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Yanovskiy A, Ojala T, Kormi A, Kivisaari R, Peltonen J, Martelius L. Peripheral vs. central parametric mapping of the liver in single ventricle patients: Measurement location matters. Eur J Radiol 2025; 188:112158. [PMID: 40334366 DOI: 10.1016/j.ejrad.2025.112158] [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: 10/14/2024] [Revised: 04/16/2025] [Accepted: 05/01/2025] [Indexed: 05/09/2025]
Abstract
BACKGROUND Fontan circulation often results in Fontan-associated liver disease, typically challenging to detect early. MRI liver parametric mapping shows potential for tissue characterization, but institution-specific reference values hinder comparability. This study investigates whether the peripheral-to-central mapping ratio can serve as a surrogate for absolute mapping values. METHODS The retrospective single tertiary center cohort study included 68 pediatric patients with single ventricle anomalies and 25 healthy controls. Parametric mapping values were measured in three liver regions, comparing central region and peripheral areas of both liver lobes. RESULTS There was a strong positive correlation between the T1 ratio and T1 mean (r = 0.68, p < 0.001), and a moderate positive correlation between the T2 ratio and T2 mean (r = 0.46, p < 0.001). T1 and T2 mapping ratios exhibited the highest values in post-total cavopulmonary connection (TCPC) patients (p < 0.05). Post-TCPC patients had significantly higher T1 and T2 mapping, and ECV values in the right lobe compared to the left lobe (p < 0.05). T1 mean showed significant weak associations with duration of post-TCPC follow-up (r = 0.3, p = 0.029), ejection fraction (r = -0.36, p = 0.006), oxygen saturation (r = -0.31, p = 0.022), and univentricular end-diastolic volume (r = 0.27, p = 0.043), and severe lymphatic collaterals were linked to higher T1 mean values (p = 0.024) in post-TCPC patients. Absolute T1 values were significantly higher in cirrhosis across all tested regions (p < 0.05). The T1 ratio was significantly associated with the duration of post-TCPC follow-up (r = 0.27, p = 0.041). CONCLUSIONS Measurement location influences liver parametric mapping values. The T1 ratio shows the most promise among the peripheral-to-central ratios, though its associations with hemodynamics are weaker than those of absolute values.
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Affiliation(s)
- Anna Yanovskiy
- HUS Medical Imaging Center, Helsinki University Hospital, University of Helsinki, Finland.
| | - Tiina Ojala
- Department of Pediatric Cardiology, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Finland
| | - Alma Kormi
- Department of Pediatric Cardiology, New Children's Hospital, Helsinki University Hospital and University of Helsinki, Finland
| | - Reetta Kivisaari
- HUS Medical Imaging Center, Helsinki University Hospital, University of Helsinki, Finland
| | - Juha Peltonen
- HUS Medical Imaging Center, Helsinki University Hospital, University of Helsinki, Finland
| | - Laura Martelius
- HUS Medical Imaging Center, Helsinki University Hospital, University of Helsinki, Finland
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2
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Juneja P, Yadav R, Tripathi DM, Kaur S. The interplay between lymphatic system and portal hypertension: a comprehensive review. Hepatol Int 2025:10.1007/s12072-025-10815-5. [PMID: 40178721 DOI: 10.1007/s12072-025-10815-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 02/28/2025] [Indexed: 04/05/2025]
Abstract
BACKGROUND The pathophysiology of portal hypertension revolves around numerous structural and functional changes in the intra- and extra-hepatic vascular compartments. In recent years, a dysfunction of the lymphatic system has garnered increasing attention as one of the key sequelae of portal hypertension. PURPOSE AND METHODS The review comprehensively deliberates about the anatomical and functional attributes of the hepatic lymphatic system during portal hypertension. Along with liver lymphatic system, important modifications that occur in extrahepatic lymphatics during advanced liver disease are discussed. RESULTS During progression of liver disease, elevated portal pressures cause increased sinusoidal blood and enhanced lymph flow, leading to dilation and proliferation of hepatic lymphatic vessels. In advanced liver disease, portal and central lymphatic systems also undergo profound changes to accommodate increased lymph flows. These changes in lymphatic system seem to have evolved as compensatory mechanisms to alleviate enhanced portal pressures. However, further increase in the splanchnic lymph production causes a complete failure of the drainage capacity of local and central lymphatic vessels, leading to maldistribution of extracellular fluid along with immune system anomalies aggravating ascites and pathological bacterial translocation. CONCLUSION Lymphatic dysfunction plays a crucial role in the progression and complications of portal hypertension. Development of routine imaging techniques for lymphatic vessels in clinics, protocols for measuring lymphovenous pressure gradient and in vitro and in vivo experimental studies are requisite to further our understanding in this field. Targeting lymphatic dysfunction could offer promising therapeutic options for managing cirrhosis, portal hypertension and related complications.
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Affiliation(s)
- Pinky Juneja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rajni Yadav
- Department of Molecular and Cellular Medicine, 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
| | - Savneet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India.
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Mocan D, Jipa R, Jipa DA, Lala RI, Rasinar FC, Groza I, Sabau R, Sulea Bratu D, Balta DF, Cioban ST, Puschita M. Unveiling the Systemic Impact of Congestion in Heart Failure: A Narrative Review of Multisystem Pathophysiology and Clinical Implications. J Cardiovasc Dev Dis 2025; 12:124. [PMID: 40278183 PMCID: PMC12028304 DOI: 10.3390/jcdd12040124] [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: 02/23/2025] [Revised: 03/25/2025] [Accepted: 03/27/2025] [Indexed: 04/26/2025] Open
Abstract
Congestion is a key clinical feature of heart failure (HF), contributing to hospitalizations, disease progression, and poor outcomes. While traditionally considered a hemodynamic issue, congestion is now recognized as a systemic process affecting multiple organs. Renal dysfunction arises from impaired perfusion and sodium retention, leading to maladaptive left ventricular remodeling. Hepatic congestion contributes to cholestatic liver injury, while metabolic disturbances drive anemia, muscle wasting, and systemic inflammation. Additionally, congestion disrupts the intestinal barrier and immune function, exacerbating HF progression. Given its widespread impact, effective congestion management requires a shift from a cardiovascular-centered approach to a comprehensive, multidisciplinary strategy. Targeted decongestive therapy, metabolic and nutritional optimization, and immune modulation are crucial in mitigating congestion-related organ dysfunction. Early recognition and intervention are essential to slow disease progression, preserve functional capacity, and improve survival. Addressing HF congestion through personalized, evidence-based strategies is vital for optimizing long-term care and advancing treatment paradigms.
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Affiliation(s)
- Daniela Mocan
- Multidisciplinary Doctoral School, Vasile Goldis Western University of Arad, 310025 Arad, Romania; (D.M.); (R.I.L.); (M.P.)
- Research Center of the Institute of Cardiovascular Diseases Timisoara, 300310 Timisoara, Romania
- Department VII, Internal Medicine II, Discipline of Cardiology, University of Medicine and Pharmacy “Victor Babes” Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
- Institute of Cardiovascular Diseases of Timisoara, 300310 Timisoara, Romania
| | - Radu Jipa
- Faculty of Medicine, Department of “Life Sciences”, Vasile Goldis Western University of Arad, Romania 86, Liviu Rebreanu Street, 310048 Arad, Romania
- Arad County Clinical Emergency Hospital, 310037 Arad, Romania
| | - Daniel Alexandru Jipa
- Doctoral School, Victor Babes University of Timisoara, 300041 Timisoara, Romania;
- Victor Babes Clinical Hospital for Infectious Diseases and Pneumology of Timisoara, 300041 Timisoara, Romania
| | - Radu Ioan Lala
- Multidisciplinary Doctoral School, Vasile Goldis Western University of Arad, 310025 Arad, Romania; (D.M.); (R.I.L.); (M.P.)
- Victor Babes Clinical Hospital for Infectious Diseases and Pneumology of Timisoara, 300041 Timisoara, Romania
| | - Florin Claudiu Rasinar
- Research Center of the Institute of Cardiovascular Diseases Timisoara, 300310 Timisoara, Romania
- Department VII, Internal Medicine II, Discipline of Cardiology, University of Medicine and Pharmacy “Victor Babes” Timisoara, E. Murgu Square, Nr. 2, 300041 Timisoara, Romania
- Institute of Cardiovascular Diseases of Timisoara, 300310 Timisoara, Romania
- Doctoral School, Victor Babes University of Timisoara, 300041 Timisoara, Romania;
| | - Iulia Groza
- Arad County Clinical Emergency Hospital, 310037 Arad, Romania
- Doctoral School, Victor Babes University of Timisoara, 300041 Timisoara, Romania;
| | - Ronela Sabau
- Arad County Clinical Emergency Hospital, 310037 Arad, Romania
| | | | - Diana Federica Balta
- Multidisciplinary Doctoral School, Vasile Goldis Western University of Arad, 310025 Arad, Romania; (D.M.); (R.I.L.); (M.P.)
- Arad County Clinical Emergency Hospital, 310037 Arad, Romania
| | | | - Maria Puschita
- Multidisciplinary Doctoral School, Vasile Goldis Western University of Arad, 310025 Arad, Romania; (D.M.); (R.I.L.); (M.P.)
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Farooq MA, Johnston APR, Trevaskis NL. Impact of nanoparticle properties on immune cell interactions in the lymph node. Acta Biomater 2025; 193:65-82. [PMID: 39701340 DOI: 10.1016/j.actbio.2024.12.039] [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: 08/07/2024] [Revised: 11/21/2024] [Accepted: 12/16/2024] [Indexed: 12/21/2024]
Abstract
The lymphatic system plays an important role in health and many diseases, such as cancer, autoimmune, cardiovascular, metabolic, hepatic, viral, and other infectious diseases. The lymphatic system is, therefore, an important treatment target site for a range of diseases. Lymph nodes (LNs), rich in T cells, B cells, dendritic cells, and macrophages, are also primary sites of action for vaccines and immunotherapies. Promoting the delivery of therapeutics and vaccines to LNs can, therefore, enhance treatment efficacy and facilitate avoidance of off-target side effects by enabling a reduction in therapeutic dose. Several nanoparticle (NP) based delivery systems, such as polymeric NPs, lipid NPs, liposomes, micelles, and dendrimers, have been reported to enhance the delivery of therapeutics and/or vaccines to LNs. Specific uptake into the lymph following injection into tissues is highly dependent on particle properties, particularly particle size, as small molecules are more likely to be taken up by blood capillaries due to higher blood flow rates, whereas larger molecules and NPs can be specifically transported via the lymphatic vessels to LNs as the initial lymphatic capillaries are more permeable than blood capillaries. Once NPs enter LNs, particle properties also have an important influence on their disposition within the node and association with immune cells, which has significant implications for the design of vaccines and immunotherapies. This review article focuses on the impact of NP properties, such as size, surface charge and modification, and route of administration, on lymphatic uptake, retention, and interactions with immune cells in LNs. We suggest that optimizing all these factors can enhance the efficacy of vaccines or therapeutics with targets in the lymphatics and also be helpful for the rational design of vaccines. STATEMENT OF SIGNIFICANCE: The lymphatic system plays an essential role in health and is an important treatment target site for a range of diseases. Promoting the delivery of immunotherapies and vaccines to immune cells in lymph nodes can enhance efficacy and facilitate avoidance of off-target side effects by enabling a reduction in therapeutic dose. One of the major approaches used to deliver therapeutics and vaccines to lymph nodes is via injection in nanoparticle delivery systems. This review aims to provide an overview of the impact of nanoparticle properties, such as size, surface charge, modification, and route of administration, on lymphatic uptake, lymph node retention, and interactions with immune cells in lymph nodes. This will inform the design of future improved nanoparticle systems for vaccines and immunotherapies.
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Affiliation(s)
- Muhammad Asim Farooq
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia
| | - Angus P R Johnston
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia
| | - Natalie L Trevaskis
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 399 Royal Parade, Parkville, VIC 3052, Australia.
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Janardhan HP, Wachter BT, Trivedi CM. Lymphatic System Development and Function. Curr Cardiol Rep 2024; 26:1209-1219. [PMID: 39172295 DOI: 10.1007/s11886-024-02120-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/13/2024] [Indexed: 08/23/2024]
Abstract
PURPOSE OF REVIEW This review delves into recent advancements in understanding generalized and organ-specific lymphatic development. It emphasizes the distinct characteristics and critical anomalies that can impair lymphatic function. By exploring developmental mechanisms, the review seeks to illuminate the profound impact of lymphatic malformations on overall health and disease progression. RECENT FINDINGS The introduction of genome sequencing, single-cell transcriptomic analysis, and advanced imaging technologies has significantly enhanced our ability to identify and characterize developmental defects within the lymphatic system. As a result, a wide range of lymphatic anomalies have been uncovered, spanning from congenital abnormalities present at birth to conditions that can become life-threatening in adulthood. Additionally, recent research highlights the heterogeneity of lymphatics, revealing organ-specific developmental pathways, unique molecular markers, and specialized physiological functions specific to each organ. A deeper understanding of the unique characteristics of lymphatic cell populations in an organ-specific context is essential for guiding future research into lymphatic disease processes. An integrated approach to translational research could revolutionize personalized medicine, where treatments are precisely tailored to individual lymphatic profiles, enhancing effectiveness and minimizing side effects.
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Affiliation(s)
- Harish P Janardhan
- Division of Cardiovascular Medicine, UMass Chan Medical School, Worcester, MA, 01605, USA
- Department of Medicine, UMass Chan Medical School, Worcester, MA, 01605, USA
| | - Brianna T Wachter
- Division of Cardiovascular Medicine, UMass Chan Medical School, Worcester, MA, 01605, USA
- Department of Medicine, UMass Chan Medical School, Worcester, MA, 01605, USA
- MD-PhD Program, Morningside Graduate School of Biomedical Sciences, UMass Chan Medical School, Worcester, MA, 01605, USA
| | - Chinmay M Trivedi
- Division of Cardiovascular Medicine, UMass Chan Medical School, Worcester, MA, 01605, USA.
- Department of Medicine, UMass Chan Medical School, Worcester, MA, 01605, USA.
- MD-PhD Program, Morningside Graduate School of Biomedical Sciences, UMass Chan Medical School, Worcester, MA, 01605, USA.
- Department of Molecular, Cell, and Cancer Biology, UMass Chan Medical School, Worcester, MA, 01605, USA.
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Ahn Y, Koo HJ, Choe J, Chu HH, Yang DH, Kang JW, Shin JH. Single-Center Experience With Dynamic Contrast-Enhanced Magnetic Resonance Lymphangiography for Diagnosing Lymphatic Disorders and Guiding Percutaneous Embolization. J Korean Med Sci 2024; 39:e260. [PMID: 39403749 PMCID: PMC11473261 DOI: 10.3346/jkms.2024.39.e260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Accepted: 07/28/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND The pragmatic role of dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) needs to be evaluated and compared across distinct lymphatic disorders. We aimed to evaluate the performance of DCMRL for identifying the underlying causes of lymphatic disorders and to define the potential benefit of DCMRL for planning lymphatic interventions. METHODS Patients who underwent DCMRL between August 2017 and July 2022 were included in this retrospective analysis. DCMRL was performed with intranodal injection of a gadolinium-based contrast medium through inguinal lymph nodes under local anesthesia. Technical success of DCMRL and feasibility of percutaneous embolization were assessed based on the lymphatic anatomy visualized by DCMRL. Based on the underlying causes, clinical outcomes were evaluated and compared. RESULTS Seventy consecutive patients were included. The indications were traumatic chylothorax (n = 42), traumatic chylous ascites (n = 11), and nontraumatic lymphatic leak (n = 17). The technical success rate of DCMRL was the highest in association with nontraumatic lymphatic disorders (94.1% [16/17]), followed by traumatic chylothorax (92.9% [39/42]) and traumatic chylous ascites (81.8% [9/11]). Thirty-one (47.7%) patients among 65 patients who underwent technically successful DCMRL had feasible anatomy for intervention. Clinical success was achieved in 90.3% (28/31) of patients with feasible anatomy for radiologic intervention, while 62.5% (10/16) of patients with anatomical challenges showed improvement. Most patients with traumatic chylothorax showed improvement (92.9% [39/42]), whereas only 23.5% (4/17) of patients with nontraumatic lymphatic disorders showed clinical improvement. CONCLUSION DCMRL can help identify the underlying causes of lymphatic disorders. The performance of DCMRL and clinical outcomes vary based on the underlying cause. The feasibility of lymphatic intervention can be determined using DCMRL, which can help in predicting clinical outcomes.
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Affiliation(s)
- Yura Ahn
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyun Jung Koo
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jooae Choe
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hee Ho Chu
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong Hyun Yang
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Joon-Won Kang
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ji Hoon Shin
- Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
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Kosaka S, Muraji T, Ohtani H, Harumatsu T, Shimizu S, Toma M, Yanai T, Ieiri S. Lymphangiogenesis in the liver of biliary atresia. BMC Gastroenterol 2024; 24:266. [PMID: 39143576 PMCID: PMC11325597 DOI: 10.1186/s12876-024-03370-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 08/13/2024] [Indexed: 08/16/2024] Open
Abstract
BACKGROUND Lymphatic vessels (LVs) play a crucial role in immune reactions by serving as the principal conduits for immune cells. However, to date, no study has analyzed the morphological changes in the LVs of patients with biliary atresia (BA). In this study, we aimed to determine the morphological changes in the LVs irrigating the liver in patients with BA, elucidate their correlations with the morphology of the portal vein (PV) branches, and discuss their etiopathogenetic significance. METHODS Morphometric analyses of liver biopsy specimens from patients treated between 1986 and 2016 were performed. The parameters measured were as follows: the whole liver area of the specimen, fibrotic area, number of LVs, LVs without patent lumen (designated as Ly0) and PV branches, and diameters of the LVs with patent lumen and the PVs. RESULTS The numbers of LVs, Ly0, and PV branches per unit area of the whole liver specimen were significantly higher in patients with BA than in control participants with liver disease and those with normal livers. However, no correlation was observed between the fibrotic area and the average diameter of LVs or PVs, and between the fibrotic area and the number of LVs or PV branches. Furthermore, no correlation was observed between the total number of LVs and the number of PV branches. CONCLUSIONS The present study showed a significant increase in the number of total LVs and Ly0, characterized by a high Ly0 to total LVs ratio, suggesting that lymphangiogenesis occurs in the liver of patients with BA.
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Affiliation(s)
- Seitaro Kosaka
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Ibaraki, Japan.
- Department of Pediatric General and Urogenital Surgery, Juntendo University School of Medicine, 3-3-13 Hongo, Bunkyo-Ku, Tokyo, Japan.
| | - Toshihiro Muraji
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Haruo Ohtani
- Department of Pathology, Ibaraki Children's Hospital, Ibaraki, Japan
| | - Toshio Harumatsu
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Sakika Shimizu
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Ibaraki, Japan
| | - Miki Toma
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Ibaraki, Japan
| | - Toshihiro Yanai
- Department of Pediatric Surgery, Ibaraki Children's Hospital, Ibaraki, Japan
| | - Satoshi Ieiri
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
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Pastrovic F, Novak R, Grgurevic I, Hrkac S, Salai G, Zarak M, Grgurevic L. Serum proteomic profiling of patients with compensated advanced chronic liver disease with and without clinically significant portal hypertension. PLoS One 2024; 19:e0301416. [PMID: 38603681 PMCID: PMC11008873 DOI: 10.1371/journal.pone.0301416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 03/16/2024] [Indexed: 04/13/2024] Open
Abstract
INTRODUCTION Portal hypertension (PH) drives the progression of liver cirrhosis to decompensation and death. Hepatic venous pressure gradient (HVPG) measurement is the standard of PH quantification, and HVPG≥10 mmHg defines clinically significant PH (CSPH). We performed proteomics-based serum profiling to search for a proteomic signature of CSPH in patients with compensated advanced chronic liver disease (cACLD). MATERIALS AND METHODS Consecutive patients with histologically confirmed cACLD and results of HVPG measurements were prospectively included. Serum samples were pooled according to the presence/absence of CSPH and analysed by liquid chromatography-mass spectrometry. Gene set enrichment analysis was performed, followed by comprehensive literature review for proteins identified with the most striking difference between the groups. RESULTS We included 48 patients (30 with, and 18 without CSPH). Protein CD44, involved in the inflammatory response, vascular endothelial growth factor C (VEGF-C) and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), both involved in lymphangiogenesis were found solely in the CSPH group. Although identified in both groups, proteins involved in neutrophil extracellular traps (NET) formation, as well as tenascin C, autotaxin and nephronectin which mediate vascular contractility and lymphangiogenesis were more abundant in CSPH. DISCUSSION AND CONCLUSION We propose that altered inflammatory response, including NET formation, vascular contractility and formation of new lymph vessels are key steps in PH development. Proteins such as CD44, VEGF-C, LYVE-1, tenascin C, Plasminogen activator inhibitor 1, Nephronectin, Bactericidal permeability-increasing protein, Autotaxin, Myeloperoxidase and a disintegrin and metalloproteinase with thrombospondin motifs-like protein 4 might be considered for further validation as potential therapeutic targets and candidate biomarkers of CSPH in cACLD.
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Affiliation(s)
- Frane Pastrovic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, Laboratory for Liver Diseases and Portal Hypertension, University Hospital Dubrava, Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
| | - Rudjer Novak
- Department of Proteomics, Center for Translational and Clinical Research, University of Zagreb School of Medicine, Zagreb, Croatia
- University of Zagreb, School of Medicine, Zagreb, Croatia
- Biomedical Research Center Salata, University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, Laboratory for Liver Diseases and Portal Hypertension, University Hospital Dubrava, Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
- University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Stela Hrkac
- Department of Clinical Immunology, Allergology and Rheumatology, University Hospital Dubrava, Zagreb, Croatia
| | - Grgur Salai
- Department of Pulmonology, University Hospital Dubrava, Zagreb, Croatia
| | - Marko Zarak
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
- Clinical Department of Laboratory Diagnostics, University Hospital Dubrava, Zagreb, Croatia
| | - Lovorka Grgurevic
- Department of Proteomics, Center for Translational and Clinical Research, University of Zagreb School of Medicine, Zagreb, Croatia
- Biomedical Research Center Salata, University of Zagreb, School of Medicine, Zagreb, Croatia
- Department of Anatomy, ˝Drago Perovic˝, School of Medicine, University of Zagreb, Zagreb, Croatia
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Yano R, Hirooka M, Koizumi Y, Nakamura Y, Imai Y, Morita M, Okazaki Y, Watanabe T, Yoshida O, Tokumoto Y, Abe M, Hiasa Y. Lymphatic drainage dysfunction via narrowing of the lumen of cisterna chyli and thoracic duct after luminal dilation. Hepatol Int 2023; 17:1557-1569. [PMID: 37500943 DOI: 10.1007/s12072-023-10563-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Accepted: 06/13/2023] [Indexed: 07/29/2023]
Abstract
BACKGROUND The chronological pattern of extrahepatic lymphatic vessel progression in the course of chronic liver disease has not been clarified. This study aimed to clarify the chronological changes in lymphatic vessels with liver disease progression. METHODS This was a prospective cross-sectional study that enrolled a total of 199 patients. The maximum diameter of the cisterna chyli (CC) or terminal thoracic duct (tTD) was measured using computed tomography or ultrasonography, respectively. Changes in the maximum diameters of the CC and tTD were evaluated with patients with chronic liver disease as the pilot set (n = 138). Subsequently, we examined whether CC/tTD could be used to re-allocate unclassified patients by the Baveno-VII criteria to appropriately diagnose clinically significant portal hypertension (CSPH) in the pilot and validation sets. RESULTS In the pilot set, a scatter-plot showed that both CC and tTD were narrowed as terminal features in chronic liver disease after dilation. Because there was a significant correlation between the CC diameter and hepatic venous pressure gradient (r = 0.724) in unclassified patients, the diagnostic value of CC and tTD for CSPH was good (AUC: 0.961 and 0.913, respectively). After re-allocation, 68 and 27 unclassified patients were reduced to 4 and 5 in the pilot and validation sets, respectively. CONCLUSION Both the CC and tTD narrow in the course of liver disease after dilation. Moreover, the maximum diameter of the CC and tTD can be used to re-allocate patients who are unclassified according to the Baveno-VII criteria. CLINICAL TRIAL NUMBER UMIN trial no. 000044857.
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Affiliation(s)
- Ryo Yano
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitukawa 454, Toon, Ehime, 791-0295, Japan
| | - Masashi Hirooka
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitukawa 454, Toon, Ehime, 791-0295, Japan.
| | - Yohei Koizumi
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitukawa 454, Toon, Ehime, 791-0295, Japan
| | - Yoshiko Nakamura
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitukawa 454, Toon, Ehime, 791-0295, Japan
| | - Yusuke Imai
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitukawa 454, Toon, Ehime, 791-0295, Japan
| | - Makoto Morita
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitukawa 454, Toon, Ehime, 791-0295, Japan
| | - Yuki Okazaki
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitukawa 454, Toon, Ehime, 791-0295, Japan
| | - Takao Watanabe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitukawa 454, Toon, Ehime, 791-0295, Japan
| | - Osamu Yoshida
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitukawa 454, Toon, Ehime, 791-0295, Japan
| | - Yoshio Tokumoto
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitukawa 454, Toon, Ehime, 791-0295, Japan
| | - Masanori Abe
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitukawa 454, Toon, Ehime, 791-0295, Japan
| | - Yoichi Hiasa
- Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitukawa 454, Toon, Ehime, 791-0295, Japan
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Jeong J, Tanaka M, Yang Y, Arefyev N, DiRito J, Tietjen G, Zhang X, McConnell MJ, Utsumi T, Iwakiri Y. An optimized visualization and quantitative protocol for in-depth evaluation of lymphatic vessel architecture in the liver. Am J Physiol Gastrointest Liver Physiol 2023; 325:G379-G390. [PMID: 37605828 PMCID: PMC10887843 DOI: 10.1152/ajpgi.00139.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/11/2023] [Accepted: 08/11/2023] [Indexed: 08/23/2023]
Abstract
The liver lymphatic system is essential for maintaining tissue fluid balance and immune function. The detailed structure of lymphatic vessels (LVs) in the liver remains to be fully demonstrated. The aim of this study is to reveal LV structures in normal and diseased livers by developing a tissue-clearing and coimmunolabeling protocol optimized for the tissue size and the processing time for three-dimensional (3-D) visualization and quantification of LVs in the liver. We showed that our optimized protocol enables in-depth exploration of lymphatic networks in the liver, consisting of LVs along the portal tract (deep lymphatic system) and within the collagenous Glisson's capsule (superficial lymphatic system) in different species. With this protocol, we have shown 3-D LVs configurations in relation to blood vessels and bile ducts in cholestatic mouse livers, in which LVs were highly dilated and predominantly found around highly proliferating bile ducts and peribiliary vascular plexuses in the portal tract. We also established a quantification method using a 3-D volume-rendering approach. We observed a 1.6-fold (P < 0.05) increase in the average diameter of LVs and a 2.4-fold increase (P < 0.05) in the average branch number of LVs in cholestatic/fibrotic livers compared with control livers. Furthermore, cholestatic/fibrotic livers showed a 4.3-fold increase (P < 0.05) in total volume of LVs compared with control livers. Our optimized protocol and quantification method demonstrate an efficient and simple liver tissue-clearing procedure that allows the comprehensive analysis of liver lymphatic system.NEW & NOTEWORTHY This article showed a comprehensive 3-D-structural analysis of liver lymphatic vessel (LV) in normal and diseased livers in relation to blood vessels and bile ducts. In addition to the LVs highly localized at the portal tract, we revealed capsular LVs in mouse, rat, and human livers. In cholestatic livers, LVs are significantly increased and dilated compared with normal livers. Our optimized protocol provides detailed spatial information for LVs remodeling in normal and pathological conditions.
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Affiliation(s)
- Jain Jeong
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Masatake Tanaka
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
- Division of Pathophysiology, Medical Institute of Bioregulation and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yilin Yang
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Nikolai Arefyev
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Jenna DiRito
- Department of Surgery, Section of Organ Transplantation and Immunology, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Gregory Tietjen
- Department of Surgery, Section of Organ Transplantation and Immunology, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Xuchen Zhang
- Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Matthew J McConnell
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Teruo Utsumi
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
| | - Yasuko Iwakiri
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, Connecticut, United States
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11
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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, Ruhina Rahman SN, Jakhar D, Mourya AK, Tripathi DM, Kaur I, Tiwari V, Rohilla S, Gupta A, Rawal P, Baweja S, Rastogi A, Naidu V, Sarin SK, Banerjee S, Kaur S. Recombinant VEGF-C (Cys156Ser) improves mesenteric lymphatic drainage and gut immune surveillance in experimental cirrhosis. JHEP Rep 2023; 5:100816. [PMID: 37663117 PMCID: PMC10472308 DOI: 10.1016/j.jhepr.2023.100816] [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: 11/04/2022] [Revised: 04/30/2023] [Accepted: 05/24/2023] [Indexed: 09/05/2023] Open
Abstract
Background & Aims Lymphatic vessels (LVs) are crucial for maintaining abdominal fluid homoeostasis and immunity. In cirrhosis, mesenteric LVs (mLVs) are dilated and dysfunctional. Given the established role of vascular endothelial growth factor-C (VEGF-C) in improving LVs, we hypothesised that VEGF-C treatment could ameliorate the functions of mLVs in cirrhosis. Methods In this study, we developed a nanoformulation comprising LV-specific growth factor, recombinant human VEGF-C (Cys156Ser) protein (E-VEGF-C) and delivered it orally in different models of rat cirrhosis to target mLVs. Cirrhotic rats were given nanoformulation without VEGF-C served as vehicles. Drainage of mLVs was analysed using tracer dye. Portal and systemic physiological assessments and computed tomography were performed to measure portal pressures and ascites. Gene expression and permeability of primary mesenteric lymphatic endothelial cells (LyECs) was studied. Immune cells in mesenteric lymph nodes (MLNs) were quantified by flow cytometry. Endogenous and exogenous gut bacterial translocation to MLNs was examined. Results In cirrhotic rats, mLVs were dilated and leaky with impaired drainage. Treatment with E-VEGF-C induced proliferation of mLVs, reduced their diameter, and improved functional drainage. Ascites and portal pressures were significantly reduced in E-VEGF-C rats compared with vehicle rats. In MLNs of E-VEGF-C animals, CD8+CD134+ T cells were increased, whereas CD25+ regulatory T cells were decreased. Both endogenous and exogenous bacterial translocation were limited to MLNs in E-VEGF-C rats with reduced levels of endotoxins in ascites and blood in comparison with those in vehicle rats. E-VEGF-C treatment upregulated the expression of vascular endothelial-cadherin in LyECs and functionally improved the permeability of these cells. Conclusions E-VEGF-C treatment ameliorates mesenteric lymph drainage and portal pressure and strengthens cytotoxic T-cell immunity in MLNs in experimental cirrhosis. It may thus serve as a promising therapy to manage ascites and reduce pathogenic gut bacterial translocation in cirrhosis. Impact and Implications A human recombinant pro-lymphangiogenic growth factor, VEGF-C, was encapsulated in nanolipocarriers (E-VEGF-C) and orally delivered in different models of rat liver cirrhosis to facilitate its gut lymphatic vessel uptake. E-VEGF-C administration significantly increased mesenteric lymphatic vessel proliferation and improved lymph drainage, attenuating abdominal ascites and portal pressures in the animal models. E-VEGF-C treatment limited bacterial translocation to MLNs only with reduced gut bacterial load and ascitic endotoxins. E-VEGF-C therapy thus holds the potential to manage ascites and portal pressure and reduce gut bacterial translocation in patients with cirrhosis.
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Affiliation(s)
- Pinky Juneja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Syed Nazrin Ruhina Rahman
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, India
| | - Deepika Jakhar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Akash Kumar Mourya
- Department of Molecular and Cellular Medicine, 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
| | - Impreet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Vaibhav Tiwari
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sumati Rohilla
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Abhishek Gupta
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Preety Rawal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Sukriti Baweja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - V.G.M. Naidu
- Department of Pharmacology and Toxicology, NIPER-Guwahati, Changsari, India
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Subham Banerjee
- Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Guwahati, Changsari, India
| | - Savneet Kaur
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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Banerjee P, Gaddam N, Chandler V, Chakraborty S. Oxidative Stress-Induced Liver Damage and Remodeling of the Liver Vasculature. THE AMERICAN JOURNAL OF PATHOLOGY 2023; 193:1400-1414. [PMID: 37355037 DOI: 10.1016/j.ajpath.2023.06.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 05/29/2023] [Accepted: 06/08/2023] [Indexed: 06/26/2023]
Abstract
As an organ critically important for targeting and clearing viruses, bacteria, and other foreign material, the liver operates via immune-tolerant, anti-inflammatory mechanisms indispensable to the immune response. Stress and stress-induced factors disrupt the homeostatic balance in the liver, inflicting tissue damage, injury, and remodeling. These factors include oxidative stress (OS) induced by viral infections, environmental toxins, drugs, alcohol, and diet. A recurrent theme seen among stressors common to multiple liver diseases is the induction of mitochondrial dysfunction, increased reactive oxygen species expression, and depletion of ATP. Inflammatory signaling additionally exacerbates the condition, generating a proinflammatory, immunosuppressive microenvironment and activation of apoptotic and necrotic mechanisms that disrupt the integrity of liver morphology. These pathways initiate signaling pathways that significantly contribute to the development of liver steatosis, inflammation, fibrosis, cirrhosis, and liver cancers. In addition, hypoxia and OS directly enhance angiogenesis and lymphangiogenesis in chronic liver diseases. Late-stage consequences of these conditions often narrow the outcomes for liver transplantation or result in death. This review provides a detailed perspective on various stress-induced factors and the specific focus on role of OS in different liver diseases with special emphasis on different molecular mechanisms. It also highlights how resultant changes in the liver vasculature correlate with pathogenesis.
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Affiliation(s)
- Priyanka Banerjee
- Department of Medical Physiology, Texas A&M Health Science Center, Bryan, Texas.
| | - Niyanshi Gaddam
- Department of Medical Physiology, Texas A&M Health Science Center, Bryan, Texas
| | - Vanessa Chandler
- Department of Medical Physiology, Texas A&M Health Science Center, Bryan, Texas
| | - Sanjukta Chakraborty
- Department of Medical Physiology, Texas A&M Health Science Center, Bryan, Texas.
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14
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Pal S, Bhowmick S, Sharma A, Sierra-Fonseca JA, Mondal S, Afolabi F, Roy D. Lymphatic vasculature in ovarian cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188950. [PMID: 37419192 PMCID: PMC10754213 DOI: 10.1016/j.bbcan.2023.188950] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 06/29/2023] [Accepted: 06/29/2023] [Indexed: 07/09/2023]
Abstract
Ovarian cancer (OVCA) is the second most common gynecological cancer and one of the leading causes of cancer related mortality among women. Recent studies suggest that among ovarian cancer patients at least 70% of the cases experience the involvement of lymph nodes and metastases through lymphatic vascular network. However, the impact of lymphatic system in the growth, spread and the evolution of ovarian cancer, its contribution towards the landscape of ovarian tissue resident immune cells and their metabolic responses is still a major knowledge gap. In this review first we present the epidemiological aspect of the OVCA, the lymphatic architecture of the ovary, we discuss the role of lymphatic circulation in regulation of ovarian tumor microenvironment, metabolic basis of the upregulation of lymphangiogenesis which is often observed during progression of ovarian metastasis and ascites development. Further we describe the implication of several mediators which influence both lymphatic vasculature as well as ovarian tumor microenvironment and conclude with several therapeutic strategies for targeting lymphatic vasculature in ovarian cancer progression in present day.
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Affiliation(s)
- Sarit Pal
- Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX 77843, United States
| | - Sramana Bhowmick
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, West Bengal, India
| | - Anurag Sharma
- Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH, United States
| | | | - Susmita Mondal
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, West Bengal, India
| | - Favour Afolabi
- Department of Biological Sciences, Alcorn State University, Lorman, MS 39096, United States
| | - Debarshi Roy
- Department of Biological Sciences, Alcorn State University, Lorman, MS 39096, United States.
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15
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Iwakiri Y. Lymphatics in the liver for translational science. Clin Liver Dis (Hoboken) 2023; 21:122-124. [PMID: 37936952 PMCID: PMC10627586 DOI: 10.1097/cld.0000000000000019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 12/23/2022] [Indexed: 11/09/2023] Open
Abstract
1_k31wzfrsKaltura.
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16
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de Lange C, Möller T, Hebelka H. Fontan-associated liver disease: Diagnosis, surveillance, and management. Front Pediatr 2023; 11:1100514. [PMID: 36937979 PMCID: PMC10020358 DOI: 10.3389/fped.2023.1100514] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 02/09/2023] [Indexed: 03/06/2023] Open
Abstract
The Fontan operation is a lifesaving procedure for patients with functional single-ventricle congenital heart disease, where hypoplastic left heart syndrome is the most frequent anomaly. Hemodynamic changes following Fontan circulation creation are now increasingly recognized to cause multiorgan affection, where the development of a chronic liver disease, Fontan-associated liver disease (FALD), is one of the most important morbidities. Virtually, all patients with a Fontan circulation develop liver congestion, resulting in fibrosis and cirrhosis, and most patients experience childhood onset. FALD is a distinctive type of congestive hepatopathy, and its pathogenesis is thought to be a multifactorial process driven by increased nonpulsatile central venous pressure and decreased cardiac output, both of which are inherent in the Fontan circulation. In the advanced stage of liver injury, complications of portal hypertension often occur, and there is a risk of developing secondary liver cancer, reported at young age. However, FALD develops with few clinical symptoms, a surprisingly variable degree of severity in liver disease, and with little relation to poor cardiac function. The disease mechanisms and modifying factors of its development are still not fully understood. As one of the more important noncardiac complications of the Fontan circulation, FALD needs to be diagnosed in a timely manner with a structured monitoring scheme of disease development, early detection of malignancy, and determination of the optimal time point for transplantation. There is also a clear need for consensus on the best surveillance strategy for FALD. In this regard, imaging plays an important role together with clinical scoring systems, biochemical workups, and histology. Patients operated on with a Fontan circulation are generally followed up in cardiology units. Ultimately, the resulting multiorgan affection requires a multidisciplinary team of healthcare personnel to address the different organ complications. This article discusses the current concepts, diagnosis, and management of FALD, with special emphasis on the role of different imaging techniques in the diagnosis and monitoring of disease progression, as well as current recommendations for liver disease surveillance.
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Affiliation(s)
- Charlotte de Lange
- Department of Pediatric Radiology, Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
- Institution of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Thomas Möller
- Department of Pediatric Cardiology, Oslo University Hospital, Oslo, Norway
| | - Hanna Hebelka
- Department of Pediatric Radiology, Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden
- Institution of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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17
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Firat A, Abbasoglu TT, Karcaaltincaba M, Balaban YH. Clinical anatomy of hepatic vessels by computed tomography angiography: A minireview. World J Radiol 2023; 15:1-9. [PMID: 36721671 PMCID: PMC9884335 DOI: 10.4329/wjr.v15.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 11/02/2022] [Accepted: 12/27/2022] [Indexed: 01/17/2023] Open
Abstract
The liver has a complex vascular anatomy with a unique dual blood supply. Clinical conditions of the liver vary widely and include disorders originating in the vascular and biliary systems as well as the parenchyma. In most vascular disorders, the effects on the liver are generally subclinical because of its abundant blood supply. However, early diagnosis of such vascular diseases can significantly reduce patient morbidity and mortality. Because imaging findings of vascular disease are not always readily apparent, diagnosis can be difficult. Computed tomography angiography is an excellent imaging modality for visualizing the vascular anatomy of patients for treatment planning. In this review article, we focus on the vascular anatomy of the liver and the imaging findings in some acute hepatic vascular diseases.
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Affiliation(s)
- Aysegul Firat
- Department of Anatomy, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
| | | | | | - Yasemin H Balaban
- Department of Gastroenterology, Hacettepe University Faculty of Medicine, Ankara 06100, Turkey
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18
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Harris NR, Bálint L, Dy DM, Nielsen NR, Méndez HG, Aghajanian A, Caron KM. The ebb and flow of cardiac lymphatics: a tidal wave of new discoveries. Physiol Rev 2023; 103:391-432. [PMID: 35953269 PMCID: PMC9576179 DOI: 10.1152/physrev.00052.2021] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 06/16/2022] [Accepted: 07/18/2022] [Indexed: 12/16/2022] Open
Abstract
The heart is imbued with a vast lymphatic network that is responsible for fluid homeostasis and immune cell trafficking. Disturbances in the forces that regulate microvascular fluid movement can result in myocardial edema, which has profibrotic and proinflammatory consequences and contributes to cardiovascular dysfunction. This review explores the complex relationship between cardiac lymphatics, myocardial edema, and cardiac disease. It covers the revised paradigm of microvascular forces and fluid movement around the capillary as well as the arsenal of preclinical tools and animal models used to model myocardial edema and cardiac disease. Clinical studies of myocardial edema and their prognostic significance are examined in parallel to the recent elegant animal studies discerning the pathophysiological role and therapeutic potential of cardiac lymphatics in different cardiovascular disease models. This review highlights the outstanding questions of interest to both basic scientists and clinicians regarding the roles of cardiac lymphatics in health and disease.
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Affiliation(s)
- Natalie R Harris
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - László Bálint
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Danielle M Dy
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Natalie R Nielsen
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Hernán G Méndez
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Amir Aghajanian
- Division of Cardiology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Kathleen M Caron
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
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19
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Goldberg AR, Ferguson M, Pal S, Cohen R, Orlicky DJ, McCullough RL, Rutkowski JM, Burchill MA, Tamburini BAJ. Oxidized low density lipoprotein in the liver causes decreased permeability of liver lymphatic- but not liver sinusoidal-endothelial cells via VEGFR-3 regulation of VE-Cadherin. Front Physiol 2022; 13:1021038. [PMID: 36338478 PMCID: PMC9626955 DOI: 10.3389/fphys.2022.1021038] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/05/2022] [Indexed: 01/27/2023] Open
Abstract
The lymphatic vasculature of the liver is vital for liver function as it maintains fluid and protein homeostasis and is important for immune cell transport to the lymph node. Chronic liver disease is associated with increased expression of inflammatory mediators including oxidized low-density lipoprotein (oxLDL). Intrahepatic levels of oxLDL are elevated in nonalcoholic fatty liver disease (NAFLD), chronic hepatitis C infection (HCV), alcohol-associated liver disease (ALD), and cholestatic liver diseases. To determine if liver lymphatic function is impaired in chronic liver diseases, in which increased oxLDL has been documented, we measured liver lymphatic function in murine models of NAFLD, ALD and primary sclerosing cholangitis (PSC). We found that Mdr2-/- (PSC), Lieber-DeCarli ethanol fed (ALD) and high fat and high cholesterol diet fed (NAFLD) mice all had a significant impairment in the ability to traffic FITC labeled dextran from the liver parenchyma to the liver draining lymph nodes. Utilizing an in vitro permeability assay, we found that oxLDL decreased the permeability of lymphatic endothelial cells (LEC)s, but not liver sinusoidal endothelial cells (LSEC)s. Here we demonstrate that LECs and LSECs differentially regulate SRC-family kinases, MAPK kinase and VE-Cadherin in response to oxLDL. Furthermore, Vascular Endothelial Growth Factor (VEGF)C or D (VEGFR-3 ligands) appear to regulate VE-Cadherin expression as well as decrease cellular permeability of LECs in vitro and in vivo after oxLDL treatment. These findings suggest that oxLDL acts to impede protein transport through the lymphatics through tightening of the cell-cell junctions. Importantly, engagement of VEGFR-3 by its ligands prevents VE-Cadherin upregulation and improves lymphatic permeability. These studies provide a potential therapeutic target to restore liver lymphatic function and improve liver function.
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Affiliation(s)
- Alyssa R. Goldberg
- Department of Pediatrics, Section of Pediatric Gastroenterology, Hepatology & Nutrition. Children’s Hospital Colorado, Digestive Health Institute- Pediatric Liver Center, University of Colorado School of Medicine, Aurora, CO, United States
| | - Megan Ferguson
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Sarit Pal
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Rachel Cohen
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, United States
| | - David J. Orlicky
- Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Rebecca L. McCullough
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado School of Medicine, Aurora, CO, United States
| | - Joseph M. Rutkowski
- Division of Lymphatic Biology, Department of Medical Physiology, Texas A&M University School of Medicine, Bryan, TX, United States
| | - Matthew A. Burchill
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, United States
| | - Beth A. Jirón Tamburini
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Aurora, CO, United States
- Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, CO, United States
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Jeong J, Tanaka M, Iwakiri Y. Hepatic lymphatic vascular system in health and disease. J Hepatol 2022; 77:206-218. [PMID: 35157960 PMCID: PMC9870070 DOI: 10.1016/j.jhep.2022.01.025] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/13/2022] [Accepted: 01/31/2022] [Indexed: 02/07/2023]
Abstract
In recent years, significant advances have been made in the study of lymphatic vessels with the identification of their specific markers and the development of research tools that have accelerated our understanding of their role in tissue homeostasis and disease pathogenesis in many organs. Compared to other organs, the lymphatic system in the liver is understudied despite its obvious importance for hepatic physiology and pathophysiology. In this review, we describe fundamental aspects of the hepatic lymphatic system and its role in a range of liver-related pathological conditions such as portal hypertension, ascites formation, malignant tumours, liver transplantation, congenital liver diseases, non-alcoholic fatty liver disease, and hepatic encephalopathy. The article concludes with a discussion regarding the modulation of lymphangiogenesis as a potential therapeutic strategy for liver diseases.
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Affiliation(s)
- Jain Jeong
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Masatake Tanaka
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuko Iwakiri
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA.
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21
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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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22
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A Metabolomic Analysis of Cirrhotic Ascites. Molecules 2022; 27:molecules27123935. [PMID: 35745058 PMCID: PMC9228447 DOI: 10.3390/molecules27123935] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Revised: 05/26/2022] [Accepted: 06/16/2022] [Indexed: 11/23/2022] Open
Abstract
Ascites is a common complication of decompensated liver cirrhosis, and yet relatively little is known about its biochemical composition. We conducted two metabolomic investigations, comparing the profile of ascites from 33 cirrhotic patients and postoperative peritoneal drainage fluid from 33 surgical patients (Experiment 1). The profile of paired ascites and plasma was also compared in 17 cirrhotic patients (Experiment 2). Gas chromatography−mass spectrometry-based metabolomics identified 29 metabolites that significantly characterized ascites fluid, whether postoperative drainage fluid or plasma were used as controls. Ten elevated amino acids (glutamine, proline, histidine, tyrosine, glycine, valine, threonine, methionine, lysine, phenylalanine) and seven diminished lipids (laurate, myristate, palmitate, oleate, vaccenate, stearate, cholesterol) largely comprised the cirrhotic ascites metabolomic phenotype that differed significantly (adjusted p < 0.002 to 0.03) from peritoneal drainage fluid or plasma. The pattern of upregulated amino acids in cirrhotic ascites did not indicate albumin proteolysis by peritoneal bacteria. Bidirectional clustering showed that the more severe the cirrhosis, the lower the lipid concentration in ascitic fluid. The metabolomic compartment of ascites in patients with decompensated cirrhosis is characterized by increased amino acids and decreased lipids. These novel findings have potential relevance for diagnostic purposes.
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Cisterna chyli as an optimal marker of tolvaptan response in severe cirrhotic ascites. Sci Rep 2022; 12:8124. [PMID: 35581243 PMCID: PMC9114325 DOI: 10.1038/s41598-022-11889-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/03/2022] [Indexed: 12/13/2022] Open
Abstract
For patients with cirrhosis, no definitive predictor of the efficacy and prognosis of tolvaptan treatment exists. We assessed the cisterna chyli's utility as an optimal marker. We retrospectively enrolled 172 patients with cirrhosis. The effect of tolvaptan was evaluated using post-treatment survival time. The overall response to tolvaptan was 52.3%. The median cisterna chyli diameter was 4.1 mm. Of 172 patients, 100 were included in the pilot set and 72 in the validation set. According to the Youden index, the cisterna chyli diameter's cutoff value was 4 mm, with a sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio of 92%, 83%, 86%, 91%, 5.43, and 0.09, respectively, in the pilot set. The area under the curve of the cisterna chyli diameter for evaluating tolvaptan's effect was 0.911 and 0.988 in the pilot and validation sets, respectively. During multivariate analysis, cisterna chyli narrowing and furosemide treatment were significant predictive factors for tolvaptan's insufficient effect. Cumulative liver transplantation-free survival rates were significantly higher in patients with cisterna chyli dilatation than in those without (p = 0.028). Our findings suggest a strong association of cisterna chyli with tolvaptan treatment response in patients with cirrhosis and hepatic edema.
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Serial T2-Weighted Thoracic and Abdominal Lymphatic Imaging in Fontan Patients—New Insights into Dynamics of Lymphatic Abnormalities after Total Cavopulmonary Connection. J Cardiovasc Dev Dis 2022; 9:jcdd9050138. [PMID: 35621849 PMCID: PMC9144783 DOI: 10.3390/jcdd9050138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/26/2022] [Accepted: 04/27/2022] [Indexed: 11/24/2022] Open
Abstract
Lymphatic congestion in single-ventricle patients has been associated with increased morbidity and poor outcomes. Little is known about the dynamics of lymphatic abnormalities over time, on their association with clinical presentation or response to catheter interventions. This retrospective, single-center study describes Fontan patients who underwent at least two magnetic resonance imaging (MRI) studies. T2-weighted lymphatic imaging was used to classify thoracic and abdominal (para-aortic and portal-venous) lymphatic abnormalities. The relationship between lymphatic congestion and hemodynamic changes after cardiac catheter interventions, clinical presentation and MRI data was analyzed. A total of 33 Fontan patients underwent at least two cardiac MRI studies. Twenty-two patients had two, eight had three and three had four lymphatic imaging studies (total of 80 MRIs studies). No significant changes in lymphatic classification between MRI 1 and 2 were observed for thoracic (p = 0.400), para-aortic (0.670) and portal-venous (p = 0.822) abnormalities. No significant correlation between lymphatic classification and hemodynamic changes after intervention or MRI parameters was found. This study illustrates thoracic and abdominal lymphatic abnormalities in serial T2-weighted imaging after Fontan. Fontan patients did not demonstrate significant changes in their lymphatic perfusion, despite clinical or hemodynamic changes. We assume that lymphatic congestion might develop after total cavopulmonary connection (TCPC) and remain relatively stable, despite further intervention targeting hemodynamic parameters.
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25
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Warner ER, Aloor FZ, Satapathy SK. A narrative review of nutritional abnormalities, complications, and optimization in the cirrhotic patient. Transl Gastroenterol Hepatol 2022; 7:5. [PMID: 35243114 PMCID: PMC8826036 DOI: 10.21037/tgh-20-325] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Accepted: 04/08/2021] [Indexed: 08/10/2023] Open
Abstract
OBJECTIVE The purpose of this manuscript is to identify the pathophysiology of the metabolic abnormalities observed in cirrhosis and to uncover associations, if any, to its complications, such as sarcopenia and hepatic encephalopathy (HE). BACKGROUND Liver dysfunction in cirrhosis is known to be a precipitating factor in the disruption of many physiological pathways, specifically nutrient metabolism. As a result, affected patients are highly susceptible to derangements of processes affecting multiple classes of macro- and micronutrients, including proteins, carbohydrates, electrolytes, vitamins, and minerals. These disruptions are thought to be contributory to the pathogenesis of known complications of cirrhosis. METHODS Literature research of relevant topics was conducted for the above stated objective; sources were limited to articles from peer-reviewed journals published within the last 30 years. CONCLUSION This research established that there is positive correlation between nutrient derangements and the increased risk of complications of cirrhosis, which themselves carry significant morbidity and mortality risk. It also established that some nutrient and electrolyte abnormalities are independent indicators of prognosis and adverse outcomes, such as mortality. This also highlights the importance of comprehension of anomalous metabolism and its complications as it necessitates serious consideration in clinical care. In addition to medical management, cirrhotic patients also require ancillary assessment, such as comprehensive nutritional evaluation, to identify and treat reversible nutritional derangements. This consideration provides the best opportunity to achieve maximal health outcomes in the cirrhotic patient population.
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Affiliation(s)
- Edgewood R. Warner
- Department of Medicine, Donald and Barbara Zucker School of Medicine/Northwell Health, Manhasset, NY, USA
| | - Fuad Z. Aloor
- Department of Medicine, Donald and Barbara Zucker School of Medicine/Northwell Health, Manhasset, NY, USA
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases and Transplantation, Department of Medicine, Donald and Barbara Zucker School of Medicine/Northwell Health, Manhasset, New York, USA
| | - Sanjaya K. Satapathy
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases and Transplantation, Department of Medicine, Donald and Barbara Zucker School of Medicine/Northwell Health, Manhasset, New York, USA
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26
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OUP accepted manuscript. Eur J Cardiothorac Surg 2022; 62:6537500. [DOI: 10.1093/ejcts/ezac103] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 01/15/2022] [Accepted: 01/27/2022] [Indexed: 11/13/2022] Open
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27
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Byun KA, Oh S, Son M, Park CH, Son KH, Byun K. Dieckol Decreases Caloric Intake and Attenuates Nonalcoholic Fatty Liver Disease and Hepatic Lymphatic Vessel Dysfunction in High-Fat-Diet-Fed Mice. Mar Drugs 2021; 19:495. [PMID: 34564157 PMCID: PMC8469311 DOI: 10.3390/md19090495] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/20/2021] [Accepted: 08/27/2021] [Indexed: 02/06/2023] Open
Abstract
Increased inflammation is the main pathophysiology of nonalcoholic fatty liver disease (NAFLD). Inflammation affects lymphatic vessel function that contributes to the removal of immune cells or macromolecules. Dysfunctional lymphatic vessels with decreased permeability are present in NAFLD. High-fat diet (HFD) is known to increase body weight, food intake, and inflammation in the liver. Previously, it was reported that Ecklonia cava extracts (ECE) decreased food intake or weight gain, and low-calorie diet and weight loss is known as a treatment for NAFLD. In this study, the effects of ECE and dieckol (DK)-which is one component of ECE that decreases inflammation and increases lymphangiogenesis and lymphatic drainage by controlling lymphatic permeability in high-fat diet (HFD)-fed mice-on weight gain and food intake were investigated. ECE and DK decreased weight gain and food intake in the HFD-fed mice. NAFLD activities such as steatosis, lobular inflammation, and ballooning were increased by HFD and attenuated by ECE and DK. The expression of inflammatory cytokines such as IL-6 and TNF-α and infiltration of M1 macrophages were increased by HFD, and they were decreased by ECE or DK. The signaling pathways of lymphangiogenesis, VEGFR-3, PI3K/pAKT, and pERK were decreased by HFD, and they were restored by either ECE or DK. The expression of VE-cadherin (which represents lymphatic junctional function) was increased by HFD, although it was restored by either ECE or DK. In conclusion, ECE and DK attenuated NAFLD by decreasing weight gain and food intake, decreasing inflammation, and increasing lymphangiogenesis, as well as modulating lymphatic vessel permeability.
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Affiliation(s)
- Kyung-A Byun
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Korea; (K.-A.B.); (M.S.)
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon 21999, Korea;
| | - Seyeon Oh
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon 21999, Korea;
| | - Myeongjoo Son
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Korea; (K.-A.B.); (M.S.)
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon 21999, Korea;
| | - Chul-Hyun Park
- Department of Thoracic and Cardiovascular Surgery, Gil Medical Center, Gachon University, Incheon 21565, Korea;
| | - Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gil Medical Center, Gachon University, Incheon 21565, Korea;
| | - Kyunghee Byun
- Department of Anatomy & Cell Biology, College of Medicine, Gachon University, Incheon 21936, Korea; (K.-A.B.); (M.S.)
- Functional Cellular Networks Laboratory, Lee Gil Ya Cancer and Diabetes Institute, College of Medicine, Gachon University, Incheon 21999, Korea;
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28
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Itkin M, Rockson SG, Burkhoff D. Pathophysiology of the Lymphatic System in Patients With Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol 2021; 78:278-290. [PMID: 34266581 DOI: 10.1016/j.jacc.2021.05.021] [Citation(s) in RCA: 63] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 05/04/2021] [Accepted: 05/10/2021] [Indexed: 12/15/2022]
Abstract
The removal of interstitial fluid from the tissues is performed exclusively by the lymphatic system. Tissue edema in congestive heart failure occurs only when the lymphatic system fails or is overrun by fluid leaving the vascular space across the wall of the capillaries into the interstitial space. This process is driven by Starling forces determined by hydrostatic and osmotic pressures and organ-specific capillary permeabilities to proteins of different sizes. In this review, we summarize current knowledge of the generation of lymph in different organs, the mechanics by which lymph is returned to the circulation, and the consequences of the inadequacy of lymph flow. We review recent advances in imaging techniques that have allowed for new research, diagnostic, and therapeutic approaches to the lymphatic system. Finally, we review how efforts to increase lymph flow have demonstrated potential as a viable therapeutic approach for refractory heart failure.
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Affiliation(s)
- Maxim Itkin
- Center for Lymphatic Disorders, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
| | - Stanley G Rockson
- Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Daniel Burkhoff
- Cardiovascular Research Foundation, New York, New York, USA. https://twitter.com/burkhoffmd
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29
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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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30
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Frenkel NC, Poghosyan S, Verheem A, Padera TP, Rinkes IHMB, Kranenburg O, Hagendoorn J. Liver lymphatic drainage patterns follow segmental anatomy in a murine model. Sci Rep 2020; 10:21808. [PMID: 33311587 PMCID: PMC7732834 DOI: 10.1038/s41598-020-78727-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Accepted: 11/12/2020] [Indexed: 02/07/2023] Open
Abstract
The liver’s cellular functions are sustained by a hierarchical, segmentally-organized vascular system. Additionally, liver lymphatic vessels are thought to drain to perihepatic lymph nodes. Surprisingly, while recent findings highlight the importance of organ-specific lymphatics, the functional anatomy of liver lymphatics has not been mapped out. In literature, no segmental or preferential lymphatic drainage patterns are known to exist. We employ a novel murine model of liver lymphangiography and in vivo microscopy to delineate the lymphatic drainage patterns of individual liver lobes. Our data from blue dye liver lymphangiography show preferential lymphatic drainage patterns: Right lobe mainly to hepatoduodenal ligament lymph node 1 (LN1); left lobe to hepatoduodenal ligament LN1 + LN2 concurrently; median lobe showed a more variable LN1/LN2 drainage pattern with increased (sometimes exclusive) mediastinal thoracic lymph node involvement, indicating that part of the liver can drain directly to the mediastinum. Upon ferritin lymphangiography, we observed no functional communication between the lobar lymphatics. Altogether, these results show the existence of preferential lymphatic drainage patterns in the murine liver. Moreover, this drainage can occur directly to mediastinal lymph nodes and there is no interlobar lymphatic flow. Collectively, these data provide the first direct evidence that liver lymphatic drainage patterns follow segmental anatomy.
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Affiliation(s)
- Nicola C Frenkel
- Laboratory for Translational Oncology, Cancer Center, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Susanna Poghosyan
- Laboratory for Translational Oncology, Cancer Center, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - André Verheem
- Laboratory for Translational Oncology, Cancer Center, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Timothy P Padera
- E.L. Steele Laboratory for Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Inne H M Borel Rinkes
- Laboratory for Translational Oncology, Cancer Center, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Onno Kranenburg
- Laboratory for Translational Oncology, Cancer Center, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Jeroen Hagendoorn
- Laboratory for Translational Oncology, Cancer Center, University Medical Center Utrecht and Utrecht University, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.
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31
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Kondo R, Iwakiri Y. The lymphatic system in alcohol-associated liver disease. Clin Mol Hepatol 2020; 26:633-638. [PMID: 32951411 PMCID: PMC7641555 DOI: 10.3350/cmh.2020.0179] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 08/18/2020] [Accepted: 08/18/2020] [Indexed: 12/18/2022] Open
Abstract
The lymphatic system plays vital roles in interstitial fluid balance and immune cell surveillance. The effect of alcohol on the lymphatic system is poorly understood. This review article explores the role of the lymphatic system in the pathogenesis of alcohol-related disease including alcoholic liver disease (ALD) and the therapeutic potential of targeting hepatic lymphatics for the treatment of ALD.
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Affiliation(s)
- Reiichiro Kondo
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
- Department of Pathology, Kurume University School of Medicine, Kurume, Japan
| | - Yasuko Iwakiri
- Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA
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32
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Shiina Y, Inai K, Ohashi R, Nagao M. Potential of Liver T 1 Mapping for the Detection of Fontan-associated Liver Disease in Adults. Magn Reson Med Sci 2020; 20:295-302. [PMID: 32893257 PMCID: PMC8424020 DOI: 10.2463/mrms.mp.2020-0063] [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] [Indexed: 11/10/2022] Open
Abstract
Purpose: The native T1 value at 3T MRI is a sensitive marker for diffuse fibrosis or damage in various organs including the heart, liver, and pancreas. Despite the fact that Fontan-associated liver disease (FALD) is a crucial issue in adults with Fontan circulation, there are only a few studies with liver T1 mapping in children and adolescents. We investigated the potential of the liver native T1 mapping in detecting FALD in adult patients. Methods: We prospectively enrolled 16 consecutive adults with Fontan circulation (age 31.3 ± 8.5 years), who were in New York Heart Association Functional class II–IV. Twenty with tetralogy of Fallot (TOF), and 20 age-matched controls also underwent cardiac magnetic resonance (CMR) imaging at 3T. Myocardial T1 mapping with a Modified Look-Locker Inversion recovery sequence was applied to liver T1 mapping. Patients in the Fontan group underwent the right heart catheter and liver function tests, including those for fibrotic markers. Results: Liver native T1 values in the Fontan group were significantly higher than that in TOF and controls (P < 0.001). In the Fontan group, the liver native T1 value was significantly correlated with age, γ -glutamyltransferase, model for end-stage liver disease XI score, and albumin-bilirubin score (P = 0.01, 0.01, 0.044, 0.001). However, it demonstrated no correlation with central venous pressure, pulmonary vessel resistance, or fibrotic markers. Conclusion: Liver native T1 value derived from CMR may be a non-invasive adjunctive and/or screening marker to detect FALD.
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Affiliation(s)
- Yumi Shiina
- Department of Pediatric Cardiology and Adult Congenital Cardiology, Tokyo Women's Medical University.,Cardiovascular Center, St. Luke's International Hospital
| | - Kei Inai
- Department of Pediatric Cardiology and Adult Congenital Cardiology, Tokyo Women's Medical University
| | - Ryoko Ohashi
- Department of Diagnostic Imaging & Nuclear Medicine, Tokyo Women's Medical University
| | - Michinobu Nagao
- Department of Diagnostic Imaging & Nuclear Medicine, Tokyo Women's Medical University
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AlShehri E, Lam CZ, Kamath BM, Chavhan GB. Abdominal lymphatic system visibility, morphology, and abnormalities in children as seen on routine MCRP and its association with immune-mediated diseases. Eur Radiol 2020; 31:292-301. [PMID: 32797311 DOI: 10.1007/s00330-020-07152-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 06/08/2020] [Accepted: 08/05/2020] [Indexed: 12/17/2022]
Abstract
PURPOSE (1) To assess the visibility and diameters of the thoracic duct (TD) and cisterna chyli (CC) on MR cholangiopancreatography (MRCP) in children. (2) To evaluate for the presence of any lymphatic abnormalities and assess their association with diseases in which the immune system is implicated in etiopathogenesis. METHODS This retrospective study included 142 MRCPs performed in children 8-17 years old and without prior surgeries. Two radiologists reviewed all exams for visibility and diameters of the TD and CC, and presence of abnormal lymphatic collaterals. TD and CC diameters in various disease processes were compared using Student's t tests. The association of collaterals with immune-mediated diseases was assessed using Fisher's exact tests. RESULTS The TD and CC were seen in 134/142 (93.7%) cases with mean diameter of 3.25 ± 1.07 mm and 126/142 (88.7%) cases with mean diameter of 4.55 ± 1.37 mm respectively. The mean diameter of CC was larger in patients with portal hypertension (p = 0.021). There were no significant differences in the TD and CC diameters between immune-mediated and non-immune-mediated diseases. Retroperitoneal collaterals were seen in 41/142 (28.8%) of cases and were associated with both portal hypertension (p = 0.0019) and immune-mediated diseases (p = 0.0083). CONCLUSION The TD and CC can be visualized in the majority of children on routine MRCP images, and CC has larger diameter in patients with portal hypertension. The association of collaterals with immune-mediated diseases supports a potential role of the lymphatic system in the etiopathogenesis of immune-mediated diseases. KEY POINTS • The lymphatic system has been increasingly implicated in a number of inflammatory and immune-mediated diseases. • The abdominal lymphatic system can be visualized in the majority of children above 8 years on routine MRCP images. Similar to adult studies, the cisterna chyli is significantly larger in children with portal hypertension. • Retroperitoneal lymphatic collaterals, seen in 29% children, are associated with immune-mediated diseases, which supports the potential role of the lymphatic system in the pathogenesis of immune-mediated diseases.
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Affiliation(s)
- Ebtehaj AlShehri
- Department of Diagnostic Imaging, The Hospital For Sick Children and Medical Imaging, University Of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada
| | - Christopher Z Lam
- Department of Diagnostic Imaging, The Hospital For Sick Children and Medical Imaging, University Of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada
| | - Binita M Kamath
- Department of Gastroenterology Hepatology and Nutrition, The Hospital For Sick Children, University Of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada
| | - Govind B Chavhan
- Department of Diagnostic Imaging, The Hospital For Sick Children and Medical Imaging, University Of Toronto, 555 University Avenue, Toronto, Ontario, M5G 1X8, Canada.
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Abdallah M, Müllertz OO, Styles IK, Mörsdorf A, Quinn JF, Whittaker MR, Trevaskis NL. Lymphatic targeting by albumin-hitchhiking: Applications and optimisation. J Control Release 2020; 327:117-128. [PMID: 32771478 DOI: 10.1016/j.jconrel.2020.07.046] [Citation(s) in RCA: 67] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 12/20/2022]
Abstract
The lymphatic system plays an integral role in the development and progression of a range of disease conditions, which has impelled medical researchers and clinicians to design, develop and utilize advanced lymphatic drug delivery systems. Following interstitial administration, most therapeutics and molecules are cleared from tissues via the draining blood capillaries. Macromolecules and delivery systems >20 kDa in size or 10-100 nm in diameter are, however, transported from the interstitium via draining lymphatic vessels as they are too large to cross the blood capillary endothelium. Lymphatic uptake of small molecules can be promoted by two general approaches: administration in association with synthetic macromolecular constructs, or through hitchhiking on endogenous cells or macromolecular carriers that are transported from tissues via the lymphatics. In this paper we review the latter approach where molecules are targeted to lymph by hitchhiking on endogenous albumin transport pathways after subcutaneous, intramuscular or intradermal injection. We describe the properties of the lymphatic system and albumin that are relevant to lymphatic targeting, the characteristics of drugs and delivery systems designed to hitchhike on albumin trafficking pathways and how to further optimise these properties, and finally the current applications and potential future directions for albumin-hitchhiking approaches to target the lymphatics.
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Affiliation(s)
- Mohammad Abdallah
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
| | - Olivia O Müllertz
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ian K Styles
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia
| | - Alexander Mörsdorf
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
| | - John F Quinn
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
| | - Michael R Whittaker
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
| | - Natalie L Trevaskis
- Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Australia.
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Norden PR, Kume T. The Role of Lymphatic Vascular Function in Metabolic Disorders. Front Physiol 2020; 11:404. [PMID: 32477160 PMCID: PMC7232548 DOI: 10.3389/fphys.2020.00404] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Accepted: 04/06/2020] [Indexed: 12/13/2022] Open
Abstract
In addition to its roles in the maintenance of interstitial fluid homeostasis and immunosurveillance, the lymphatic system has a critical role in regulating transport of dietary lipids to the blood circulation. Recent work within the past two decades has identified an important relationship between lymphatic dysfunction and patients with metabolic disorders, such as obesity and type 2 diabetes, in part characterized by abnormal lipid metabolism and transport. Utilization of several genetic mouse models, as well as non-genetic models of diet-induced obesity and metabolic syndrome, has demonstrated that abnormal lymphangiogenesis and poor collecting vessel function, characterized by impaired contractile ability and perturbed barrier integrity, underlie lymphatic dysfunction relating to obesity, diabetes, and metabolic syndrome. Despite the progress made by these models, the contribution of the lymphatic system to metabolic disorders remains understudied and new insights into molecular signaling mechanisms involved are continuously developing. Here, we review the current knowledge related to molecular mechanisms resulting in impaired lymphatic function within the context of obesity and diabetes. We discuss the role of inflammation, transcription factor signaling, vascular endothelial growth factor-mediated signaling, and nitric oxide signaling contributing to impaired lymphangiogenesis and perturbed lymphatic endothelial cell barrier integrity, valve function, and contractile ability in collecting vessels as well as their viability as therapeutic targets to correct lymphatic dysfunction and improve metabolic syndromes.
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Affiliation(s)
- Pieter R. Norden
- Feinberg Cardiovascular and Renal Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Tsutomu Kume
- Feinberg Cardiovascular and Renal Research Institute, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
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Hamada T, Hidaka M, Takatsuki M, Sakai Y, Yu H, Natsuda K, Ono S, Adachi T, Soyama A, Eguchi S. The Relationship Between Lymphangiogenesis and Liver Regeneration After Partial Hepatectomy in Cholestatic Mice. Lymphat Res Biol 2020; 18:322-328. [PMID: 32069131 DOI: 10.1089/lrb.2019.0068] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Background: The mechanisms of lymphangiogenesis in the cholestatic liver after partial hepatectomy (PH) remain unclear. We aimed to demonstrate the relationship between lymphangiogenesis and liver regeneration after partial hepatectomy in the cholestatic liver. Methods and Results: C57BL/6 mice were subjected to 70% partial hepatectomy only (PH group, n = 20) and 70% partial hepatectomy with temporary common bile duct (BD) obstruction by clipping (BD+PH group, n = 20). Five mice per group were sacrificed at 1, 3, 5, and 7 days after the procedure. The liver function was examined by blood tests, and the liver regeneration rate was assessed by body weight and liver weight. Immunohistochemical staining of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) showed liver lymphangiogenesis. The gene expression of lymphangiogenesis-associated factors (e.g., vascular endothelial growth factor receptor-3 [VEGFR-3]) was examined by a real-time polymerase chain reaction. The liver function in the BD+PH group was worse than that in the PH group on postoperative day 1 (POD1) (aspartate aminotransferase: 6528 ± 1641 U/L vs. 2741 ± 368 U/L, p < 0.05, alanine aminotransferase: 4160 ± 1255 U/L vs. 2315 ± 357 U/L, total bilirubin: 1.36 ± 1.16 mg/dL vs. 0.09 ± 0.01 mg/dL), and the liver regeneration rate in the BD+PH group was worse on POD7 (4.57% vs. 5.91%, p < 0.05). The LYVE-1 expression in Glisson's capsule peaked on POD5 and POD7 in the PH and BD+PH groups, respectively. The peak gene expression of VEGFR-3 in the BD+PH group was delayed in comparison with the PH group. Conclusions: Lymphangiogenesis after partial hepatectomy in the cholestatic liver was suggested to be delayed due to impaired liver regeneration and the late expression of VEGFR-3.
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Affiliation(s)
- Takashi Hamada
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Mitsuhisa Takatsuki
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Yusuke Sakai
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Haung Yu
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Koji Natsuda
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Shinichiro Ono
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Tomohiko Adachi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
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Tee JK, Yip LX, Tan ES, Santitewagun S, Prasath A, Ke PC, Ho HK, Leong DT. Nanoparticles' interactions with vasculature in diseases. Chem Soc Rev 2019; 48:5381-5407. [PMID: 31495856 DOI: 10.1039/c9cs00309f] [Citation(s) in RCA: 210] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The ever-growing use of inorganic nanoparticles (NPs) in biomedicine provides an exciting approach to develop novel imaging and drug delivery systems, owing to the ease with which these NPs can be functionalized to cater to various applications. In cancer therapeutics, nanomedicine generally relies on the enhanced permeability and retention (EPR) effect observed in tumour vasculature to deliver anti-cancer drugs across the endothelium. However, such a phenomenon is dependent on the tumour microenvironment and is not consistently observed in all tumour types, thereby limiting drug transport to the tumour site. On the other hand, there is a rise in utilizing inorganic NPs to intentionally induce endothelial leakiness, creating a window of opportunity to control drug delivery across the endothelium. While this active targeting approach creates a similar phenomenon compared to the EPR effect arising from tumour tissues, its drug delivery applications extend beyond cancer therapeutics and into other vascular-related diseases. In this review, we summarize the current findings of the EPR effect and assess its limitations in the context of anti-cancer drug delivery systems. While the EPR effect offers a possible route for drug passage, we further explore alternative uses of NPs to create controllable endothelial leakiness within short exposures, a phenomenon we coined as nanomaterial-induced endothelial leakiness (NanoEL). Furthermore, we discuss the main mechanistic features of the NanoEL effect that make it unique from conventionally established endothelial leakiness in homeostatic and pathologic conditions, as well as examine its potential applicability in vascular-related diseases, particularly cancer. Therefore, this new paradigm changes the way inorganic NPs are currently being used for biomedical applications.
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Affiliation(s)
- Jie Kai Tee
- Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore.
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Aller MA, Arias N, Blanco-Rivero J, Arias J. Metabolism in Acute-On-Chronic Liver Failure: The Solution More than the Problem. Arch Med Res 2019; 50:271-284. [PMID: 31593852 DOI: 10.1016/j.arcmed.2019.09.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 09/09/2019] [Indexed: 12/13/2022]
Abstract
Chronic inflammatory liver disease with an acute deterioration of liver function is named acute-on-chronic inflammation and could be regulated by the metabolic impairments related to the liver dysfunction. In this way, the experimental cholestasis model is excellent for studying metabolism in both types of inflammatory responses. Along the evolution of this model, the rats develop biliary fibrosis and an acute-on-chronic decompensation. The acute decompensation of the liver disease is associated with encephalopathy, ascites, acute renal failure, an acute phase response and a splanchnic increase of pro- and anti-inflammatory cytokines. This multiorgan inflammatory dysfunction is mainly associated with a splanchnic and systemic metabolic switch with dedifferentiation of the epithelial, endothelial and mesothelial splanchnic barriers. Furthermore, a splanchnic infiltration by mast cells occurs, which suggests that these cells could carry out a compensatory metabolic role, especially through the modulation of hepatic and extrahepatic mitochondrial-peroxisome crosstalk. For this reason, we propose the hypothesis that mastocytosis in the acute-on-chronic hepatic insufficiency could represent the development of a survival metabolic mechanisms that mitigates the noxious effect of the hepatic functional deficit. A better understanding the pathophysiological response of the mast cells in liver insufficiency and portal hypertension would help to find new pathways for decreasing the high morbidity and mortality rate of these patients.
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Affiliation(s)
- Maria-Angeles Aller
- Department of Surgery, School of Medicine, Complutense University of Madrid, Madrid, Spain.
| | - Natalia Arias
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK; INEUROPA (Instituto de Neurociencias del Principado de Asturias), Oviedo, Spain
| | - Javier Blanco-Rivero
- Department of Physiology, School of Medicine, Autonoma University of Madrid, Madrid, Spain, Instituto de Investigación Biomédica La Paz (IdIPAZ), Madrid, España; Centro de Investigación Biomédica en Red (Ciber) de Enfermedades Cardiovasculares, Madrid, España
| | - Jaime Arias
- Department of Surgery, School of Medicine, Complutense University of Madrid, Madrid, Spain
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Gordon-Walker TT, Bove K, Veldtman G. Fontan-associated liver disease: A review. J Cardiol 2019; 74:223-232. [DOI: 10.1016/j.jjcc.2019.02.016] [Citation(s) in RCA: 134] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 02/21/2019] [Indexed: 02/07/2023]
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40
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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: 56] [Impact Index Per Article: 9.3] [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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Arrivé L, Monnier-Cholley L, Cazzagon N, Wendum D, Chambenois E, El Mouhadi S. Non-contrast MR lymphography of the lymphatic system of the liver. Eur Radiol 2019; 29:5879-5888. [DOI: 10.1007/s00330-019-06151-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 02/08/2019] [Accepted: 03/08/2019] [Indexed: 12/16/2022]
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Affiliation(s)
- Floris E.A. Udink ten Cate
- Academic Center for Congenital Heart Disease, Department of Pediatric Cardiology, Amalia Children’s Hospital, Radboud University Medical Center, Nijmegen, The Netherlands (F.E.A.U.t.C.)
- Division of Pediatric Cardiology, Department of Pediatrics, Sophia Children’s Hospital, Erasmus Medical Center, Rotterdam, The Netherlands (F.E.A.U.t.C.)
- The Nijmegen Fontan Initiative, Radboud University Medical Center, The Netherlands (F.E.A.U.t.C., E.T.T.L.T.)
| | - Eric T.T.L. Tjwa
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands (E.T.T.L.T.)
- The Nijmegen Fontan Initiative, Radboud University Medical Center, The Netherlands (F.E.A.U.t.C., E.T.T.L.T.)
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Wong BW, Zecchin A, García-Caballero M, Carmeliet P. Emerging Concepts in Organ-Specific Lymphatic Vessels and Metabolic Regulation of Lymphatic Development. Dev Cell 2018; 45:289-301. [PMID: 29738709 DOI: 10.1016/j.devcel.2018.03.021] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 12/12/2017] [Accepted: 03/26/2018] [Indexed: 02/08/2023]
Abstract
The lymphatic system has been less well characterized than the blood vascular system; however, work in recent years has uncovered novel regulators and non-venous lineages that contribute to lymphatic formation in various organs. Further, the identification of organ-specific lymphatic beds underscores their potential interaction with organ development and function, and highlights the possibility of targeting these organ-specific lymphatics beds in disease. This review focuses on newly described metabolic and epigenetic regulators of lymphangiogenesis and the interplay between lymphatic development and function in a number of major organ systems.
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Affiliation(s)
- Brian W Wong
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Leuven Cancer Institute, KU Leuven, Herestraat 49 - B912, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven 3000, Belgium
| | - Annalisa Zecchin
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Leuven Cancer Institute, KU Leuven, Herestraat 49 - B912, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven 3000, Belgium
| | - Melissa García-Caballero
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Leuven Cancer Institute, KU Leuven, Herestraat 49 - B912, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven 3000, Belgium
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, Leuven Cancer Institute, KU Leuven, Herestraat 49 - B912, Leuven 3000, Belgium; Laboratory of Angiogenesis and Vascular Metabolism, VIB-KU Leuven Center for Cancer Biology, VIB, Leuven 3000, Belgium.
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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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Chubb SAP, Williams RA. Biochemical Analysis of Pleural Fluid and Ascites. Clin Biochem Rev 2018; 39:39-50. [PMID: 30473591 PMCID: PMC6223608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Biochemical testing of peritoneal and pleural fluids is carried out widely, although the range of tests likely to be useful is limited in comparison to the repertoire of tests available in a modern biochemistry laboratory. Fluids accumulate when pathological processes cause an imbalance between hydrostatic pressure gradients, capillary membrane permeability and lymphatic capacity, resulting in protein-poor transudates or inflammatory exudates. In peritoneal fluid, albumin is the most useful test, for the calculation of the serum-ascites albumin gradient; protein and LDH have a role regarding risk and diagnosis of spontaneous bacterial peritonitis and amylase may be useful in diagnosing fluid accumulation due to pancreatitis. Peritoneal fluid pH and glucose are not indicated analyses. For pleural fluid, protein and LDH are important in distinguishing between transudate and exudate using Light's criteria; albumin and the serum-effusion albumin gradient may have a complementary role in patients already on diuretics. Pleural fluid pH is the most useful marker of infection although LDH and glucose are also used. Pleural fluid amylase is often measured but, if raised, is more likely to reflect a malignant process than pancreatic disease as the former is much more prevalent. Tumour markers in both peritoneal and pleural fluids generally have limited diagnostic accuracy for detecting local malignancy. Limited studies validating standard serum test methods for use with pleural and peritoneal fluids have been published but work is progressing in this area both in Australasia and overseas and opportunities exist for contributing to this effort.
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Affiliation(s)
- SA Paul Chubb
- Biochemistry Department, PathWest Laboratory Medicine WA, Fiona Stanley Hospital, Murdoch, WA 6150, Australia
- School of Biomedical Science, University of Western Australia, Crawley, WA 6009, Australia
| | - Robin A Williams
- Biochemistry Department, PathWest Laboratory Medicine WA, Fiona Stanley Hospital, Murdoch, WA 6150, Australia
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Abstract
Portal hypertension develops as a result of increased intrahepatic vascular resistance often caused by chronic liver disease that leads to structural distortion by fibrosis, microvascular thrombosis, dysfunction of liver sinusoidal endothelial cells (LSECs), and hepatic stellate cell (HSC) activation. While the basic mechanisms of LSEC and HSC dysregulation have been extensively studied, the role of microvascular thrombosis and platelet function in the pathogenesis of portal hypertension remains to be clearly characterized. As a secondary event, portal hypertension results in splanchnic and systemic arterial vasodilation, leading to the development of a hyperdynamic circulatory syndrome and subsequently to clinically devastating complications including gastroesophageal varices and variceal hemorrhage, hepatic encephalopathy from the formation of portosystemic shunts, ascites, and renal failure due to the hepatorenal syndrome. This review article discusses: (1) mechanisms of sinusoidal portal hypertension, focusing on HSC and LSEC biology, pathological angiogenesis, and the role of microvascular thrombosis and platelets, (2) the mesenteric vasculature in portal hypertension, and (3) future directions for vascular biology research in portal hypertension.
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Affiliation(s)
- Matthew McConnell
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, 1080 LMP, 333 Cedar St., New Haven, CT, 06520, USA
| | - Yasuko Iwakiri
- Department of Internal Medicine, Section of Digestive Diseases, Yale University School of Medicine, 1080 LMP, 333 Cedar St., New Haven, CT, 06520, USA.
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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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Itkin M, Nadolski GJ. Modern Techniques of Lymphangiography and Interventions: Current Status and Future Development. Cardiovasc Intervent Radiol 2017; 41:366-376. [PMID: 29256071 DOI: 10.1007/s00270-017-1863-2] [Citation(s) in RCA: 80] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 12/14/2017] [Indexed: 12/28/2022]
Abstract
One of the crucial functions of the lymphatic system is maintenance of fluid balance. Nonetheless, due to lack of clinical imaging and interventional techniques, the lymphatic system has been under the radar of the medical community. The recently developed intranodal lymphangiography and dynamic contrast-enhanced MR lymphangiography provide new insight into lymphatic pathology. Thoracic duct embolization has become the method of choice for the treatment of patients with chylous leaks. Interstitial lymphatic embolization further expanded the lymphatic embolization approaches. Liver lymphatic lymphangiography and embolization allow treatment of postsurgical liver lymphorrhea and protein-losing enteropathy. The potential for further growth of lymphatic interventions is vast and includes liver lymphatic procedures and advanced thoracic duct interventions, such as thoracic duct externalization and stenting. These current and future advances will open up a realm of new treatments and diagnostic opportunities.
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Affiliation(s)
- Maxim Itkin
- HUP/CHOP Center for Lymphatic Imaging and Interventions, Penn Medicine, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA, 19104, USA.
| | - Gregory J Nadolski
- HUP/CHOP Center for Lymphatic Imaging and Interventions, Penn Medicine, Children's Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA, 19104, USA
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Yamada Y, Matsumoto S, Mori H, Takaji R, Kiyonaga M, Hijiya N, Tanoue R, Tomonari K, Tanoue S, Hongo N, Ohta M, Seike M, Inomata M, Murakami K, Moriyama M. Periportal lymphatic system on post-hepatobiliary phase Gd-EOB-DTPA-enhanced MR imaging in normal subjects and patients with chronic hepatitis C. Abdom Radiol (NY) 2017; 42:2410-2419. [PMID: 28444420 DOI: 10.1007/s00261-017-1155-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE We sought to evaluate visualization of periportal lymphatics and lymph nodes (lymphatic system) on Gd-EOB-DTPA-enhanced magnetic resonance (MR) images using a fat-suppressed T2-weighted sequence with 3-dimensional (3D) volume isotropic turbo spin echo acquisition (VISTA) at 3.0 T in normal subjects and patients with chronic hepatitis C. METHODS MR imaging was performed in 254 subjects between June 2013 and May 2016. After applying inclusion and exclusion criteria, the final population was 31 normal subjects and 34 patients with chronic hepatitis C. Images were acquired after the hepatobiliary phase following intravenous administration of Gd-EOB-DTPA, which causes signal loss in the bile ducts, to facilitate the visualization of the periportal lymphatic system. Two radiologists assessed the visualization of the periportal lymphatic system in 31 normal subjects. The axial dimensions of the main periportal lymphatic system in normal subjects were measured and compared with those of 34 patients with chronic hepatitis C using the Mann-Whitney U-test, and their correlation with a hepatic fibrosis marker, the Fibrosis-4 (FIB-4), was assessed using Spearman's rank correlation test. RESULTS The periportal lymphatic system was detected as high signal intensity areas surrounding the portal vein up to the third branches by each reader in all normal subjects. The axial dimensions of the main periportal lymphatic system in patients with chronic hepatitis C were significantly larger than those in normal subjects (p < 0.0001), and showed a significantly positive correlation with the FIB-4 score (ρ = 0.73, p < 0.001). CONCLUSIONS Fat-suppressed T2-weighted MR imaging with 3D-VISTA acquired after the hepatobiliary phase on Gd-EOB-DTPA-enhanced imaging may be a useful noninvasive method for evaluating the periportal lymphatic system and the degree of hepatic fibrosis.
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Affiliation(s)
- Yasunari Yamada
- Department of Radiology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan
| | - Shunro Matsumoto
- Department of Radiology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan.
| | - Hiromu Mori
- Department of Radiology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan
| | - Ryo Takaji
- Department of Radiology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan
| | - Maki Kiyonaga
- Department of Radiology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan
| | - Naoki Hijiya
- Department of Molecular Pathology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan
| | - Rika Tanoue
- Oita Diagnostic Imaging Center, Beppu, Oita, 874-0023, Japan
| | | | - Shuichi Tanoue
- Department of Radiology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan
| | - Norio Hongo
- Department of Radiology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan
| | - Masayuki Ohta
- Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan
| | - Masataka Seike
- Gastroenterology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan
| | - Masafumi Inomata
- Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan
| | - Kazunari Murakami
- Gastroenterology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan
| | - Masatsugu Moriyama
- Department of Molecular Pathology, Oita University Faculty of Medicine, Yufu, Oita, 879-5593, Japan
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Kreutzer C, Kreutzer G. The Lymphatic System: The Achilles Heel of the Fontan-Kreutzer Circulation. World J Pediatr Congenit Heart Surg 2017; 8:613-623. [DOI: 10.1177/2150135117720685] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
In spite of excellent long term survival the Fontan Kreutzer procedure commonly presents late failure due to end-organ damage. Several advances have been described to refine single ventricle management and surgical techniques. However, very little research has been dedicated to the lymphatic circulation in the precarious Fontan hemodynamic state. The lymphatic circulation is clearly affected since there is increased lymph production, which requires to be drained at a similar or higher pressure than it is produced, commonly resulting in chronic lymphedema. Chronic lymphedema induces fibrosis and end-organ failure even in normal circulation. Diverting lymph drainage to the low-pressured systemic atrium in Fontan may represent a valid alternative for the treatment of devastating complications as protein-losing enteropathy and plastic bronchitis and may prevent or decrease the development of end-organ fibrosis or failure.
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Affiliation(s)
- Christian Kreutzer
- Division of Pediatric Cardiovascular Surgery, Hospital Universitario Austral, Pilar, Buenos Aires, Argentina
| | - Guillermo Kreutzer
- Division of Pediatric Cardiovascular Surgery, Clinica Bazterrica, Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina
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