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Zaka AZ, Mangoura SA, Ahmed MA. New updates on hepatopulmonary syndrome: A comprehensive review. Respir Med 2025; 236:107911. [PMID: 39662637 DOI: 10.1016/j.rmed.2024.107911] [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: 09/12/2024] [Revised: 11/28/2024] [Accepted: 12/08/2024] [Indexed: 12/13/2024]
Abstract
Hepatopulmonary syndrome (HPS) is a serious pulmonary vascular complication that causes arterial hypoxemia in the setting of liver disease. HPS has a progressive course and is associated with a two-fold increased risk of mortality relative to cirrhotic patients without HPS. It primarily affects patients with portal hypertension. The key pathological features of HPS include intrapulmonary angiogenesis and vascular dilations (IPVDs). The prevalence of HPS varies widely due to inconsistent diagnostic criteria and a lack of standardized protocols. Despite advances in understanding its pathophysiology, no effective curative treatments for HPS exist. Liver transplantation remains the only definitive treatment, improving survival and altering the disease natural course. This review explores the pathophysiology, clinical features, and therapeutic strategies for HPS, highlighting recent advances in the literature.
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Affiliation(s)
- Andrew Z Zaka
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt.
| | - Safwat A Mangoura
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Badr University in Cairo (BUC), Badr, Cairo, 11829, Egypt.
| | - Marwa A Ahmed
- Department of Medical Pharmacology, Faculty of Medicine, Assiut University, Assiut, 71515, Egypt
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Chen B, Yang Y, Yang C, Duan J, Chen L, Lu K, Yi B, Chen Y, Xu D, Huang H. M2 macrophage accumulation contributes to pulmonary fibrosis, vascular dilatation, and hypoxemia in rat hepatopulmonary syndrome. J Cell Physiol 2021; 236:7682-7697. [PMID: 34041750 DOI: 10.1002/jcp.30420] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 05/04/2021] [Accepted: 05/08/2021] [Indexed: 12/11/2022]
Abstract
Hepatopulmonary syndrome (HPS) markedly increases the mortality of patients. However, its pathogenesis remains incompletely understood. Rat HPS develops in common bile duct ligation (CBDL)-induced, but not thioacetamide (TAA)-induced cirrhosis. We investigated the mechanisms of HPS by comparing these two models. Pulmonary histology, blood gas exchange, and the related signals regulating macrophage accumulation were assessed in CBDL and TAA rats. Anti-polymorphonuclear leukocyte (antiPMN) and anti-granulocyte-macrophage colony stimulating factor (antiGM-CSF) antibodies, clodronate liposomes (CL), and monocyte chemoattractant protein 1 (MCP1) inhibitor (bindarit) were administrated in CBDL rats, GM-CSF, and MCP1 were administrated in bone marrow-derived macrophages (BMDMs). Pulmonary inflammatory cell recruitment, vascular dilatation, and hypoxemia were progressively developed by 1 week after CBDL, but only occurred at 4 week after TAA. Neutrophils were the primary inflammatory cells within 3 weeks after CBDL and at 4 week after TAA. M2 macrophages were the primary inflammatory cells, meantime, pulmonary fibrosis, GM-CSFR, and CCR2 were specifically increased from 4 week after CBDL. AntiPMN antibody treatment decreased neutrophil and macrophage accumulation, CL or the combination of antiGM-CSF antibody and bindarit treatment decreased macrophage recruitment, resulting in pulmonary fibrosis, vascular dilatation, and hypoxemia in CBDL rats alleviated. The combination treatment of GM-CSF and MCP1 promoted cell migration, M2 macrophage differentiation, and transforming growth factor-β1 (TGF-β1) production in BMDMs. Conclusively, our results highlight neutrophil recruitment mediates pulmonary vascular dilatation and hypoxemia in the early stage of rat HPS. Further, M2 macrophage accumulation induced by GM-CSF/GM-CSFR and MCP1/CCR2 leads to pulmonary fibrosis and promotes vascular dilatation and hypoxemia, as a result, HPS develops.
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Affiliation(s)
- Bing Chen
- Department of Anesthesia, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Anesthesia, Southwest Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Yong Yang
- Department of Anesthesia, Southwest Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Congwen Yang
- Department of Anesthesia, Southwest Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Jiaxiang Duan
- Department of Anesthesia, Southwest Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Lin Chen
- Department of Anesthesia, Southwest Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Kaizhi Lu
- Department of Anesthesia, Southwest Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Bin Yi
- Department of Anesthesia, Southwest Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Yang Chen
- Department of Anesthesia, Southwest Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - Duo Xu
- Department of Anesthesia, Southwest Hospital, Army Medical University (The Third Military Medical University), Chongqing, China
| | - He Huang
- Department of Anesthesia, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Mendoza N, Rivas E, Rodriguez-Roisin R, Garcia T, Bruguera M, Agusti A, Faner R. Liver epigenome changes in patients with hepatopulmonary syndrome: A pilot study. PLoS One 2021; 16:e0245046. [PMID: 33630849 PMCID: PMC7906328 DOI: 10.1371/journal.pone.0245046] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 12/22/2020] [Indexed: 11/25/2022] Open
Abstract
The hepatopulmonary syndrome (HPS) is defined by the presence of pulmonary gas exchange abnormalities due to intrapulmonary vascular dilatations in patients with chronic liver disease. Changes in DNA methylation reflect the genomic variation. Since liver transplant (LT) reverts HPS we hypothesized that it may be associated with specific liver epigenetic changes. Thus, the aim of this study was to investigate the role of the liver epigenome in patients with HPS. We extracted DNA from paraffin embedded liver tissue samples from 10 patients with HPS and 10 age-, sex- and MELD (Model for End-stage Liver Disease)-matched controls. DNA methylation was determined using the 850K array (Illumina). Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify modules related to defining physiologic characteristics of HPS. Only 12 out of the 20 liver biopsies (7 HPS and 5 controls) had sufficient quality to be analyzed. None of the 802,688 DNA probes analyzed in the case control comparison achieved a significant False Discovery Rate (FDR). WGCNA identified 5 co-methylated gene-modules associated to HPS markers, mainly related to nervous and neuroendocrine system, apoptotic processes, gut bacterial translocation, angiogenesis and vascular remodeling ontologies. To conclude, HPS is associated with nervous/neuroendocrine system and vascular remodeling related liver epigenetic changes.
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Affiliation(s)
- Nuria Mendoza
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Eva Rivas
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Department of Anesthesia, Hospital Clinic, Barcelona, Spain
- Respiratory Institute, Hospital Clinic, Barcelona, Spain
| | - Roberto Rodriguez-Roisin
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Respiratory Institute, Hospital Clinic, Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Tamara Garcia
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
| | - Miquel Bruguera
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Alvar Agusti
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Respiratory Institute, Hospital Clinic, Barcelona, Spain
- University of Barcelona, Barcelona, Spain
| | - Rosa Faner
- Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain
- * E-mail:
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Grilo-Bensusan I, Pascasio-Acevedo JM. Hepatopulmonary syndrome: What we know and what we would like to know. World J Gastroenterol 2016; 22:5728-5741. [PMID: 27433086 PMCID: PMC4932208 DOI: 10.3748/wjg.v22.i25.5728] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Revised: 05/26/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatopulmonary syndrome (HPS) is characterized by abnormalities in blood oxygenation caused by the presence of intrapulmonary vascular dilations (IPVD) in the context of liver disease, generally at a cirrhotic stage. Knowledge about the subject is still only partial. The majority of the information about the etiopathogenesis of HPS has been obtained through experiments on animals. Reported prevalence in patients who are candidates for a liver transplantation (LT) varies between 4% and 32%, with a predominance of mild or moderate cases. Although it is generally asymptomatic it does have an impact on their quality of life and survival. The diagnosis requires taking an arterial blood gas sample of a seated patient with alveolar-arterial oxygen gradient (AaO2) ≥ 15 mm Hg, or ≥ 20 mm Hg in those over 64 years of age. The IPVD are identified through a transthoracic contrast echocardiography or a macroaggregated albumin lung perfusion scan (99mTc-MAA). There is currently no effective medical treatment. LT has been shown to reverse the syndrome and improve survival rates, even in severe cases. Therefore the policy of prioritizing LT would appear to increase survival rates. This paper takes a critical and clinical look at the current understanding of HPS, as well as the controversies surrounding it and possible future research.
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Thenappan T, Goel A, Marsboom G, Fang YH, Toth PT, Zhang HJ, Kajimoto H, Hong Z, Paul J, Wietholt C, Pogoriler J, Piao L, Rehman J, Archer SL. A central role for CD68(+) macrophages in hepatopulmonary syndrome. Reversal by macrophage depletion. Am J Respir Crit Care Med 2011; 183:1080-91. [PMID: 21148721 PMCID: PMC3086745 DOI: 10.1164/rccm.201008-1303oc] [Citation(s) in RCA: 141] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2010] [Accepted: 11/21/2010] [Indexed: 12/16/2022] Open
Abstract
RATIONALE The etiology of hepatopulmonary syndrome (HPS), a common complication of cirrhosis, is unknown. Inflammation and macrophage accumulation occur in HPS; however, their importance is unclear. Common bile duct ligation (CBDL) creates an accepted model of HPS, allowing us to investigate the cause of HPS. OBJECTIVES We hypothesized that macrophages are central to HPS and investigated the therapeutic potential of macrophage depletion. METHODS Hemodynamics, alveolar-arterial gradient, vascular reactivity, and histology were assessed in CBDL versus sham rats (n = 21 per group). The effects of plasma on smooth muscle cell proliferation and endothelial tube formation were measured. Macrophage depletion was used to prevent (gadolinium) or regress (clodronate) HPS. CD68(+) macrophages and capillary density were measured in the lungs of patients with cirrhosis versus control patients (n = 10 per group). MEASUREMENTS AND MAIN RESULTS CBDL increased cardiac output and alveolar-arterial gradient by causing capillary dilatation and arteriovenous malformations. Activated CD68(+)macrophages (nuclear factor-κB+) accumulated in HPS pulmonary arteries, drawn by elevated levels of plasma endotoxin and lung monocyte chemoattractant protein-1. These macrophages expressed inducible nitric oxide synthase, vascular endothelial growth factor, and platelet-derived growth factor. HPS plasma increased endothelial tube formation and pulmonary artery smooth muscle cell proliferation. Macrophage depletion prevented and reversed the histological and hemodynamic features of HPS. CBDL lungs demonstrated increased medial thickness and obstruction of small pulmonary arteries. Nitric oxide synthase inhibition unmasked exaggerated pulmonary vasoconstrictor responses in HPS. Patients with cirrhosis had increased pulmonary intravascular macrophage accumulation and capillary density. CONCLUSIONS HPS results from intravascular accumulation of CD68(+)macrophages. An occult proliferative vasculopathy may explain the occasional transition to portopulmonary hypertension. Macrophage depletion may have therapeutic potential in HPS.
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MESH Headings
- Animals
- Antigens, CD/immunology
- Antigens, CD/physiology
- Antigens, Differentiation, Myelomonocytic/immunology
- Antigens, Differentiation, Myelomonocytic/physiology
- Arteriovenous Malformations/etiology
- Arteriovenous Malformations/physiopathology
- Disease Models, Animal
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Hepatopulmonary Syndrome/etiology
- Hepatopulmonary Syndrome/immunology
- Humans
- Lung/blood supply
- Lung/cytology
- Lung/immunology
- Macrophages/immunology
- Macrophages/physiology
- Male
- Muscle, Smooth, Vascular/physiopathology
- Nitric Oxide Synthase Type II/antagonists & inhibitors
- Nitric Oxide Synthase Type II/physiology
- Platelet-Derived Growth Factor/antagonists & inhibitors
- Platelet-Derived Growth Factor/physiology
- Rats
- Rats, Sprague-Dawley
- Signal Transduction/physiology
- Vascular Endothelial Growth Factor A/antagonists & inhibitors
- Vascular Endothelial Growth Factor A/physiology
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Affiliation(s)
- Thenappan Thenappan
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Ankush Goel
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Glenn Marsboom
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Yong-Hu Fang
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Peter T. Toth
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Hannah J. Zhang
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Hidemi Kajimoto
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Zhigang Hong
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Jonathan Paul
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Christian Wietholt
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Jennifer Pogoriler
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Lin Piao
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Jalees Rehman
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
| | - Stephen L. Archer
- Section of Cardiology, Department of Medicine, The University of Chicago, Chicago, Illinois; and The Cardiovascular Research Institute, Kurume University, Kurume, Fukuoka, Japan
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Kim JS, Kim C, Kim GS, Lim DS, Hwang HK, Ro YM. A Case of Hepatopulmonary Syndrome in a Patient with Child-Pugh Class A Liver Cirrhosis. Tuberc Respir Dis (Seoul) 2009. [DOI: 10.4046/trd.2009.66.1.47] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Jung Sun Kim
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Changhwan Kim
- Department of Internal Medicine and Sejong Medical Research Institute, Sejong General Hospital, Bucheon, Korea
| | - Gye Su Kim
- Department of Internal Medicine and Sejong Medical Research Institute, Sejong General Hospital, Bucheon, Korea
| | - Dal Soo Lim
- Department of Internal Medicine and Sejong Medical Research Institute, Sejong General Hospital, Bucheon, Korea
| | - Hweung Kon Hwang
- Department of Internal Medicine and Sejong Medical Research Institute, Sejong General Hospital, Bucheon, Korea
| | - Young Moo Ro
- Department of Internal Medicine and Sejong Medical Research Institute, Sejong General Hospital, Bucheon, Korea
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Gill SS, Suri SS, Janardhan KS, Caldwell S, Duke T, Singh B. Role of pulmonary intravascular macrophages in endotoxin-induced lung inflammation and mortality in a rat model. Respir Res 2008; 9:69. [PMID: 18950499 PMCID: PMC2584635 DOI: 10.1186/1465-9921-9-69] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2008] [Accepted: 10/24/2008] [Indexed: 12/18/2022] Open
Abstract
Background Bile-duct ligated (BDL) rats recruit pulmonary intravascular macrophages (PIMs) and are highly susceptible to endotoxin-induced mortality. The mechanisms of this enhanced susceptibility and mortality in BDL rats, which are used as a model of hepato-pulmonary syndrome, remain unknown. We tested a hypothesis that recruited PIMs promote endotoxin-induced mortality in a rat model. Methods Rats were subjected to BDL to induce PIM recruitment followed by treatment with gadolinium chloride (GC) to deplete PIMs. Normal and BDL rats were treated intravenously with E. coli lipopolysaccharide (LPS) with or without GC pre-treatment followed by collection and analyses of lungs for histopathology, electron microscopy and cytokine quantification. Results BDL rats recruited PIMs without any change in the expression of IL-1β, TNF-α and IL-10. GC caused reduction in PIMs at 48 hours post-treatment (P < 0.05). BDL rats treated intravenously with E. coli LPS died within 3 hours of the challenge while the normal LPS-treated rats were euthanized at 6 hours after the LPS treatment. GC treatment of rats 6 hours or 48 hours before LPS challenge resulted in 80% (1/5) and 100% (0/5) survival, respectively, at 6 hours post-LPS treatment. Lungs from BDL+LPS rats showed large areas of perivascular hemorrhages compared to those pre-treated with GC. Concentrations of IL-1β, TNF-α and IL-10 were increased in lungs of BDL+LPS rats compared to BDL rats treated with GC 48 hours but not 6 hours before LPS (P < 0.05). Conclusion We conclude that PIMs increase susceptibility for LPS-induced lung injury and mortality in this model, which is blocked by a reduction in their numbers or their inactivation.
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Affiliation(s)
- Sukhjit S Gill
- Department of Veterinary Biomedical Sciences, University of Saskatchewan, Saskatoon, SK S7N5B4, Canada.
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