/21/2021] [Accepted: 08/26/2021] [Indexed: 12/17/2022]
Abstract
Increased lymphangiogenesis and lymph node metastasis, the important prognostic indicators of aggressive hepatobiliary malignancies such as hepatocellular cancer and cholangiocarcinoma, are associated with poor patient outcome. The liver produces 25% to 50% of total lymphatic fluid in the body and has a dense network of lymphatic vessels. The lymphatic system plays critical roles in fluid homeostasis and inflammation and immune response. Yet, lymphatic vessel alterations and function are grossly understudied in the context of liver pathology. Expansion of the lymphatic network has been documented in clinical samples of liver cancer; and although largely overlooked in the liver, tumor-induced lymphangiogenesis is an important player, increasing tumor metastasis in several cancers. This review aims to provide a detailed perspective on the current knowledge of alterations in the hepatic lymphatic system during liver malignancies, as well as various molecular signaling mechanisms and growth factors that may provide future targets for therapeutic intervention. In addition, the review also addresses current mechanisms and bottlenecks for effective therapeutic targeting of tumor-associated lymphangiogenesis.
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Affiliation(s)
- Sukanya Roy
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Priyanka Banerjee
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Burcin Ekser
- Division of Transplant Surgery, Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kayla Bayless
- Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - David Zawieja
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, Indiana; Richard L Roudebush VA Medical Center, Indianapolis, Indiana
| | - Shannon S Glaser
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas
| | - Sanjukta Chakraborty
- Department of Medical Physiology, College of Medicine, Texas A&M University Health Science Center, Bryan, Texas.
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10
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Kumar R, Anand U, Priyadarshi RN. Lymphatic dysfunction in advanced cirrhosis: Contextual perspective and clinical implications. World J Hepatol 2021; 13:300-314. [PMID: 33815674 PMCID: PMC8006079 DOI: 10.4254/wjh.v13.i3.300] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/31/2021] [Accepted: 03/10/2021] [Indexed: 02/06/2023] Open
Abstract
The lymphatic system plays a very important role in body fluid homeostasis, adaptive immunity, and the transportation of lipid and waste products. In patients with liver cirrhosis, capillary filtration markedly increases, primarily due to a rise in hydrostatic pressure, leading to enhanced production of lymph. Initially, lymphatic vasculature expansion helps to prevent fluid from accumulating by returning it back to the systemic circulation. However, the lymphatic functions become compromised with the progression of cirrhosis and, consequently, the lymphatic compensatory mechanism gets overwhelmed, contributing to the development and eventual worsening of ascites and edema. Neurohormonal changes, low-grade chronic inflammation, and compounding effects of predisposing factors such as old age, obesity, and metabolic syndrome appear to play a significant role in the lymphatic dysfunction of cirrhosis. Sustained portal hypertension can contribute to the development of intestinal lymphangiectasia, which may rupture into the intestinal lumen, resulting in the loss of protein, chylomicrons, and lymphocyte, with many clinical consequences. Rarely, due to high pressure, the rupture of the subserosal lymphatics into the abdomen results in the formation of chylous ascites. Despite being highly significant, lymphatic dysfunctions in cirrhosis have largely been ignored; its mechanistic pathogenesis and clinical implications have not been studied in depth. No recommendation exists for the diagnostic evaluation and therapeutic strategies, with respect to lymphatic dysfunction in patients with cirrhosis. This article discusses the perspectives and clinical implications, and provides insights into the management strategies for lymphatic dysfunction in patients with cirrhosis.
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Affiliation(s)
- Ramesh Kumar
- Department of Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India.
| | - Utpal Anand
- Department of Surgical Gastroenterology, All India Institute of Medical Sciences, Patna 801507, Bihar, India
| | - Rajeev Nayan Priyadarshi
- Department of Radiodiagnosis, All India Institute of Medical Sciences, Patna 801507, Bihar, India
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11
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Hirooka M, Koizumi Y, Tanaka T, Sunago K, Nakamura Y, Yukimoto A, Watanabe T, Yoshida O, Tokumoto Y, Abe M, Hiasa Y. Dilatation of lymphatic vessels increases liver stiffness on transient elastography irrespective of fibrosis. Hepatol Res 2021; 51:284-293. [PMID: 33368940 DOI: 10.1111/hepr.13610] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/25/2020] [Accepted: 12/10/2020] [Indexed: 02/08/2023]
Abstract
AIM Liver stiffness measured using transient elastography (TE) is affected by tissue viscosity. The role of intrahepatic lymphatic fluid in liver stiffness is unclear. The present study aimed to investigate the effects of lymphatic vessel dilatation on liver stiffness. METHODS Patients with chronic liver disease (n = 116) were enrolled from June 2018 to March 2020. All specimens were acquired by laparoscopic liver biopsy. Biopsy samples were stained with D2-40 for lymphatic vessel quantification based on a five-point scale for each specimen. Independent associations of liver stiffness measured by TE, strain elasticity (liver fibrosis index), and controlled attenuation parameter with fibrosis, lymphatic vessels, alanine aminotransferase, bilirubin, and steatosis were evaluated. RESULTS Fibrosis, splenic stiffness measurement, and splenic volume were significantly correlated with the area of lymphatic vessels. Fibrosis, lymphatic vessels, and alanine aminotransferase were independent factors significantly associated with liver stiffness measurement (LSM; standardized coefficient [β] = 0.375, P < 0.001; β = 0.342, P < 0.001; and β = 0.359, P < 0.001, respectively). Fibrosis was the only independent factor significantly associated with liver fibrosis index (β = 0.360, P < 0.001), whereas the fat deposit area was the only independent factor significantly associated with controlled attenuation parameter (β = 0.455, P < 0.001). The areas under the receiver operating characteristic curves for diagnosing controlled ascites based on LSM, liver fibrosis index, splenic stiffness measurement, collagen proportionate area, and area of lymphatic vessels were 0.94, 0.66, 0.76, 0.64, and 0.79, respectively. CONCLUSIONS Lymphatic vessel dilatation can affect liver stiffness measured using TE. Liver stiffness measurement is a predictive factor for ascites.
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Affiliation(s)
- Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Takaaki Tanaka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Kotarou Sunago
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yoshiko Nakamura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Atsushi Yukimoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Toon, Japan
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12
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Nakamoto S, Ito Y, Nishizawa N, Goto T, Kojo K, Kumamoto Y, Watanabe M, Majima M. Lymphangiogenesis and accumulation of reparative macrophages contribute to liver repair after hepatic ischemia-reperfusion injury. Angiogenesis 2020; 23:395-410. [PMID: 32162023 DOI: 10.1007/s10456-020-09718-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 03/02/2020] [Indexed: 12/20/2022]
Abstract
Hepatic tissue repair plays a critical role in determining the outcome of hepatic ischemia-reperfusion (I/R) injury. Hepatic lymphatics participate in the clearance of dead tissues and contribute to the reparative process after acute hepatic injury; however, it remains unknown whether lymphangiogenesis in response to hepatic inflammation is involved in liver repair. Herein, we determined if hepatic lymphangiogenesis improves liver repair after hepatic I/R injury. Using a mouse model of hepatic I/R injury, we investigated hepatic lymphatic structure, growth, and function in injured murine livers. Hepatic I/R injury enhanced lymphangiogenesis around the portal tract and this was associated with increased expression of pro-lymphangiogenic growth factors including vascular endothelial growth factor (VEGF)-C and VEGF-D. Recombinant VEGF-D treatment facilitated liver repair in association with the expansion of lymphatic vessels and increased expression of genes related to the reparative macrophage phenotype. Treatment with a VEGF receptor 3 (VEGFR3) inhibitor suppressed liver repair, lymphangiogenesis, drainage function, and accumulation of VEGFR3-expressing reparative macrophages. VEGF-C and VEGF-D upregulated expression of genes related to lymphangiogenic factors and the reparative macrophage phenotype in cultured macrophages. These results suggest that activation of VEGFR3 signaling increases lymphangiogenesis and the number of reparative macrophages, both of which play roles in liver repair. Expanded lymphatics and induction of reparative macrophage accumulation may be therapeutic targets to enhance liver repair after hepatic injury.
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Affiliation(s)
- Shuji Nakamoto
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Kanagawa, Sagamihara, 252-0374, Japan
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yoshiya Ito
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Kanagawa, Sagamihara, 252-0374, Japan
| | - Nobuyuki Nishizawa
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Takuya Goto
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Kanagawa, Sagamihara, 252-0374, Japan
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Ken Kojo
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Yusuke Kumamoto
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Masahiko Watanabe
- Department of Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa, Japan
| | - Masataka Majima
- Department of Molecular Pharmacology, Graduate School of Medical Sciences, Kitasato University, Sagamihara, Kanagawa, Japan.
- Department of Pharmacology, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Kanagawa, Sagamihara, 252-0374, Japan.
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13
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Pawlak JB, Caron KM. Lymphatic Programing and Specialization in Hybrid Vessels. Front Physiol 2020; 11:114. [PMID: 32153423 PMCID: PMC7044189 DOI: 10.3389/fphys.2020.00114] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2019] [Accepted: 01/31/2020] [Indexed: 12/14/2022] Open
Abstract
Building on a large body of existing blood vascular research, advances in lymphatic research have helped kindle broader investigations into vascular diversity and endothelial plasticity. While the endothelium of blood and lymphatic vessels can be distinguished by a variety of molecular markers, the endothelia of uniquely diverse vascular beds can possess distinctly heterogeneous or hybrid expression patterns. These expression patterns can then provide further insight on the development of these vessels and how they perform their specialized function. In this review we examine five highly specialized hybrid vessel beds that adopt partial lymphatic programing for their specialized vascular functions: the high endothelial venules of secondary lymphoid organs, the liver sinusoid, the Schlemm’s canal of the eye, the renal ascending vasa recta, and the remodeled placental spiral artery. We summarize the morphology and endothelial expression pattern of these vessels, compare them to each other, and interrogate their specialized functions within the broader blood and lymphatic vascular systems.
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Affiliation(s)
- John B Pawlak
- Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Kathleen M Caron
- Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
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14
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Burchill MA, Goldberg AR, Tamburini BAJ. Emerging Roles for Lymphatics in Chronic Liver Disease. Front Physiol 2020; 10:1579. [PMID: 31992991 PMCID: PMC6971163 DOI: 10.3389/fphys.2019.01579] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2019] [Accepted: 12/17/2019] [Indexed: 12/17/2022] Open
Abstract
Chronic liver disease (CLD) is a global health epidemic causing ∼2 million deaths annually worldwide. As the incidence of CLD is expected to rise over the next decade, understanding the cellular and molecular mediators of CLD is critical for developing novel therapeutics. Common characteristics of CLD include steatosis, inflammation, and cholesterol accumulation in the liver. While the lymphatic system in the liver has largely been overlooked, the liver lymphatics, as in other organs, are thought to play a critical role in maintaining normal hepatic function by assisting in the removal of protein, cholesterol, and immune infiltrate. Lymphatic growth, permeability, and/or hyperplasia in non-liver organs has been demonstrated to be caused by obesity or hypercholesterolemia in humans and animal models. While it is still unclear if changes in permeability occur in liver lymphatics, the lymphatics do expand in number and size in all disease etiologies tested. This is consistent with the lymphatic endothelial cells (LEC) upregulating proliferation specific genes, however, other transcriptional changes occur in liver LECs that are dependent on the inflammatory mediators that are specific to the disease etiology. Whether these changes induce lymphatic dysfunction or if they impact liver function has yet to be directly addressed. Here, we will review what is known about liver lymphatics in health and disease, what can be learned from recent work on the influence of obesity and hypercholesterolemia on the lymphatics in other organs, changes that occur in LECs in the liver during disease and outstanding questions in the field.
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Affiliation(s)
- Matthew A Burchill
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO, United States
| | - Alyssa R Goldberg
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO, United States.,Section of Pediatric Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children's Hospital Colorado, Aurora, CO, United States
| | - Beth A Jirón Tamburini
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO, United States.,Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus, School of Medicine, Aurora, CO, United States
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15
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Tamburini BAJ, Finlon JM, Gillen AE, Kriss MS, Riemondy KA, Fu R, Schuyler RP, Hesselberth JR, Rosen HR, Burchill MA. Chronic Liver Disease in Humans Causes Expansion and Differentiation of Liver Lymphatic Endothelial Cells. Front Immunol 2019; 10:1036. [PMID: 31156626 PMCID: PMC6530422 DOI: 10.3389/fimmu.2019.01036] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Accepted: 04/23/2019] [Indexed: 12/21/2022] Open
Abstract
Liver lymphatic vessels support liver function by draining interstitial fluid, cholesterol, fat, and immune cells for surveillance in the liver draining lymph node. Chronic liver disease is associated with increased inflammation and immune cell infiltrate. However, it is currently unknown if or how lymphatic vessels respond to increased inflammation and immune cell infiltrate in the liver during chronic disease. Here we demonstrate that lymphatic vessel abundance increases in patients with chronic liver disease and is associated with areas of fibrosis and immune cell infiltration. Using single-cell mRNA sequencing and multi-spectral immunofluorescence analysis we identified liver lymphatic endothelial cells and found that chronic liver disease results in lymphatic endothelial cells (LECs) that are in active cell cycle with increased expression of CCL21. Additionally, we found that LECs from patients with NASH adopt a transcriptional program associated with increased IL13 signaling. Moreover, we found that oxidized low density lipoprotein, associated with NASH pathogenesis, induced the transcription and protein production of IL13 in LECs both in vitro and in a mouse model. Finally, we show that oxidized low density lipoprotein reduced the transcription of PROX1 and decreased lymphatic stability. Together these data indicate that LECs are active participants in the liver, expanding in an attempt to maintain tissue homeostasis. However, when inflammatory signals, such as oxidized low density lipoprotein are increased, as in NASH, lymphatic function declines and liver homeostasis is impeded.
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Affiliation(s)
- Beth A Jiron Tamburini
- Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, United States.,Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO, United States.,RNA Biosciences Initiative, School of Medicine, University of Colorado, Aurora, CO, United States
| | - Jeffrey M Finlon
- Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, United States
| | - Austin E Gillen
- RNA Biosciences Initiative, School of Medicine, University of Colorado, Aurora, CO, United States
| | - Michael S Kriss
- Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, United States
| | - Kent A Riemondy
- RNA Biosciences Initiative, School of Medicine, University of Colorado, Aurora, CO, United States
| | - Rui Fu
- RNA Biosciences Initiative, School of Medicine, University of Colorado, Aurora, CO, United States
| | - Ronald P Schuyler
- Department of Immunology and Microbiology, School of Medicine, University of Colorado, Aurora, CO, United States
| | - Jay R Hesselberth
- RNA Biosciences Initiative, School of Medicine, University of Colorado, Aurora, CO, United States.,Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado, Aurora, CO, United States
| | - Hugo R Rosen
- Keck School of Medicine, University of Southern California, Los Angeles, CA, United States
| | - Matthew A Burchill
- Division of Gastroenterology and Hepatology, Department of Medicine, School of Medicine, University of Colorado, Aurora, CO, United States.,RNA Biosciences Initiative, School of Medicine, University of Colorado, Aurora, CO, United States
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16
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Finlon JM, Burchill MA, Tamburini BAJ. Digestion of the Murine Liver for a Flow Cytometric Analysis of Lymphatic Endothelial Cells. J Vis Exp 2019. [PMID: 30663671 DOI: 10.3791/58621] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Within the liver, lymphatic vessels are found within the portal triad, and their described function is to remove interstitial fluid from the liver to the lymph nodes where cellular debris and antigens can be surveyed. We are very interested in understanding how the lymphatic vasculature might be involved in inflammation and immune cell function within the liver. However, very little has been published establishing digestion protocols for the isolation of lymphatic endothelial cells (LECs) from the liver or specific markers that can be used to evaluate liver LECs on a per cell basis. Therefore, we optimized a method for the digestion and staining of the liver in order to evaluate the LEC population in the liver. We are confident that the method outlined here will be useful for the identification and isolation of LECs from the liver and will strengthen our understanding of how LECs respond to the liver microenvironment.
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Affiliation(s)
- Jeffrey M Finlon
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, School of Medicine
| | - Matthew A Burchill
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, School of Medicine
| | - Beth A Jirón Tamburini
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, School of Medicine; Department of Immunology and Microbiology, University of Colorado Anschutz Medical Campus;
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17
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18
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Choi CB, Park YB, Lee SW. Antineutrophil Cytoplasmic Antibody-Associated Vasculitis in Korea: A Narrative Review. Yonsei Med J 2019; 60:10-21. [PMID: 30554486 PMCID: PMC6298898 DOI: 10.3349/ymj.2019.60.1.10] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Indexed: 12/15/2022] Open
Abstract
Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a group of systemic necrotising vasculitides, which often involve small vessels, and which lead to few or no immune deposits in affected organs. According to clinical manifestations and pathological features, AAV is classified into three variants: microscopic polyangiitis, granulomatosis with polyangiitis (GPA), and eosinophilic GPA. The American College of Rheumatology 1990 criteria contributed to the classification of AAV, although currently the algorithm suggested by the European Medicines Agency in 2007 and the Chapel Hill Consensus Conference Nomenclature of Vasculitides proposed in 2012 have encouraged physicians to classify AAV patients properly. So far, there have been noticeable advancements in studies on the pathophysiology of AAV and the classification criteria for AAV in Western countries. However, studies analysing clinical features of Korean patients with AAV have only been conducted and reported since 2000. One year-, 5 year-, and 10 year-cumulative patient survival rates are reported as 96.1, 94.8, and 92.8%. Furthermore, initial vasculitis activity, prognostic factor score, age and specific organ-involvement have been found to be associated with either all-cause mortality or poor disease course. The rate of serious infection is 28.6%, and 1 year-, 5 year- and 10 year-cumulative hospitalised infection free survival rates range from 85.1% to 72.7%. The overall standardised incidence ratio of cancer in AAV patients was deemed 1.43 compared to the general Korean population.
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Affiliation(s)
- Chan Bum Choi
- Department of Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, Korea
| | - Yong Beom Park
- Division of Rheumatology, Department of Internal Medicine, and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Won Lee
- Division of Rheumatology, Department of Internal Medicine, and Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.
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19
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Yokomori H, Ando W, Kaneko F, Suzuki H, Igarashi K, Oda M. Autotaxin and vascular endothelial growth factor receptor-2 and -3 are related to vascular development during the progression of chronic viral hepatitis C. APMIS 2018; 126:913-921. [PMID: 30456868 DOI: 10.1111/apm.12904] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 10/15/2018] [Indexed: 11/28/2022]
Abstract
Vascular endothelial growth factor (VEGF) and autotaxin (ATX) play important roles in embryonic vasculogenesis and cancer progression. This study examines whether these two angiogenic factors cooperate in the mechanism that regulates vascular development during the progression of chronic viral hepatitis C (CVH-C) (Inuyama classification, F1-F4). First, surgical wedge biopsy specimens and needle biopsy specimens were obtained. Immunohistochemical staining for ATX and vascular endothelial growth factor receptor was assessed in serial sections. Immunoelectron microscopy was conducted with a perfusion-fixation method. In normal control liver tissue specimens, ATX was expressed at low levels within the branches of the hepatic artery and hepatic sinusoids. In F1 CVH-C liver tissue specimens, ATX was expressed within the branches of the hepatic artery. Additionally, VEGFR-2 was expressed within the branches of the hepatic artery and capillaries. In F3-F4 CVH-C liver tissue specimens, positive staining for ATX and VEGFR-2 or VEGFR-3 was detected in the branches of the hepatic artery or microlymphatic vessels. ATX-1 reaction products were specifically expressed on the plasma membrane of some microvascular endothelial cells (ECs) in the proliferative capillary artery. VEGFR-2 was expressed on caveolae in ECs and vascular smooth muscle cells. VEGFR-3 immunogold particles were also observed in lymphatic ECs. These results suggest functional interactions among ATX, VEGFR-2, and VEGFR-3 in the modulation of hemovascular and lymphovascular cell activation during vascular development.
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Affiliation(s)
- Hiroaki Yokomori
- Department of Internal Medicine, Kitasato University Medical Center, Saitama, Japan
| | - Wataru Ando
- Department of Clinical Pharmacy, School of Pharmacy, Kitasato University, Tokyo, Japan
| | - Fumihiko Kaneko
- Department of Internal Medicine, Saitama Medical Center, Saitama, Japan
| | - Hidekazu Suzuki
- Medical Education Center, School of Medicine, Keio University, Tokyo, Japan
| | - Koji Igarashi
- Bioscience Division, Reagent Development Department, AIA Research Group Tosoh Corp., Kanagawa, Japan
| | - Masaya Oda
- Organized Center of Clinical Medicine, International University of Health and Welfare, Tokyo, Japan
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20
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Tanaka M, Iwakiri Y. Lymphatics in the liver. Curr Opin Immunol 2018; 53:137-142. [PMID: 29772409 DOI: 10.1016/j.coi.2018.04.028] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Accepted: 04/27/2018] [Indexed: 01/13/2023]
Abstract
The liver is the largest lymph producing organ. A significant increase in the number of hepatic lymphatic vessels, or lymphangiogenesis, has been reported in various liver diseases, including, but not limited to, cirrhosis, viral hepatitis and hepatocellular carcinoma. Despite its apparent relevance in healthy and diseased livers as these and other observations indicate, the hepatic lymphatic system has been poorly studied. With knowledge of the lymphatic system in other organs and tissues incorporated, this review article addresses the current knowledge of the hepatic lymphatic system and the potential role of lymphatic endothelial cells in the health and the disease of the liver and concludes with a brief description on future directions of the study of the hepatic lymphatic system.
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Affiliation(s)
- Masatake Tanaka
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA
| | - Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
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21
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Abstract
Liver sinusoidal endothelial cells (LSECs) line the low shear, sinusoidal capillary channels of the liver and are the most abundant non-parenchymal hepatic cell population. LSECs do not simply form a barrier within the hepatic sinusoids but have vital physiological and immunological functions, including filtration, endocytosis, antigen presentation and leukocyte recruitment. Reflecting these multifunctional properties, LSECs display unique structural and phenotypic features that differentiate them from the capillary endothelium present within other organs. It is now clear that LSECs have a critical role in maintaining immune homeostasis within the liver and in mediating the immune response during acute and chronic liver injury. In this Review, we outline how LSECs influence the immune microenvironment within the liver and discuss their contribution to immune-mediated liver diseases and the complications of fibrosis and carcinogenesis.
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22
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Abd El-Aal NF, Hamza RS, Magdy M. Anti-angiogenic and anti-lymphangiogenic role of praziquantel and artemether in experimental mansoniasis. Acta Parasitol 2017; 62:708-716. [PMID: 29035850 DOI: 10.1515/ap-2017-0085] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Accepted: 06/28/2017] [Indexed: 12/15/2022]
Abstract
Angiogenesis is one of the pillars of neoplasia. Lymphangiogenesis in context of granulomas is not yet understood. This study aimed to evaluate the role of praziquantel (PZQ) and artemether (ART) as anti-angiogenic and anti-lymphangiogenic drugs in Schistosoma mansoni induced experimental hepatic model through immunohistochemical and serological studies, this can be used as a potential novel prophylactic approach in hepatic malignancy prevention and possible management. Forty female CD-1 Swiss albino mice were used divided into 4 groups (10 mice each); control healthy, control infected untreated, PZQ-treated and ART-treated. Angiogenic and lymphangiogenic effect of the drugs assessed pathologically through counting of the newly formed capillaries and lymphatics that immunohistochemically expressed by vascular Endothelial Growth Factor (VEGF), CD34 and D2-40 in liver sections using Cell Image Analyzer and serologically by evaluation of serum level of Tumor Necrosis Factor-Alpha (TNF-α). Our results showed significant decrease in serum TNF-α in ART-treated group compared to control infected and PZQ treated groups. ART exhibited significant anti-angiogenic role on granulomas illustrated by remarkable milder intensity and significantly lower expression values of VEGF and CD34 immunostaining compared to PZQ and non-treated groups. Also, ART treated group exhibited negative D2-40 expression in the granulomas in contrast to the other groups, supporting the potent ART' anti-lymphangiogenic role that exceeded PZQ. In conclusion, ART showed not only anti-angiogenic effect but also prominent anti-lymphangiogenic effect on hepatic S. mansoni granulomas compared to PZQ. Our study supports the potential use of ART as a potential novel prophylactic approach in hepatic malignancy prevention and possible management.
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Asano Y, Shimoda H, Matsusaki M, Akashi M. Transplantation of artificial human lymphatic vascular tissues fabricated using a cell‐accumulation technique and their engraftment in mouse tissue with vascular remodelling. J Tissue Eng Regen Med 2017; 12:e1501-e1510. [DOI: 10.1002/term.2570] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2016] [Revised: 07/31/2017] [Accepted: 08/31/2017] [Indexed: 12/12/2022]
Affiliation(s)
- Yoshiya Asano
- Department of Neuroanatomy, Cell Biology and HistologyHirosaki University Graduate School of Medicine Hirosaki Aomori Japan
| | - Hiroshi Shimoda
- Department of Neuroanatomy, Cell Biology and HistologyHirosaki University Graduate School of Medicine Hirosaki Aomori Japan
- Department of Anatomical ScienceHirosaki University Graduate School of Medicine Hirosaki Aomori Japan
| | - Michiya Matsusaki
- Department of Applied Chemistry, Graduate School of EngineeringOsaka University Osaka Japan
| | - Mitsuru Akashi
- Building Block Science, Graduate School of Frontier BiosciencesOsaka University Osaka Japan
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Lukacs-Kornek V. The Role of Lymphatic Endothelial Cells in Liver Injury and Tumor Development. Front Immunol 2016; 7:548. [PMID: 27965673 PMCID: PMC5127193 DOI: 10.3389/fimmu.2016.00548] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2016] [Accepted: 11/16/2016] [Indexed: 01/20/2023] Open
Abstract
Lymphatics and lymphatic endothelial cells (LECs) possess multiple immunological functions besides affecting immune cell migration, such as inhibiting T cell proliferation and antigen presentation by dendritic cells. Moreover, they control the trans-endothelial transport of multiple molecules and antigens. Emerging evidence suggest their active involvements in immunregulation, tumor, and metastases formation. In the liver, increased lymphangiogenesis, specifically at the portal area has been associated with multiple liver diseases in particular primary biliary cirrhosis, idiopathic portal hypertension, and liver malignancies. Nevertheless, the exact role and contribution of LECs to liver diseases are poorly understood. The review summarizes the current understanding of LECs in liver diseases.
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Tanaka M, Iwakiri Y. The Hepatic Lymphatic Vascular System: Structure, Function, Markers, and Lymphangiogenesis. Cell Mol Gastroenterol Hepatol 2016; 2:733-749. [PMID: 28105461 PMCID: PMC5240041 DOI: 10.1016/j.jcmgh.2016.09.002] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2016] [Accepted: 09/02/2016] [Indexed: 02/06/2023]
Abstract
The lymphatic vascular system has been minimally explored in the liver despite its essential functions including maintenance of tissue fluid homeostasis. The discovery of specific markers for lymphatic endothelial cells has advanced the study of lymphatics by methods including imaging, cell isolation, and transgenic animal models and has resulted in rapid progress in lymphatic vascular research during the last decade. These studies have yielded concrete evidence that lymphatic vessel dysfunction plays an important role in the pathogenesis of many diseases. This article reviews the current knowledge of the structure, function, and markers of the hepatic lymphatic vascular system as well as factors associated with hepatic lymphangiogenesis and compares liver lymphatics with those in other tissues.
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Key Words
- CCl4, carbon tetrachloride
- Cirrhosis
- EHE, epithelioid hemangioendothelioma
- HA, hyaluronan
- HBx Ag, hepatitis B x antigen
- HCC, hepatocellular carcinoma
- IFN, interferon
- IL, interleukin
- Inflammation
- LSEC, liver sinusoidal endothelial cell
- LYVE-1, lymphatic vessel endothelial hyaluronan receptor 1
- LyEC, lymphatic endothelial cell
- NO, nitric oxide
- Portal Hypertension
- Prox1, prospero homeobox protein 1
- VEGF
- VEGF, vascular endothelial growth factor
- VEGFR, vascular endothelial growth factor receptor
- mTOR, mammalian target of rapamycin
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Affiliation(s)
| | - Yasuko Iwakiri
- Reprint requests Address requests for reprints to: Yasuko Iwakiri, PhD, Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, TAC S223B, 333 Cedar Street, New Haven, Connecticut 06520. fax: (203) 785-7273.Section of Digestive DiseasesDepartment of Internal MedicineYale University School of MedicineTAC S223B, 333 Cedar StreetNew HavenConnecticut 06520
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Lee BS, Lee BC, Park JE, Choi HK, Choi SJ, Soh KS. Primo Vascular System in Human Umbilical Cord and Placenta. J Acupunct Meridian Stud 2014; 7:291-7. [DOI: 10.1016/j.jams.2014.09.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2014] [Accepted: 09/29/2014] [Indexed: 11/16/2022] Open
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