|
1
|
Chen J, Guo Y, Zhang X, Zhou D, Zhou Y, Pan Q, Chai J, Gao J. Disruption of Hepatic Sinusoidal Homeostasis Leads to Hepatopulmonary Syndrome. J Cell Mol Med 2025; 29:e70585. [PMID: 40344298 PMCID: PMC12061640 DOI: 10.1111/jcmm.70585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2025] [Revised: 04/22/2025] [Accepted: 04/26/2025] [Indexed: 05/11/2025] Open
Abstract
Hepatopulmonary syndrome (HPS) is a pulmonary vascular complication of liver disease and/or portal hypertension. HPS manifests as impaired gas exchange and hypoxemia due to intrapulmonary vascular dilatations and shunts. In response to primary liver disease, the abnormal adaptation of respiratory epithelial cells, pulmonary endothelial cells and immune cells leads to pulmonary microenvironment disequilibrium and HPS. In this review, we explore the pathophysiologic mechanisms of HPS, including vascular dilation, angiogenesis and alveolar dysfunction. The liver is the primary contributor to HPS, and liver transplantation is the only treatment that generally reverses HPS. We then discuss how disruption of hepatic sinusoidal homeostasis may impact the progression of HPS, mainly focusing on hepatocytes, cholangiocytes, LSECs and macrophages. As HPS occurs more commonly in advanced liver cirrhosis, we also discuss that normalisation of liver dysfunction and portal hypertension is crucial for the resolution of HPS. In conclusion, liver-targeted therapies may be effective in treating HPS.
Collapse
Affiliation(s)
- Jiaxin Chen
- Department of Gastroenterology, Lab of Gastroenterology and HepatologyWest China Hospital, Sichuan UniversityChengduChina
| | - Yangkun Guo
- Department of Gastroenterology, Lab of Gastroenterology and HepatologyWest China Hospital, Sichuan UniversityChengduChina
| | - Xiaoxun Zhang
- Department of Gastroenterology, Institute of Digestive Disease of PLA, Cholestatic Liver Diseases Center and Center for Metabolic Associated Fatty Liver DiseaseThe First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University)ChongqingChina
| | - Dengcheng Zhou
- Key Laboratory of Birth Defects of MOE, State Key Laboratory of Biotherapy, West China Second Hospital, College of Life SciencesSichuan UniversityChengduChina
| | - Yongfang Zhou
- Department of Respiratory CareWest China Hospital of Sichuan UniversityChengduSichuanChina
| | - Qiong Pan
- Department of Gastroenterology, Institute of Digestive Disease of PLA, Cholestatic Liver Diseases Center and Center for Metabolic Associated Fatty Liver DiseaseThe First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University)ChongqingChina
| | - Jin Chai
- Department of Gastroenterology, Institute of Digestive Disease of PLA, Cholestatic Liver Diseases Center and Center for Metabolic Associated Fatty Liver DiseaseThe First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University)ChongqingChina
| | - Jinhang Gao
- Department of Gastroenterology, Lab of Gastroenterology and HepatologyWest China Hospital, Sichuan UniversityChengduChina
| |
Collapse
|
|
2
|
Wu ZP, Wang YF, Shi FW, Cao WH, Sun J, Yang L, Ding FP, Hu CX, Kang WW, Han J, Yang RH, Song QK, Jin JW, Shi HB, Ma YM. Predictive models and clinical manifestations of intrapulmonary vascular dilatation and hepatopulmonary syndrome in patients with cirrhosis: Prospective comparative study. World J Gastroenterol 2025; 31:105720. [PMID: 40309225 PMCID: PMC12038555 DOI: 10.3748/wjg.v31.i15.105720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2025] [Revised: 03/13/2025] [Accepted: 03/26/2025] [Indexed: 04/18/2025] Open
Abstract
BACKGROUND Patients with cirrhosis with hepatopulmonary syndrome (HPS) have a poorer prognosis. The disease has a subtle onset, symptoms are easily masked, clinical attention is insufficient, and misdiagnosis rates are high. AIM To compare the clinical characteristics of patients with cirrhosis, cirrhosis combined with intrapulmonary vascular dilatation (IPVD), and HPS, and to establish predictive models for IPVD and HPS. METHODS Patients with cirrhosis were prospectively screened at a liver-specialized university teaching hospital. Clinical information and blood samples were collected, and biomarker levels in blood samples were measured. Patients with cirrhosis were divided into three groups: Those with pure cirrhosis, those with combined IPVD, and those with HPS based on contrast-enhanced transthoracic echocardiography results and the pulmonary alveolar-arterial oxygen gradient values. Univariate logistic regression and Least Absolute Shrinkage and Selection Operator (LASSO) regression methods were utilized to identify risk factors for IPVD and HPS, and nomograms were constructed to predict IPVD and HPS. RESULTS A total of 320 patients were analyzed, with 101 diagnosed with IPVD, of whom 54 were diagnosed with HPS. There were statistically significant differences in clinical parameters among these three groups of patients. Among the tested biomarkers, sphingosine 1 phosphate, angiopoietin-2, and platelet-derived growth factor BB were significantly associated with IPVD and HPS in patients with cirrhosis. Following LASSO logistic regression screening, prediction models for IPVD and HPS were established. The area under the receiver operating characteristic curve for IPVD prediction was 0.792 (95% confidence interval [CI]: 0.737-0.847), and for HPS prediction was 0.891 (95%CI: 0.848-0.934). CONCLUSION This study systematically compared the clinical characteristics of patients with cirrhosis, IPVD, and HPS, and constructed predictive models for IPVD and HPS based on clinical parameters and laboratory indicators. These models showed good predictive value for IPVD and HPS in patients with cirrhosis. They can assist clinicians in the early prognosis assessment of patients with cirrhosis, ultimately benefiting the patients.
Collapse
Affiliation(s)
- Zhi-Peng Wu
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Ying-Fei Wang
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Feng-Wei Shi
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Wen-Hui Cao
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Jie Sun
- Department of Respiratory and Critical Care Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Liu Yang
- Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Fang-Ping Ding
- Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Cai-Xia Hu
- Hepatic Disease and Tumor Interventional Treatment Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Wei-Wei Kang
- Fourth Department of Liver Disease, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Jing Han
- Ultrasound and Functional Diagnosis Center, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Rong-Hui Yang
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Qing-Kun Song
- Division of Clinical Epidemiology and Evidence-Based Medicine, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Jia-Wei Jin
- Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, China
| | - Hong-Bo Shi
- Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China
| | - Ying-Min Ma
- Beijing Institute of Hepatology, Department of Respiratory and Critical Care Medicine, Beijing Youan Hospital, Capital Medical University, Beijing 100069, Beijing, China
| |
Collapse
|
|
3
|
Robert F, Benchenouf F, Ha MN, Cuomo A, Ottaviani M, Surbier M, Thuillet R, Normand C, Dumont F, Verstuyft C, Fiore F, Guinut F, Humbert M, Coilly A, Gonzales E, Sitbon O, Tu L, Guignabert C, Savale L. Placental growth factor modulates endothelial NO production and exacerbates experimental hepatopulmonary syndrome. JHEP Rep 2025; 7:101297. [PMID: 39980753 PMCID: PMC11840504 DOI: 10.1016/j.jhepr.2024.101297] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 11/27/2024] [Accepted: 12/05/2024] [Indexed: 02/22/2025] Open
Abstract
Background & Aims Hepatopulmonary syndrome (HPS) results from portal hypertension, with or without cirrhosis, and is marked by pulmonary vascular dilations leading to severe hypoxemia. Although placental growth factor (PlGF) is important for vascular growth and endothelial function, its role in HPS is unclear. This study investigated the involvement of PlGF in experimental models of HPS and in patients. Methods Circulating PlGF levels were measured in 64 controls and 137 patients with liver disease, with or without HPS. Two rat models, common bile duct ligation (CBDL) and long-term partial portal vein ligation (PPVL), were used. Plgf-knockout (Plgf -/-) rats were generated using CRISPR-Cas9. Lung RNA-sequencing analysis was performed in the CBDL model. The effects of PlGF on endothelial nitric oxide synthase (eNOS) activity in human pulmonary microvascular endothelial cells were also investigated. Results Circulating PlGF levels were significantly higher in patients with cirrhosis compared with healthy controls (29.4 ± 1.2 vs. 20.2 ± 0.8 pg/ml, p <0.0001), but no difference were found between patients with and without HPS. PlGF levels were not elevated in patients with extrahepatic portal hypertension. In Plgf -/- rats, there was a protective effect against CBDL-induced HPS, whereas PPVL-induced HPS severity remained unchanged. RNA sequencing coupled with ingenuity pathway analysis identified significant interactions between PlGF and pulmonary eNOS activity. Following CBDL, Plgf -/- rats showed decreased pulmonary eNOS activity and reduced circulating nitric oxide metabolites. In vitro, PlGF stimulation enhanced eNOS activity in human pulmonary microvascular endothelial cells, whereas PlGF knockdown led to a decrease. Conclusions These findings indicate that PlGF aggravates cirrhosis-induced HPS through modulation of pulmonary eNOS activity, and is not involved in HPS from extrahepatic portal hypertension. Impact and implications This study identified PlGF as a significant contributor to the exacerbation of HPS associated with cirrhosis, through its regulation of pulmonary nitric oxide production. Our findings demonstrated that PlGF deficiency mitigates the severity of both cirrhosis and HPS in the CBDL model, highlighting its potential as a therapeutic target in cirrhosis-induced HPS. Notably, this protective effect was absent in the PPVL model, which induces HPS associated with portal hypertension without cirrhosis. These results open avenues for novel pharmacological interventions aiming to improve outcomes for patients with cirrhosis-induced HPS.
Collapse
Affiliation(s)
- Fabien Robert
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Feriel Benchenouf
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - My Ngoc Ha
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Alessandra Cuomo
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- Department of Translational Medical Sciences, Federico II University, Naples, Italy
| | - Mina Ottaviani
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Maxime Surbier
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Raphaël Thuillet
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Corinne Normand
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Florent Dumont
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Céline Verstuyft
- Université Paris-Saclay, Centre de Ressource Biologique Paris-Saclay, Assistance Publique-Hôpitaux de Paris (APHP), Hôpital Bicêtre, Le Kremlin Bicêtre, France
| | - Frederic Fiore
- Centre d'Immunophénomique (CIPHE), Aix Marseille Université, INSERM, CNRS, CELPHEDIA, PHENOMIN, Marseille, France
| | | | - Marc Humbert
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de L’hypertension Pulmonaire (PulmoTension), AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Audrey Coilly
- Centre Hépato-Biliaire, AP-HP, Hôpital Paul Brousse, Villejuif, France
- INSERM UMR_S 1193, Hepatinov, University Paris-Saclay, Orsay, France
| | - Emmanuel Gonzales
- INSERM UMR_S 1193, Hepatinov, University Paris-Saclay, Orsay, France
- Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Biliary Atresia and Genetic Cholestasis, AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Olivier Sitbon
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de L’hypertension Pulmonaire (PulmoTension), AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| | - Ly Tu
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Christophe Guignabert
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
| | - Laurent Savale
- Université Paris-Saclay, Unité Mixte de Recherche en Santé (UMR_S) 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- INSERM, UMR_S 999 Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique (HPPIT), Le Kremlin-Bicêtre, France
- Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de L’hypertension Pulmonaire (PulmoTension), AP-HP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
| |
Collapse
|
|
4
|
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.
Collapse
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
| |
Collapse
|
|
5
|
Al-Kuraishy HM, Al-Gareeb AI, Al-Maiahy TJ, Alexiou A, Mukerjee N, Batiha GES. An insight into the placental growth factor (PlGf)/angii axis in Covid-19: a detrimental intersection. Biotechnol Genet Eng Rev 2024; 40:3326-3345. [PMID: 36096720 DOI: 10.1080/02648725.2022.2122291] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 07/29/2022] [Indexed: 11/02/2022]
Abstract
Coronavirus disease 2019 (Covid-19) is a recent and current infectious pandemic caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Covid-19 may lead to the development of acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and extrapulmonary manifestations in severe cases. Down-regulation of angiotensin-converting enzyme (ACE2) by the SARS-CoV-2 increases the production of angiotensin II (AngII), which increases the release of pro-inflammatory cytokines and placental growth factor (PlGF). PlGF is a critical molecule involved in vasculogenesis and angiogenesis. PlGF is stimulated by AngII in different inflammatory diseases through a variety of signaling pathways. PlGF and AngII are interacted in SARS-CoV-2 infection resulting in the production of pro-inflammatory cytokines and the development of Covid-19 complications. Both AngII and PlGF are interacted and are involved in the progression of inflammatory disorders; therefore, we aimed in this review to highlight the potential role of the PlGF/AngII axis in Covid-19.
Collapse
Affiliation(s)
- Hayder M Al-Kuraishy
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq
| | - Ali I Al-Gareeb
- Department of Clinical Pharmacology and Medicine, College of Medicine, ALmustansiriyia University, Baghdad, Iraq
| | - Thabat J Al-Maiahy
- Department Of Gynecology and Obstetrics, College of Medicine, Al-Mustansiriyah University, Baghdad, Iraq
| | - Athanasios Alexiou
- Department of Science and Engineering, Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia
- AFNP Med, Austria, Wien, Austria
| | - Nobendu Mukerjee
- Department of Microbiology; Ramakrishna Mission Vivekananda Centenary College, Kolkata, WestBengal, India
- Department of Health Sciences, Novel Global Community Educational Foundation, Hebersham, NSW 2770, Australia
| | - Gaber El-Saber Batiha
- Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, AlBeheira, Egypt
| |
Collapse
|
|
6
|
Verstraeten M, Lefere S, Raevens S. Pulmonary vascular complications of cirrhosis: hepatopulmonary syndrome and portopulmonary hypertension. Acta Clin Belg 2024; 79:384-391. [PMID: 39873530 DOI: 10.1080/17843286.2025.2456697] [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: 12/20/2024] [Accepted: 01/13/2025] [Indexed: 01/30/2025]
Abstract
Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH) are two distinct pulmonary vascular complications seen in patients with liver disease and/or portal hypertension. HPS is characterized by disturbed gas exchange and hypoxemia because of intrapulmonary vascular dilatations. POPH is defined by pulmonary arterial hypertension, which might lead to right heart failure. HPS affects up to 30% of patients with end-stage liver disease requiring liver transplantation. POPH is rarer and affects 1-5% of this patient population. If not recognized and left untreated, these disorders result in significant mortality. This review provides an update on HPS and POPH and discusses their clinical characteristics, screening and diagnostic modalities, and management, including the place of liver transplantation.
Collapse
Affiliation(s)
- Maïté Verstraeten
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Ghent, Belgium
| | - Sander Lefere
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Ghent, Belgium
| | - Sarah Raevens
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
- Hepatology Research Unit, Department of Internal Medicine and Pediatrics, Liver Research Center, Ghent University, Ghent, Belgium
| |
Collapse
|
|
7
|
Raja Xavier JP, Okumura T, Apweiler M, Chacko NA, Singh Y, Brucker SY, Takeda S, Lang F, Salker MS. Placental growth factor mediates pathological uterine angiogenesis by activating the NFAT5-SGK1 signaling axis in the endometrium: implications for preeclampsia development. Biol Res 2024; 57:55. [PMID: 39152497 PMCID: PMC11330076 DOI: 10.1186/s40659-024-00526-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 06/26/2024] [Indexed: 08/19/2024] Open
Abstract
After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or preeclampsia (PE). Placental growth factor (PlGF) is a known contributing factor for pathological angiogenesis but the mechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine angiogenesis by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signaling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signaling. Taken together, perturbed PlGF-NFAT5-SGK1 signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs-endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.
Collapse
Affiliation(s)
- Janet P Raja Xavier
- Department of Women's Health, University of Tübingen, 72076, Calwerstraße 7/6, Tübingen, Germany
| | - Toshiyuki Okumura
- Department of Obstetrics and Gynaecology, Juntendo University School of Medicine, Tokyo, Japan
| | - Melina Apweiler
- Department of Women's Health, University of Tübingen, 72076, Calwerstraße 7/6, Tübingen, Germany
| | - Nirzari A Chacko
- Department of Women's Health, University of Tübingen, 72076, Calwerstraße 7/6, Tübingen, Germany
| | - Yogesh Singh
- Department of Women's Health, University of Tübingen, 72076, Calwerstraße 7/6, Tübingen, Germany
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
| | - Sara Y Brucker
- Department of Women's Health, University of Tübingen, 72076, Calwerstraße 7/6, Tübingen, Germany
| | - Satoru Takeda
- Department of Obstetrics and Gynaecology, Juntendo University School of Medicine, Tokyo, Japan
| | - Florian Lang
- Department of Physiology, University of Tübingen, Tübingen, Germany
| | - Madhuri S Salker
- Department of Women's Health, University of Tübingen, 72076, Calwerstraße 7/6, Tübingen, Germany.
| |
Collapse
|
|
8
|
Yang C, Sun M, Yang Y, Han Y, Wu X, Wu X, Cao H, Chen L, Lei Y, Hu X, Chen Y, Zeng Z, Li J, Shu X, Yang Z, Lu K, Li Y, Wang X, Yi B. Elevated circulating BMP9 aggravates pulmonary angiogenesis in hepatopulmonary syndrome rats through ALK1-Endoglin-Smad1/5/9 signalling. Eur J Clin Invest 2024; 54:e14212. [PMID: 38591651 DOI: 10.1111/eci.14212] [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: 12/13/2023] [Revised: 02/29/2024] [Accepted: 03/03/2024] [Indexed: 04/10/2024]
Abstract
BACKGROUND Bone morphogenetic protein 9 (BMP9) is a hepatokine that plays a pivotal role in the progression of liver diseases. Moreover, an increasing number of studies have shown that BMP9 is associated with hepatopulmonary syndrome (HPS), but its role in HPS is unclear. Here, we evaluated the influence of CBDL on BMP9 expression and investigated potential mechanisms of BMP9 signalling in HPS. METHODS We profiled the circulating BMP9 levels in common bile duct ligation-induced HPS rat model, and then investigated the effects and mechanisms of HPS rat serum on pulmonary vascular endothelial dysfunction in rat model, as well as in primarily cultured rat pulmonary microvascular endothelial cells. RESULTS Our data revealed that circulating BMP9 levels were significantly increased in the HPS rats compared to control group. Besides, the elevated BMP9 in HPS rat serum was not only crucial for promoting endothelial cell proliferation and tube formation through the activin receptor-like kinase1 (ALK1)-Endoglin-Smad1/5/9 pathway, but also important for accumulation of monocytes. Treatments with ALK1-Fc or silencing ALK1 expression to inhibit the BMP9 signalling pathway effectively eliminated these effects. In agreement with these observations, increased circulating BMP9 was associated with an increase in lung vessel density and accumulation of pro-angiogenic monocytes in the microvasculature in HPS rats. CONCLUSIONS This study provided evidence that elevated circulating BMP9, secreted from the liver, promote pulmonary angiogenesis in HPS rats via ALK1-Endoglin-Smad1/5/9 pathway. In addition, BMP9-regulated pathways are also involved in accumulation of pro-angiogenic monocytes in the pulmonary microvasculature in HPS rats.
Collapse
Affiliation(s)
- Chunyong Yang
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Mei Sun
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yihui Yang
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
- Department of Anesthesia, The Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Yan Han
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xiulin Wu
- Institute of Geriatrics, Southwest Hospital, Army Medical University, Chongqing, China
| | - Xianfeng Wu
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Huilin Cao
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Lin Chen
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yuhao Lei
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xiaoyan Hu
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yang Chen
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Ziyang Zeng
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Junhong Li
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xin Shu
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Zhiyong Yang
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Kaizhi Lu
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Yujie Li
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Xiaobo Wang
- MCD, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Bin Yi
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University, Chongqing, China
| |
Collapse
|
|
9
|
Chooklin S, Chuklin S, Posivnych M, Krystopchuk S. Pathophysiological basis of hepatopulmonary syndrome. Gastroenterology 2024; 58:73-81. [DOI: 10.22141/2308-2097.58.1.2024.590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Circulatory changes with increased blood flow and vasodilatation/vasoconstriction imbalance are an integral consequence of liver cirrhosis and portal hypertension and can affect the pulmonary circulation with the development of vascular disorders, with hepatopulmonary syndrome (HPS) being the most common. HPS is a serious pulmonary complication of progressive liver disease, resulting in a poor clinical prognosis. Vascular tone decrease, monocytic infiltration of pulmonary vessels, formation of intrapulmonary arteriovenous shunts, dysfunction of alveolar type II cells, destruction of the endothelial glycocalyx are important in the pathogenesis of HPS. Abnormalities of pulmonary capillaries lead to hypoxemia caused by a violation of the ventilation/perfusion ratio, diffusion disorders, and the development of arteriovenous anastomoses. Infiltration of the pulmonary vessels by monocytes is one of the key factors of HPS. This migration is facilitated by the intestinal microbiota translocation into the portal bloodstream with increased expression of proinflammatory cytokines (tumor necrosis factor α, interleukins 1, 6), leading to the activation of monocytes. Monocytes located in the pulmonary circulation promote the vasodilation through the activation of inducible nitric oxide (NO) synthase and thus NO production. This is also associated with endothelial dysfunction due to a decreased hepatic secretion of bone morphogenetic protein 9 and increased endothelin 1, endothelial overexpression of endothelin B receptors, and increased endothelial NO production. Proangiogenic factors such as vascular endothelial growth factor, platelet-derived growth factor, and placental growth factor play an important role in the proliferation of pulmonary capillaries. Circulation of tumor necrosis factor α, bile acids and monocyte infiltration in the pulmonary circulation lead to increased apoptosis of alveolar type II cells and decreased surfactant synthesis. Chronic inflammation in HPS disrupts the continuity of the endothelial glycocalyx layer. This article provides an overview of the current knowledge on the pathogenesis of HPS, summarizes many features of the disease based on the literature research in MEDLINE database on the PubMed platform.
Collapse
|
|
10
|
Sayadi A, Duhaut L, Robert F, Savale L, Coilly A. [Hepatopulmonary syndrome]. Rev Med Interne 2024; 45:156-165. [PMID: 37005097 DOI: 10.1016/j.revmed.2023.03.008] [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: 11/10/2022] [Revised: 03/07/2023] [Accepted: 03/17/2023] [Indexed: 04/03/2023]
Abstract
The hepatopulmonary syndrome (HPS) is one of the lung diseases associated with cirrhosis and portal hypertension. It should be discussed for any dyspnea in cirrhotic patients. HPS is a pulmonary vascular disease characterized by intrapulmonary vascular dilatations (IPVD). The pathogenesis is complex and seems to rely on communications between the portal and pulmonary circulations. The diagnosis is based on a triad of liver disease and portal hypertension, evidence of IPVDs, and impaired gas exchange (alveolar-arterial oxygen difference [A-aO2]≥15mmHg). HPS impairs prognosis (23% survival at 5years) and patients' quality of life. Liver transplantation (LT) allows regression of IPDVD in almost 100% of cases, normalization of gas exchange and improves survival with a 5-year post-LT survival between 76 and 87%. It is the only curative treatment, indicated in patients with severe HPS, defined by an arterial partial pressure of oxygen (PaO2) below 60mmHg. When LT is not indicated or feasible, long-term oxygen therapy may be proposed as a palliative treatment. A better understanding of the pathophysiological mechanisms is needed to improve the therapeutic possibilities in a near future.
Collapse
Affiliation(s)
- A Sayadi
- UMR-S 1193, hôpital Paul-Brousse, centre hépato-biliaire, université Paris-Saclay, AP-HP, 94800 Villejuif, France
| | - L Duhaut
- UMR-S 1193, hôpital Paul-Brousse, centre hépato-biliaire, université Paris-Saclay, AP-HP, 94800 Villejuif, France
| | - F Robert
- Inserm UMR_S 999, 94270 Le Kremlin-Bicêtre, France
| | - L Savale
- Inserm UMR_S 999, 94270 Le Kremlin-Bicêtre, France; Service de pneumologie, hôpital Bicêtre, université Paris-Saclay, AP-HP, 94270 Le Kremlin-Bicêtre, France
| | - A Coilly
- UMR-S 1193, hôpital Paul-Brousse, centre hépato-biliaire, université Paris-Saclay, AP-HP, 94800 Villejuif, France.
| |
Collapse
|
|
11
|
Yang C, Yang Y, Chen Y, Huang J, Li D, Tang X, Ning J, Gu J, Yi B, Lu K. Cholangiocyte-derived exosomal long noncoding RNA PICALM-AU1 promotes pulmonary endothelial cell endothelial-mesenchymal transition in hepatopulmonary syndrome. Heliyon 2024; 10:e24962. [PMID: 39822730 PMCID: PMC11737509 DOI: 10.1016/j.heliyon.2024.e24962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 01/15/2024] [Accepted: 01/17/2024] [Indexed: 01/19/2025] Open
Abstract
Hepatopulmonary syndrome (HPS) is a severe lung injury caused by chronic liver disease, with limited understanding of the disease pathology. Exosomes are important mediators of intercellular communication that modulates various cellular functions by transferring a variety of intracellular components to target cells. Our recent studies have indicated that a new long noncoding RNA (lncRNA), PICALM-AU1, is mainly expressed in cholangiocytes, and is dramatically induced in the liver during HPS. However, the mechanism by which cholangiocyte-derived PICALM-AU1 regulates Endothelial-mesenchymal transition (EndMT) in HPS remains unclear. Here, we observed that PICALM-AU1 was synthesized in the cholangiocytes of the liver and then, secreted as exosomes into the serum; serum exosomal PICALM-AU1 levels were positively correlated with the severity of HPS in a rat model and in human patients. PICALM-AU1 carrying serum exosomes induced the EndMT of pulmonary microvascular endothelial cells (PMVECs) and promoted lung injury in vivo and in vitro. Furthermore, PICALM-AU1 acted as a molecular sponge for microRNA 144-3p (miR144-3p), resulting in the up-regulation of Zinc Finger E-Box Binding Homeobox 1 (ZEB1), a known target of EndMT and enhancement of EndMT, proliferation and migration of PMVECs. Taken together, our findings indicate that the cholangiocyte-derived exosomal lncRNA PICALM-AU1 plays a critical role in the EndMT in HPS lungs. Thus, it represents a potential therapeutic target for the treatment of HPS.
Collapse
Affiliation(s)
- Congwen Yang
- Department of Anesthesia, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, Chongqing Medical University, Chongqing, 400016, China
| | - Yihui Yang
- Department of Anesthesia, The Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000 China
| | - Yang Chen
- Department of Anesthesia, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China
| | - Jian Huang
- Department of Anesthesia, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China
| | - Dan Li
- Department of Anesthesia, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China
| | - Xi Tang
- Department of Anesthesia, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China
| | - Jiaolin Ning
- Department of Anesthesia, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China
| | - Jianteng Gu
- Department of Anesthesia, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China
| | - Bin Yi
- Department of Anesthesia, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China
| | - Kaizhi Lu
- Department of Anesthesia, Southwest Hospital, The Third Military Medical University, Chongqing 400038, China
| |
Collapse
|
|
12
|
De Muynck K, Heyerick L, De Ponti FF, Vanderborght B, Meese T, Van Campenhout S, Baudonck L, Gijbels E, Rodrigues PM, Banales JM, Vesterhuus M, Folseraas T, Scott CL, Vinken M, Van der Linden M, Hoorens A, Van Dorpe J, Lefere S, Geerts A, Van Nieuwerburgh F, Verhelst X, Van Vlierberghe H, Devisscher L. Osteopontin characterizes bile duct-associated macrophages and correlates with liver fibrosis severity in primary sclerosing cholangitis. Hepatology 2024; 79:269-288. [PMID: 37535809 PMCID: PMC10789378 DOI: 10.1097/hep.0000000000000557] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 06/29/2023] [Indexed: 08/05/2023]
Abstract
BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which pharmacological treatment options are currently unavailable. PSC is strongly associated with colitis and a disruption of the gut-liver axis, and macrophages are involved in the pathogenesis of PSC. However, how gut-liver interactions and specific macrophage populations contribute to PSC is incompletely understood. APPROACH AND RESULTS We investigated the impact of cholestasis and colitis on the hepatic and colonic microenvironment, and performed an in-depth characterization of hepatic macrophage dynamics and function in models of concomitant cholangitis and colitis. Cholestasis-induced fibrosis was characterized by depletion of resident KCs, and enrichment of monocytes and monocyte-derived macrophages (MoMFs) in the liver. These MoMFs highly express triggering-receptor-expressed-on-myeloid-cells-2 ( Trem2 ) and osteopontin ( Spp1 ), markers assigned to hepatic bile duct-associated macrophages, and were enriched around the portal triad, which was confirmed in human PSC. Colitis induced monocyte/macrophage infiltration in the gut and liver, and enhanced cholestasis-induced MoMF- Trem2 and Spp1 upregulation, yet did not exacerbate liver fibrosis. Bone marrow chimeras showed that knockout of Spp1 in infiltrated MoMFs exacerbates inflammation in vivo and in vitro , while monoclonal antibody-mediated neutralization of SPP1 conferred protection in experimental PSC. In human PSC patients, serum osteopontin levels are elevated compared to control, and significantly increased in advanced stage PSC and might serve as a prognostic biomarker for liver transplant-free survival. CONCLUSIONS Our data shed light on gut-liver axis perturbations and macrophage dynamics and function in PSC and highlight SPP1/OPN as a prognostic marker and future therapeutic target in PSC.
Collapse
Affiliation(s)
- Kevin De Muynck
- Department of Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Lander Heyerick
- Department of Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
| | - Federico F. De Ponti
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
| | - Bart Vanderborght
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
- Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium
| | - Tim Meese
- Department of Pharmaceutics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
- NXTGNT, Ghent University, Ghent, Belgium
| | - Sanne Van Campenhout
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
- Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium
| | - Leen Baudonck
- Department of Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium
| | - Eva Gijbels
- Department of Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | - Pedro M. Rodrigues
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Jesus M. Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, University of the Basque Country (UPV-EHU), Donostia-San Sebastian, Spain
- CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
- Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain
| | - Mette Vesterhuus
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Norwegian PSC Research Center, Oslo, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Trine Folseraas
- Department of Transplantation Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Norwegian PSC Research Center, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Norway
- Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway
| | - Charlotte L. Scott
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB-UGent Center for Inflammation Research, Ghent, Belgium
| | - Mathieu Vinken
- Department of Pharmaceutical and Pharmacological Sciences, Vrije Universiteit Brussel (VUB), Brussels, Belgium
| | | | - Anne Hoorens
- Department of Pathology, Ghent University Hospital, Ghent, Belgium
| | - Jo Van Dorpe
- Department of Pathology, Ghent University Hospital, Ghent, Belgium
| | - Sander Lefere
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
- Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium
| | - Anja Geerts
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
- Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Filip Van Nieuwerburgh
- Department of Pharmaceutics, Laboratory of Pharmaceutical Biotechnology, Ghent University, Ghent, Belgium
- NXTGNT, Ghent University, Ghent, Belgium
| | - Xavier Verhelst
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
- Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Hans Van Vlierberghe
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
- Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Lindsey Devisscher
- Department of Basic & Applied Medical Sciences, Gut-Liver Immunopharmacology Unit, Ghent University, Ghent, Belgium
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
| |
Collapse
|
|
13
|
Chooklin S, Chuklin S. Hepatopulmonary syndrome: diagnosis and treatment. EMERGENCY MEDICINE 2024; 19:511-518. [DOI: 10.22141/2224-0586.19.8.2023.1640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/02/2024]
Abstract
Hepatopulmonary syndrome (HPS) is one of the lung diseases associated with liver cirrhosis and portal hypertension. The diagnosis is based on the triad: liver disease and portal hypertension, evidence of intrapulmonary vascular dilatation and impaired gas exchange. HPS impairs prognosis (23 % survival after 5 years) and patients’ quality of life, so early diagnosis and timely treatment are of great importance. Liver transplantation allows for regression of intrapulmonary vascular dilatation in almost 100 % of cases, normalization of gas exchange and improves a 5-year survival after transplantation from 76 to 87 %. This is the only treatment method indicated for patients with severe HPS, defined by an arterial partial pressure of oxygen (PaO2) below 60 mm Hg. However, in the face of a global shortage of transplants, it is necessary to develop medical therapies to delay or even defer liver transplantation. This goal seems possible due to the growing understanding of the HPS pathophysiology and the development of therapies targeting key mechanisms, mainly inflammatory and angiogenic. This article provides an overview of the clinical manifestations, diagnosis and treatment of HPS based on literature sources from the MEDLINE database on the PubMed platform.
Collapse
|
|
14
|
Li YJ, Wu XF, Wang DD, Li P, Liang H, Hu XY, Gan JQ, Sun YZ, Li JH, Li J, Shu X, Song AL, Yang CY, Yang ZY, Yu WF, Yang LQ, Wang XB, Belguise K, Xia ZY, Yi B. Serum Soluble Vascular Endothelial Growth Factor Receptor 1 as a Potential Biomarker of Hepatopulmonary Syndrome. J Clin Transl Hepatol 2023; 11:1150-1160. [PMID: 37577229 PMCID: PMC10412700 DOI: 10.14218/jcth.2022.00421] [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: 08/30/2022] [Revised: 01/02/2023] [Accepted: 02/28/2023] [Indexed: 07/03/2023] Open
Abstract
Background and Aims The results of basic research implicate the vascular endothelial growth factor (VEGF) family as a potential target of hepatopulmonary syndrome (HPS). However, the negative results of anti-angiogenetic therapy in clinical studies have highlighted the need for markers for HPS. Therefore, we aimed to determine whether VEGF family members and their receptors can be potential biomarkers for HPS through clinical and experimental studies. Methods Clinically, patients with chronic liver disease from two medical centers were enrolled and examined for HPS. Patients were divided into HPS, intrapulmonary vascular dilation [positive contrast-enhanced echocardiography (CEE) and normal oxygenation] and CEE-negative groups. Baseline information and perioperative clinical data were compared between HPS and non-HPS patients. Serum levels of VEGF family members and their receptors were measured. In parallel, HPS rats were established by common bile duct ligation. Liver, lung and serum samples were collected for the evaluation of pathophysiologic changes, as well as the expression levels of the above factors. Results In HPS rats, all VEGF family members and their receptors underwent significant changes; however, only soluble VEGFR1 (sFlt-1) and the sFlt-1/ placental growth factor (PLGF) ratio were changed in almost the same manner as those in HPS patients. Furthermore, through feature selection and internal and external validation, sFlt-1 and the sFlt-1/PLGF ratio were identified as the most important variables to distinguish HPS from non-HPS patients. Conclusions Our results from animal and human studies indicate that sFlt-1 and the sFlt-1/PLGF ratio in serum are potential markers for HPS.
Collapse
Affiliation(s)
- Yu-Jie Li
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xian-Feng Wu
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Dan-Dan Wang
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Peng Li
- Department of Anesthesiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
| | - Hao Liang
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiao-Yan Hu
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jia-Qi Gan
- Department of Anesthesiology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China
| | - Yi-Zhu Sun
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jun-Hong Li
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Jun Li
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xin Shu
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Ai-Lin Song
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Chun-Yong Yang
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Zhi-Yong Yang
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Wei-Feng Yu
- Department of Anesthesiology, Renji Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
| | - Li-Qun Yang
- Department of Anesthesiology, Renji Hospital Affiliated to Shanghai Jiao Tong University, Shanghai, China
| | - Xiao-Bo Wang
- LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Karine Belguise
- LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Zheng-Yuan Xia
- Department of Anesthesiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Bin Yi
- Department of Anesthesiology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| |
Collapse
|
|
15
|
Liu J, Duan X, Yin J, Yang H, He R, Zhao S. Effective long-term sirolimus treatment in hypoxemia mainly due to intrapulmonary right-to-left shunt in a patient with multiple vascular anomalies. Orphanet J Rare Dis 2023; 18:124. [PMID: 37226169 DOI: 10.1186/s13023-023-02732-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 05/14/2023] [Indexed: 05/26/2023] Open
Abstract
Pulmonary arteriovenous malformations (PAVMs), particularly where feeding artery/arteries to PAVMs ≥ 3 mm can be treated with embolization. The treatment for hypoxemia resulting from multiple small or diffuse PAVMs remains unclear.We report a girl aged 5 years and 10 months presented with cyanosis and decreased activity after exercise (83-85% of pulse oxygen saturation, SpO2). She had 1 skin lesion on her face and 1 suspected hemangioma on her left upper extremity at birth and that gradually disappeared spontaneously. Physical examination revealed clubbed fingers, and abundant vascular networks on her back. Contrast-enhanced lung CT (slice thickness:1.25 mm) with vascular three-dimensional reconstruction and abdominal CT revealed increased bronchovascular bundles, increased diameter of the pulmonary artery and ascending aorta, and intrahepatic portosystemic venous shunts due to patent ductus venosus. Echocardiography revealed increased diameter of aortic and pulmonary artery. Transthoracic contrast echocardiography was highly positive (bubble appearing in the left ventricle after 5 cardiac cycles). Abdominal doppler ultrasound revealed hepatic-portal venous shunt. Magnetic resonance imaging, artery and vein of the brain revealed multiple malformations of venous sinuses. The patient received sirolimus for 2 years and 4 months. Her condition improved significantly. SpO2 gradually increased to 98%. Her finger clubbing gradually normalized.Our report implicates sirolimus might be a potential treatment option in persistent hypoxemia mainly due to intrapulmonary right-to-left shunt even small multiple or diffusive PAVMs in pediatric patients with multiple cutaneous and visceral vascular anomalies.
Collapse
Affiliation(s)
- Jinrong Liu
- Department of Respiratory Medicine, National Clinical Research Center of Respiratory Disease, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
| | - Xiaomin Duan
- Imaging Center, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
| | - Jie Yin
- Imaging Center, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
| | - Haiming Yang
- Department of Respiratory Medicine, National Clinical Research Center of Respiratory Disease, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
| | - Ruxuan He
- Department of Respiratory Medicine, National Clinical Research Center of Respiratory Disease, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China
| | - Shunying Zhao
- Department of Respiratory Medicine, National Clinical Research Center of Respiratory Disease, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, Beijing, China.
| |
Collapse
|
|
16
|
Jo D, Jung YS, Song J. Lipocalin-2 Secreted by the Liver Regulates Neuronal Cell Function Through AKT-Dependent Signaling in Hepatic Encephalopathy Mouse Model. Clin Nutr Res 2023; 12:154-167. [PMID: 37214781 PMCID: PMC10193436 DOI: 10.7762/cnr.2023.12.2.154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2023] [Revised: 03/17/2023] [Accepted: 03/23/2023] [Indexed: 05/24/2023] Open
Abstract
Hepatic encephalopathy (HE) associated with liver failure is accompanied by hyperammonemia, severe inflammation, depression, anxiety, and memory deficits as well as liver injury. Recent studies have focused on the liver-brain-inflammation axis to identify a therapeutic solution for patients with HE. Lipocalin-2 is an inflammation-related glycoprotein that is secreted by various organs and is involved in cellular mechanisms including iron homeostasis, glucose metabolism, cell death, neurite outgrowth, and neurogenesis. In this study, we investigated that the roles of lipocalin-2 both in the brain cortex of mice with HE and in Neuro-2a (N2A) cells. We detected elevated levels of lipocalin-2 both in the plasma and liver in a bile duct ligation mouse model of HE. We confirmed changes in cytokine expression, such as interleukin-1β, cyclooxygenase 2 expression, and iron metabolism related to gene expression through AKT-mediated signaling both in the brain cortex of mice with HE and N2A cells. Our data showed negative effects of hepatic lipocalin-2 on cell survival, iron homeostasis, and neurite outgrowth in N2A cells. Thus, we suggest that regulation of lipocalin-2 in the brain in HE may be a critical therapeutic approach to alleviate neuropathological problems focused on the liver-brain axis.
Collapse
Affiliation(s)
- Danbi Jo
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
- Biomedical Science Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Korea
| | - Yoon Seok Jung
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea
- Biomedical Science Graduate Program (BMSGP), Chonnam National University, Hwasun 58128, Korea
| |
Collapse
|
|
17
|
Li L, Cook C, Liu Y, Li J, Jiang J, Li S. Endothelial glycocalyx in hepatopulmonary syndrome: An indispensable player mediating vascular changes. Front Immunol 2022; 13:1039618. [PMID: 36618396 PMCID: PMC9815560 DOI: 10.3389/fimmu.2022.1039618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Accepted: 12/06/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatopulmonary syndrome (HPS) is a serious pulmonary vascular complication that causes respiratory insufficiency in patients with chronic liver diseases. HPS is characterized by two central pathogenic features-intrapulmonary vascular dilatation (IPVD) and angiogenesis. Endothelial glycocalyx (eGCX) is a gel-like layer covering the luminal surface of blood vessels which is involved in a variety of physiological and pathophysiological processes including controlling vascular tone and angiogenesis. In terms of lung disorders, it has been well established that eGCX contributes to dysregulated vascular contraction and impaired blood-gas barrier and fluid clearance, and thus might underlie the pathogenesis of HPS. Additionally, pharmacological interventions targeting eGCX are dramatically on the rise. In this review, we aim to elucidate the potential role of eGCX in IPVD and angiogenesis and describe the possible degradation-reconstitution equilibrium of eGCX during HPS through a highlight of recent literature. These studies strongly underscore the therapeutic rationale in targeting eGCX for the treatment of HPS.
Collapse
Affiliation(s)
- Liang Li
- Department of Thoracic Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China,*Correspondence: Liang Li, ; Shaomin Li,
| | - Christopher Cook
- Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, United States
| | - Yale Liu
- Department of Dermatology, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Jianzhong Li
- Department of Thoracic Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Jiantao Jiang
- Department of Thoracic Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Shaomin Li
- Department of Thoracic Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China,*Correspondence: Liang Li, ; Shaomin Li,
| |
Collapse
|
|
18
|
Yuan M, Zhao M, Sun X, Hui Z. The mapping of mRNA alterations elucidates the etiology of radiation-induced pulmonary fibrosis. Front Genet 2022; 13:999127. [PMID: 36353104 PMCID: PMC9638132 DOI: 10.3389/fgene.2022.999127] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 09/29/2022] [Indexed: 03/06/2025] Open
Abstract
The etiology of radiation-induced pulmonary fibrosis is not clearly understood yet, and effective interventions are still lacking. This study aimed to identify genes responsive to irradiation and compare the genome expression between the normal lung tissues and irradiated ones, using a radiation-induced pulmonary fibrosis mouse model. We also aimed to map the mRNA alterations as a predictive model and a potential mode of intervention for radiation-induced pulmonary fibrosis. Thirty C57BL/6 mice were exposed to a single dose of 16 Gy or 20 Gy thoracic irradiation, to establish a mouse model of radiation-induced pulmonary fibrosis. Lung tissues were harvested at 3 and 6 months after irradiation, for histological identification. Global gene expression in lung tissues was assessed by RNA sequencing. Differentially expressed genes were identified and subjected to functional and pathway enrichment analysis. Immune cell infiltration was evaluated using the CIBERSORT software. Three months after irradiation, 317 mRNAs were upregulated and 254 mRNAs were downregulated significantly in the low-dose irradiation (16 Gy) group. In total, 203 mRNAs were upregulated and 149 were downregulated significantly in the high-dose irradiation (20 Gy) group. Six months after radiation, 651 mRNAs were upregulated and 131 were downregulated significantly in the low-dose irradiation group. A total of 106 mRNAs were upregulated and 4 downregulated significantly in the high-dose irradiation group. Several functions and pathways, including angiogenesis, epithelial cell proliferation, extracellular matrix, complement and coagulation cascades, cellular senescence, myeloid leukocyte activation, regulation of lymphocyte activation, mononuclear cell proliferation, immunoglobulin binding, and the TNF, NOD-like receptor, and HIF-1 signaling pathways were significantly enriched in the irradiation groups, based on the differentially expressed genes. Irradiation-responsive genes were identified. The differentially expressed genes were mainly associated with cellular metabolism, epithelial cell proliferation, cell injury, and immune cell activation and regulation.
Collapse
Affiliation(s)
- Meng Yuan
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Maoyuan Zhao
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin Sun
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zhouguang Hui
- Department of VIP Medical Services, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| |
Collapse
|
|
19
|
A mouse model of hepatic encephalopathy: bile duct ligation induces brain ammonia overload, glial cell activation and neuroinflammation. Sci Rep 2022; 12:17558. [PMID: 36266427 PMCID: PMC9585018 DOI: 10.1038/s41598-022-22423-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Accepted: 10/14/2022] [Indexed: 01/13/2023] Open
Abstract
Hepatic encephalopathy (HE) is a common complication of chronic liver disease, characterized by an altered mental state and hyperammonemia. Insight into the brain pathophysiology of HE is limited due to a paucity of well-characterized HE models beyond the rat bile duct ligation (BDL) model. Here, we assess the presence of HE characteristics in the mouse BDL model. We show that BDL in C57Bl/6j mice induces motor dysfunction, progressive liver fibrosis, liver function failure and hyperammonemia, all hallmarks of HE. Swiss mice however fail to replicate the same phenotype, underscoring the importance of careful strain selection. Next, in-depth characterisation of metabolic disturbances in the cerebrospinal fluid of BDL mice shows glutamine accumulation and transient decreases in taurine and choline, indicative of brain ammonia overload. Moreover, mouse BDL induces glial cell dysfunction, namely microglial morphological changes with neuroinflammation and astrocyte reactivity with blood-brain barrier (BBB) disruption. Finally, we identify putative novel mechanisms involved in central HE pathophysiology, like bile acid accumulation and tryptophan-kynurenine pathway alterations. Our study provides the first comprehensive evaluation of a mouse model of HE in chronic liver disease. Additionally, this study further underscores the importance of neuroinflammation in the central effects of chronic liver disease.
Collapse
|
|
20
|
Yu L, Shi Q, Zhang B, Xu J. Genetically modified mesenchymal stem cells promote spinal fusion through polarized macrophages. J Transl Med 2022; 102:312-319. [PMID: 34764437 PMCID: PMC8860744 DOI: 10.1038/s41374-021-00693-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/15/2021] [Accepted: 10/18/2021] [Indexed: 01/05/2023] Open
Abstract
Spinal fusion is an effective treatment for low back pain and typically applied with prosthetic fixation devices. Spinal fusion can be improved by transplantation of mesenchymal stem cells (MSCs) into the paraspinal muscle. However, in contrast to the direct contribution of MSCs to spinal fusion, the indirect effects of MSCs on spinal infusion have not been studied and were thus addressed here. The correlation between the outcome of spinal fusion and the local macrophage number, polarization and the levels of placental growth factor (PlGF) in patients was analyzed. MSCs were genetically modified to overexpress PlGF, and its effects on macrophage proliferation and polarization were analyzed in vitro in a transwell co-culture system, as well as in vivo in a mouse model for spinal fusion, for which the cells were bilaterally injected into paravertebral muscles of the mouse lumbar spine. The effects on spinal fusion were assessed by microcomputed tomography and a custom four-point bending apparatus for structural bending stiffness. Local macrophages were analyzed by flow cytometry. We found that posterior spinal fusion could be improved by PlGF-expressing MSCs, compared to the control MSCs, evident by significant improvement of bone bridging of the targeted vertebrae. Mechanistically, PlGF-expressing MSCs appeared to attract macrophages and induce their M2 polarization, which in turn promotes the bone formation. Together, our data suggest that PlGF-expressing MSCs may improve spinal fusion through macrophage recruitment and polarization.
Collapse
Affiliation(s)
- Luchao Yu
- Department of Orthopedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
- Department of Orthopedic Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China
| | - Qiang Shi
- Department of Orthopedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Baokun Zhang
- Department of Orthopedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Jianguang Xu
- Department of Orthopedic Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, China.
| |
Collapse
|
|
21
|
Certain MC, Robert F, Baron A, Sitbon O, Humbert M, Guignabert C, Tu L, Savale L. Syndrome hépatopulmonaire : prévalence, physiopathologie et implications cliniques. Rev Mal Respir 2022; 39:84-89. [DOI: 10.1016/j.rmr.2022.02.055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 01/05/2022] [Indexed: 11/28/2022]
|
|
22
|
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.
Collapse
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
| |
Collapse
|
|
23
|
Del Valle K, DuBrock HM. Hepatopulmonary Syndrome and Portopulmonary Hypertension: Pulmonary Vascular Complications of Liver Disease. Compr Physiol 2021; 11:3281-3302. [PMID: 34636408 DOI: 10.1002/cphy.c210009] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pulmonary vascular disease is a frequent complication of chronic liver disease and portal hypertension, affecting up to 30% of patients. There are two distinct pulmonary vascular complications of liver disease: hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). HPS affects 25% of patients with chronic liver disease and is characterized by intrapulmonary vasodilatation and abnormal arterial oxygenation. HPS negatively impacts quality of life and is associated with a 2-fold increased risk of death compared to controls with liver disease without HPS. Angiogenesis, endothelin-1 mediated endothelial dysfunction, monocyte influx, and alveolar type 2 cell dysfunction seem to play important roles in disease pathogenesis but there are currently no effective medical therapies. Fortunately, HPS resolves following liver transplant (LT) with improvements in hypoxemia. POPH is a subtype of pulmonary arterial hypertension (PAH) characterized by an elevated mean pulmonary arterial pressure and pulmonary vascular resistance in the setting of normal left-sided filling pressures. POPH affects 5% to 6% of patients with chronic liver disease. Although the pathogenesis has not been fully elucidated, endothelial dysfunction, inflammation, and estrogen signaling have been identified as key pathways involved in disease pathogenesis. POPH is typically treated with PAH targeted therapy and may also improve with liver transplantation in selected patients. This article highlights what is currently known regarding the diagnosis, management, pathobiology, and outcomes of HPS and POPH. Ongoing research is needed to improve understanding of the pathophysiology and outcomes of these distinct and often misunderstood pulmonary vascular complications of liver disease. © 2021 American Physiological Society. Compr Physiol 11:1-22, 2021.
Collapse
|
|
24
|
Simbrunner B, Stadlmann A, Schwabl P, Paternostro R, Bauer DJM, Bucsics T, Scheiner B, Lampichler K, Wöran K, Beer A, Eigenbauer E, Pinter M, Stättermayer AF, Marculescu R, Szekeres T, Trauner M, Mandorfer M, Reiberger T. Placental growth factor levels neither reflect severity of portal hypertension nor portal-hypertensive gastropathy in patients with advanced chronic liver disease. Dig Liver Dis 2021; 53:345-352. [PMID: 33032973 DOI: 10.1016/j.dld.2020.09.006] [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: 08/17/2020] [Accepted: 09/07/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Experimental data indicates that placental growth factor (PLGF) is involved in the pathophysiology of portal hypertension (PH) due to advanced chronic liver disease (ACLD). We investigated serum levels of PLGF and its "scavenger", the receptor soluble fms-like tyrosine kinase-1 (sFLT1, or sVEGFR1), in ACLD patients with different severity of PH and portal-hypertensive gastropathy (PHG). METHODS PLGF and sVEGFR1 were measured in ACLD patients with hepatic venous pressure gradient (HVPG) ≥6 mmHg (n = 241) and endoscopic evaluation of PHG (n = 216). Patients with pre-/posthepatic PH, TIPS, liver transplantation and hepatocellular carcinoma were excluded. RESULTS Thirty-two (13%) patients had HVPG 6-9 mmHg, 128 (53%) 10-19 mmHg and 81 (34%) ≥20 mmHg; 141 (59%) had decompensated ACLD (dACLD). PLGF (median 17.2 vs. 20.8 vs. 22.4 pg/mL; p = 0.002), sVEGFR1 (median 96.0 vs. 104.8 vs. 119.3 pg/mL; p < 0.001) levels increased across HVPG strata, while PLGF/sVEGFR1 ratios remained similar (0.19 vs. 0.20 vs. 0.18 pg/mL; p = 0.140). The correlation between PLGF and HVPG was weak (Rho = 0.190,95%CI 0.06-0.31; p = 0.003), and the PLGF/sVEGFR1 ratio did not correlate with HVPG (p = 0.331). The area-under-the-receiver operating characteristics (AUROC) for PLGF to detect clinically significant PH (CSPH;i.e. HVPG ≥ 10 mmHg) yielded only 0.688 (0.60-0.78; p < 0.001). When compared to ACLD patients without PHG, PLGF levels (20 without vs. 21.4 with mild vs. 17.1 pg/mL with severe PHG, respectively; p = 0.005) and PLGF/sVEGFR1 ratios (0.20 vs. 0.19 vs. 0.17; p = 0.076) did not increase with mild and severe PHG. CONCLUSION While PLGF levels tended to increase with severity of PH, the PLGF/sVEGFR1 ratio remained stable across HVPG strata. Neither PLGF nor the PLGF/sVEGFR1 ratio had diagnostic value for prediction of CSPH. The severity of PHG was also not associated with stepwise increases in PLGF levels or PLGF/sVEGFR1 ratio.
Collapse
Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Alexander Stadlmann
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Hospital Hietzing, Vienna, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Rafael Paternostro
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - David J M Bauer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Theresa Bucsics
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria
| | | | - Katharina Wöran
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | - Andrea Beer
- Department of Pathology, Medical University of Vienna, Vienna, Austria
| | | | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Albert-Friedrich Stättermayer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Rodrig Marculescu
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Thomas Szekeres
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Vienna Hepatic Hemodynamic Laboratory, Medical University of Vienna, Vienna, Austria; Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria.
| |
Collapse
|
|
25
|
Recent advances in the approach to hepatopulmonary syndrome and portopulmonary hypertension. Acta Gastroenterol Belg 2021; 84:95-99. [PMID: 33639700 DOI: 10.51821/84.1.200] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Liver disease, cirrhosis and portal hypertension can be complicated by pulmonary vascular disease, which may affect prognosis and influence liver transplantation (LT) candidacy. Pulmonary vascular complications comprise hepatopulmonary syndrome (HPS) and portopulmonary hypertension (POPH). Although these two conditions develop on a same background and share a common trigger, pulmonary responses are distinct and occur at different anatomical sites of the pulmonary circulation. HPS affects 10-30% of patients referred for LT, and is characterized by gas exchange abnormalities due to pulmonary vasodilation and right-to-left shunting. POPH occurs in 5%, and is defined by pulmonary arterial hypertension due to increased pulmonary vascular resistance, which leads to hemodynamic failure. Even though HPS and POPH may have a substantial negative impact on survival, both entities are clinically underrecognized and frequently misdiagnosed. Without intervention, the 5-year survival rate is 23% in HPS and 14% in POPH. Their presence should be actively sought by organized screening in patients presenting with dyspnea and in all patients on the waitlist for LT, also because clinical symptoms are commonly non-specific or even absent. LT may lead to resolution, however, advanced stages of either HPS or POPH may jeopardize safe and successful LT. This implicates the need of proper identification of HPS and POPH cases, as well as the need to be able to successfully 'bridge' patients to LT by medical intervention. A review article on this topic has been published in this journal in 2007 (1). This updated review focuses on recent advances in the diagnosis and management of these 2 liver-induced pulmonary vascular disorders and incorporates results from our recent work.
Collapse
|
|
26
|
Zardi EM, Giorgi C, Dobrina A, Vecile E, Zardi DM. Analogies and differences between cirrhotic cardiomyopathy and hepatopulmonary syndrome. Med Res Rev 2020; 41:739-753. [PMID: 33174630 DOI: 10.1002/med.21755] [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] [Received: 07/30/2020] [Revised: 10/27/2020] [Accepted: 11/02/2020] [Indexed: 12/20/2022]
Abstract
Cirrhotic cardiomyopathy and hepatopulmonary syndrome are two quite frequent clinical entities that may complicate the course of liver cirrhosis. The common pathophysiological origin and the same clinical presentation make them difficult to compare. Cirrhotic cardiomyopathy and hepatopulmonary syndrome may start with dyspnea and breathlessness but the former is characterized by a chronic cardiac dysfunction and the latter by a defect of oxygenation due to pulmonary shunts formation. The focus is to differentiate them as soon as possible since the treatment is different until the patient undergoes liver transplant that is the real unique cure for them.
Collapse
Affiliation(s)
- Enrico Maria Zardi
- Internistic Ultrasound Service, Campus Bio-Medico University, Rome, Italy
| | - Chiara Giorgi
- Department of Radiology, S. Maria Della Misericordia Hospital, Urbino, Italy
| | - Aldo Dobrina
- Department of Physiology and Pathology, University of Trieste, Trieste, Italy
| | - Elena Vecile
- Department of Physiology and Pathology, University of Trieste, Trieste, Italy
| | - Domenico Maria Zardi
- Interventional Cardiology Department of S. Andrea Hospital, University "La Sapienza", Rome, Italy
| |
Collapse
|
|
27
|
Henkel S, Vetterly C, Squires R, McKiernan P, Squires J. Pharmacological management of portal hypertension and its complications in children: lessons from adults and opportunities for the future. Expert Opin Pharmacother 2020; 22:291-304. [PMID: 33074032 DOI: 10.1080/14656566.2020.1825685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
INTRODUCTION Portal hypertension (PHT) and its complications in children are thought to be distinct from adult PHT in several areas, including the underlying bio-physiology of a child in which PHT develops, but also because of the pediatric-specific etiologies that drive disease progression. And yet pharmacologic approaches to PHT in children are mainly based on adult data, modified for pediatric practice. This reality has been driven by a lack of data specific to children. AREAS COVERED The authors discuss current therapeutic approaches to PHT in children, including management of acute gastrointestinal variceal bleed, pharmacotherapy in prophylaxis, and established and emerging therapies to combat systemic co-morbidities that result from PHT. The few areas where pediatric-specific data exist are highlighted and the many gaps in knowledge that remain unresolved are underscored. EXPERT OPINION Despite decades of experience, optimal management of pediatric PHT remains undefined. In large part, this can be directly linked to a lack of basic understanding related to the unique pathophysiology and natural history that defines PHT in children. As a result, meaningful research into the utility and effectiveness of pharmacotherapy in children with PHT remains in its infancy. Large, multi-center, prospective studies will be needed to begin to establish an infrastructure on which a pediatric-specific research agenda can be built.
Collapse
Affiliation(s)
- Sarah Henkel
- Division of Gastroenterology and Hepatology, UPMC Children's Hospital of Pittsburgh , Pittsburgh, PA
| | - Carol Vetterly
- Department of Pharmacy, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh School of Pharmacy , Pittsburgh, PA
| | - Robert Squires
- Division of Gastroenterology and Hepatology, UPMC Children's Hospital of Pittsburgh , Pittsburgh, PA
| | - Patrick McKiernan
- Division of Gastroenterology and Hepatology, UPMC Children's Hospital of Pittsburgh , Pittsburgh, PA
| | - James Squires
- Division of Gastroenterology and Hepatology, UPMC Children's Hospital of Pittsburgh , Pittsburgh, PA
| |
Collapse
|
|
28
|
Mecoli CA, Shah AA, Boin F, Wigley FM, Hummers LK. The Utility of Plasma Vascular Biomarkers in Systemic Sclerosis: A Prospective Longitudinal Analysis. Arthritis Rheumatol 2020; 72:1341-1349. [PMID: 32200572 DOI: 10.1002/art.41265] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 03/17/2020] [Indexed: 02/07/2023]
Abstract
OBJECTIVE In cross-sectional studies, pulmonary hypertension (PH) and ischemic digital lesions are 2 scleroderma vascular outcomes associated with abnormalities in biomarkers of angiogenesis. The clinical usefulness of these biomarkers is unknown, in part due to lack of data on longitudinal measurement. This prospective longitudinal study was undertaken to evaluate vascular biomarker measurements in patients with systemic sclerosis (SSc) over time. METHODS We conducted a prospective cohort study of 300 patients with SSc who were followed up for at least a 5-year period and lacked evidence of PH and/or active ischemic digital lesions at enrollment. Levels of hepatocyte growth factor (HGF), soluble Flt-1 (sFlt-1), soluble endoglin, endostatin, and placental growth factor (PLGF) were obtained at multiple time points and assessed for their ability to predict the development of PH/ischemic digital lesions. Hazard ratios (HRs) with 95% confidence intervals (95% CIs) were calculated. RESULTS Forty-six patients (15%) developed PH and 69 patients (23%) developed an ischemic digital lesion. In time-to-event analyses, the following 3 biomarkers measured at cohort entry were found to be significantly associated with the development of PH: HGF (HR 1.99 [95% CI 1.24-3.17], P = 0.004), sFlt-1 (HR 3.04 [95% CI 1.29-7.14], P = 0.011), and PLGF (HR 2.74 [95% CI 1.32-5.69], P = 0.007). As time approaching PH diagnosis decreased, there was no corresponding increase in any biomarker level. Upon converting each continuous vascular biomarker into a binary variable, a dose-response relationship was observed for the number of elevated biomarkers at cohort entry and the risk of developing PH. With each additional elevated biomarker at cohort entry, there was a 78% increase in the risk of developing PH (HR 1.78 [95% CI 1.2-2.6], P = 0.004). CONCLUSION These data suggest that molecules involved in angiogenesis reflect vascular perturbation, and that elevations in these biomarkers at first encounter can indicate patients who are at risk of PH development.
Collapse
Affiliation(s)
| | - Ami A Shah
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | | | - Laura K Hummers
- Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
29
|
McGraw MD, Kim SY, White CW, Veress LA. Acute cytotoxicity and increased vascular endothelial growth factor after in vitro nitrogen mustard vapor exposure. Ann N Y Acad Sci 2020; 1479:223-233. [PMID: 32408394 DOI: 10.1111/nyas.14367] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 04/09/2020] [Accepted: 04/20/2020] [Indexed: 12/20/2022]
Abstract
Nitrogen mustard (NM) is a highly toxic alkylating agent. Inhalation exposure can cause acute and chronic lung injury. This study's aims were to develop an in vitro coculture model of mustard-induced airway injury and to identify growth factors contributing to airway pathology. Primary human bronchial epithelial cells cultured with pulmonary endothelial cells were exposed to NM (25, 50, 100, 250, or 500 μM) or PBS (control) for 1 hour. Lactate dehydrogenase (LDH) and transepithelial electrical resistance (TEER) were measured before and 24 h after NM exposure. Fixed cultures were stained for hematoxylin and eosin or live/dead staining. Culture media were analyzed for 11 growth factors. A 1-h vapor exposure to greater than or equal to 50 μM NM increased supernatant LDH, decreased TEER, and caused airway epithelial cell detachment. Endothelial cell death occurred at 500 μM NM. Vascular endothelial growth factor A (VEGF-A) and placental growth factor (PlGF) expression increased in 500 μM NM-exposed cultures compared with PBS-exposed control cultures. NM vapor exposure causes differential cytotoxicity to airway epithelial and endothelial injury in culture. Increased VEGF-A and PlGF expression occurred acutely in airway cocultures. Future studies are required to validate the role of VEGF signaling in mustard-induced airway pathology.
Collapse
Affiliation(s)
- Matthew D McGraw
- Department of Pediatric Pulmonology, University of Rochester Medical Center, Rochester, New York.,Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York
| | - So-Young Kim
- Department of Pediatric Pulmonology, University of Rochester Medical Center, Rochester, New York
| | - Carl W White
- Department of Pediatrics, Pulmonology Section, Pediatric Airway Research Center, University of Colorado Denver, Aurora, Colorado
| | - Livia A Veress
- Department of Pediatrics, Pulmonology Section, Pediatric Airway Research Center, University of Colorado Denver, Aurora, Colorado
| |
Collapse
|
|
30
|
Møller S, Kimer N, Barløse M, Bendtsen F. Pathophysiological-based treatments of complications of cirrhosis. Scand J Gastroenterol 2020; 55:383-394. [PMID: 32233873 DOI: 10.1080/00365521.2020.1744709] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Detailed knowledge and understanding of the pathophysiological mechanisms and changes in hepatic and splanchnic function leading to the development of haemodynamic changes and portal hypertension in patients with cirrhosis are essential since it guides the search for targets to ameliorate liver-related abnormalities. Recent research has focused on the gut-liver axis, changes in intestinal permeability, translocation of bacterial products, and inflammation as important drivers of haemodynamic alterations and thereby targets for treatment. Additionally, treatment strategies should focus on microbiotic modulation, antiangiogenics, anti-inflammatory strategies, and modulation of bile acid metabolism. This paper aims to review contemporary pathophysiological-based treatment principles of the major complications of cirrhosis and portal hypertension and future targets for treatment.
Collapse
Affiliation(s)
- Søren Møller
- Department Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark
| | - Nina Kimer
- Gastro Unit, Medical Division, Hvidovre Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.,Bridge Translational Excellence Programme, Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - Mads Barløse
- Department Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Copenhagen University Hospital, Hvidovre, Denmark
| | - Flemming Bendtsen
- Gastro Unit, Medical Division, Hvidovre Hospital, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
31
|
Soulaidopoulos S, Goulis I, Cholongitas E. Pulmonary manifestations of chronic liver disease: a comprehensive review. Ann Gastroenterol 2020; 33:237-249. [PMID: 32382226 PMCID: PMC7196609 DOI: 10.20524/aog.2020.0474] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 12/06/2019] [Indexed: 12/14/2022] Open
Abstract
Hepatopulmonary syndrome (HPS) and porto-pulmonary hypertension (PoPH) represent relatively common pulmonary vascular complications of advanced liver disease. Despite distinct differences in their pathogenetic background, both clinical states are characterized by impaired arterial oxygenation and limited functional status, and are associated with increased pre-transplantation mortality. Accumulation of ascitic fluid in the pleural cavity, known as hepatic hydrothorax (HH), is another frequent manifestation of decompensated cirrhosis, which may cause severe respiratory dysfunction, depending on the volume of the effusion, the rapidity of its development and its resistance to therapeutic measures. Orthotopic liver transplantation constitutes the only effective treatment able to resolve the pulmonary complications of liver disease. A prioritization policy for liver transplantation has evolved over the past years regarding advanced stages of HPS, yielding favorable outcomes regarding post-transplantation survival and HPS resolution. In contrast, severe PoPH is associated with poor post-transplantation survival. Hence, liver transplantation is recommended only for patients with PoPH and an acceptable reduction in pulmonary pressure values, after receiving PoPH-targeted vasodilating therapy. This review focuses on basic pathogenetic and diagnostic principles and discusses the current therapeutic approaches regarding HPS, PoPH, and HH.
Collapse
Affiliation(s)
- Stergios Soulaidopoulos
- First Department of Cardiology, Hippokration General Hospital, National and Kapodistrian University of Athens (Stergios Soulaidopoulos)
| | - Ioannis Goulis
- Fourth Department of Internal Medicine, Hippokration General Hospital, Medical School of Aristotle University of Thessaloniki (Ioannis Goulis)
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens (Evangelos Cholongitas), Greece
| |
Collapse
|
|
32
|
Yang W, Jiang Y, Wang Y, Zhang T, Liu Q, Wang C, Swisher G, Wu N, Chao C, Prasadan K, Gittes GK, Xiao X. Placental growth factor in beta cells plays an essential role in gestational beta-cell growth. BMJ Open Diabetes Res Care 2020; 8:e000921. [PMID: 32144129 PMCID: PMC7059504 DOI: 10.1136/bmjdrc-2019-000921] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 01/28/2020] [Accepted: 01/31/2020] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE Pancreatic beta cells proliferate in response to metabolic requirements during pregnancy, while failure of this response may cause gestational diabetes. A member of the vascular endothelial growth factor family, placental growth factor (PlGF), typically plays a role in metabolic disorder and pathological circumstance. The expression and function of PlGF in the endocrine pancreas have not been reported and are addressed in the current study. RESEARCH DESIGN AND METHODS PlGF levels in beta cells were determined by immunostaining or ELISA in purified beta cells in non-pregnant and pregnant adult mice. An adeno-associated virus (AAV) serotype 8 carrying a shRNA for PlGF under the control of a rat insulin promoter (AAV-rat insulin promoter (RIP)-short hairpin small interfering RNA for PlGF (shPlGF)) was prepared and infused into mouse pancreas through the pancreatic duct to specifically knock down PlGF in beta cells, and its effects on beta-cell growth were determined by beta-cell proliferation, beta-cell mass and insulin release. A macrophage-depleting reagent, clodronate, was coapplied into AAV-treated mice to study crosstalk between beta cells and macrophages. RESULTS PlGF is exclusively produced by beta cells in the adult mouse pancreas. Moreover, PlGF expression in beta cells was significantly increased during pregnancy. Intraductal infusion of AAV-RIP-shPlGF specifically knocked down PlGF in beta cells, resulting in compromised beta-cell proliferation, reduced growth in beta-cell mass and impaired glucose tolerance during pregnancy. Mechanistically, PlGF depletion in beta cells reduced islet infiltration of trophic macrophages, which appeared to be essential for gestational beta-cell growth. CONCLUSIONS Our study suggests that increased expression of PlGF in beta cells may trigger gestational beta-cell growth through recruited macrophages.
Collapse
Affiliation(s)
- Weixia Yang
- Department of Pediatrics, Affiliated Hospital of Nantong University, Nantong, China
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Yinan Jiang
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Yan Wang
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Ting Zhang
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Qun Liu
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Endocrinology, the First Affiliated Hospital of NanChang University, Nanchang, China
| | - Chaoban Wang
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Pediatric Endocrinology, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Grant Swisher
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Nannan Wu
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
- Department of Endocrinology, Lu He Hospital, Capital Medical University, Beijing, China
| | - Chelsea Chao
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Krishna Prasadan
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - George K Gittes
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Xiangwei Xiao
- Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| |
Collapse
|
|
33
|
Shi YJ, Mckiernan P, Soltys K, Mazariegos G, Wang WL. Surgical closure of large splenorenal shunt may accelerate recovery from hepato-pulmonary syndrome in liver transplant patients. World J Emerg Med 2020; 11:60-63. [PMID: 31893005 DOI: 10.5847/wjem.j.1920-8642.2020.01.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Yan-Jun Shi
- Department of Hepatobiliary & Pancreas Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China.,Thomas E. Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation, Department of Transplant Surgery, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Patrick Mckiernan
- Thomas E. Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation, Department of Transplant Surgery, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Kyle Soltys
- Thomas E. Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation, Department of Transplant Surgery, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - George Mazariegos
- Thomas E. Starzl Transplantation Institute, Hillman Center for Pediatric Transplantation, Department of Transplant Surgery, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Wei-Lin Wang
- Department of Hepatobiliary & Pancreas Surgery, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
| |
Collapse
|
|
34
|
Chen L, Han Y, Li Y, Chen B, Bai X, Belguise K, Wang X, Chen Y, Yi B, Lu K. Hepatocyte-derived exosomal MiR-194 activates PMVECs and promotes angiogenesis in hepatopulmonary syndrome. Cell Death Dis 2019; 10:853. [PMID: 31700002 PMCID: PMC6838168 DOI: 10.1038/s41419-019-2087-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/27/2019] [Accepted: 10/21/2019] [Indexed: 12/18/2022]
Abstract
Hepatopulmonary syndrome (HPS) is a serious vascular complication in the setting of liver disease. Factors produced by the liver are essential to regulate pulmonary angiogenesis in the pathogenesis of HPS; however, the pathogenic mechanisms of pulmonary angiogenesis are not fully understood. We investigated the role of HPS rat serum exosomes (HEs) and sham-operated rat serum exosomes (SEs) in the regulation of angiogenesis. We found that HEs significantly enhance PMVEC proliferation, migration, and tube formation. We further identified miR-194 was the most notably increased miRNA in HEs compared to SEs. Once released, hepatocyte-derived exosomal miR-194 was internalized by PMVECs, leading to the promotion of PMVEC proliferation, migration, and tube formation through direct targeting of THBS1, STAT1, and LIF. Importantly, the pathogenic role of exosomal miR-194 in initiating angiogenesis was reversed by P53 inhibition, exosome secretion inhibition or miR-194 inhibition. Additionally, high levels of miR-194 were found in serum exosomes and were positively correlated with P(A-a)O2 in HPS patients and rats. Thus, our results highlight that the exosome/miR-194 axis plays a critical pathologic role in pulmonary angiogenesis, representing a new therapeutic target for HPS.
Collapse
Affiliation(s)
- Lin Chen
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Yi Han
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Yujie Li
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Bing Chen
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Xuehong Bai
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China
| | - Karine Belguise
- LBCMCP, ×tégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Xiaobo Wang
- LBCMCP, ×tégrative (CBI), Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Yang Chen
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China.
| | - Bin Yi
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China.
| | - Kaizhi Lu
- Department of Anaesthesia, Southwest Hospital, The Third Military Medical University, Chongqing, China.
| |
Collapse
|
|
35
|
Van Campenhout S, Van Vlierberghe H, Devisscher L. Common Bile Duct Ligation as Model for Secondary Biliary Cirrhosis. Methods Mol Biol 2019; 1981:237-247. [PMID: 31016658 DOI: 10.1007/978-1-4939-9420-5_15] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Cholestatic liver disease covers a range of biliary disorders marked by an impaired bile duct flow. Various conditions can result in bile obstruction including choledocholithiasis, surgical trauma, and autoimmune disorders. Cholestatic liver disease can be mild but generally progresses to more severe conditions with increased hepatobiliary injury, cholangitis, and ultimately liver fibrosis and cirrhosis. An extensively used experimental model to investigate the pathophysiology of biliary cirrhosis and potential novel therapies is the common bile duct ligation in mice and rats. Common bile duct ligation induces the different stages of cholestatic-induced liver disease being cholestasis, subsequently accompanied by inflammation and finally liver fibrosis and cirrhosis. In this protocol, an outline of the surgical procedures to conduct common bile duct ligation in mice is provided. The major steps include the isolation of the common bile duct, followed by ligation and dissection.
Collapse
|
|
36
|
Yang Y, Yu H, Yang C, Zhang Y, Ai X, Wang X, Lu K, Yi B. Krüppel-like factor 6 mediates pulmonary angiogenesis in rat experimental hepatopulmonary syndrome and is aggravated by bone morphogenetic protein 9. Biol Open 2019; 8:bio.040121. [PMID: 31189661 PMCID: PMC6602319 DOI: 10.1242/bio.040121] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hepatopulmonary syndrome (HPS) is a serious pulmonary vascular disease derived from chronic liver disease, and its key pathogenesis is angiogenesis. Krüppel-like factor 6 (KLF6) mediates physiological repair and remodeling during vascular injury. However, the role of KLF6 in pulmonary microvascular endothelial cells (PMVECs) during angiogenesis of HPS and its underlying mechanism in HPS have not been investigated. Common bile duct ligation (CBDL) in rats can replicate pulmonary vascular abnormalities of human HPS. Here, we found that advanced pulmonary angiogenesis and pulmonary injury score coincided with the increase of KLF6 level in PMVECs of CBDL rat; KLF6 in PMVECs was also induced while cultured with CBDL rat serum in vitro. Inhibition of KLF6 dramatically suppressed PMVEC-mediated proliferation, migration and tube formation in vivo; this may be related to the downregulation of activin receptor-like kinase-1 (ALK1) and endoglin (ENG), which are transacted by KLF6. Bone morphogenetic protein 9 (BMP9) enhanced the expression of KLF6 in PMVECs and was involved in the angiogenesis of HPS. These results suggest that KLF6 triggers PMVEC-mediated angiogenesis of HPS and is aggravated by BMP9, and the inhibition of the BMP9/KLF6 axis may be an effective strategy for HPS treatment. Summary: Krüppel-like factor 6, which is triggered by pulmonary injury and promoted by bone morphogenetic protein 9, mediates pulmonary angiogenesis in rat experimental hepatopulmonary syndrome and then aggravates lung dysfunction.
Collapse
Affiliation(s)
- Yihui Yang
- Department of Anaesthesia, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China.,Department of Anesthesia, The Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000 China
| | - Hongfu Yu
- Department of Anaesthesia, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China
| | - Congwen Yang
- Department of Anaesthesia, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China
| | - Yunfei Zhang
- Department of Anaesthesia, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China.,Department of Anesthesia, The Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000 China
| | - Xiangfa Ai
- Department of Anaesthesia, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China
| | - Xiaobo Wang
- Department of LBCMCP, Centre de Biologie Intégrative (CBI), Université de Toulouse, CNRS, UPS, 31062 Toulouse, France
| | - Kaizhi Lu
- Department of Anaesthesia, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China
| | - Bin Yi
- Department of Anaesthesia, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038 China
| |
Collapse
|
|
37
|
Dane DM, Yilmaz C, Gyawali D, Iyer R, Menon J, Nguyen KT, Ravikumar P, Estrera AS, Hsia CCW. Erythropoietin inhalation enhances adult canine alveolar-capillary formation following pneumonectomy. Am J Physiol Lung Cell Mol Physiol 2019; 316:L936-L945. [PMID: 30785346 DOI: 10.1152/ajplung.00504.2018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Paracrine erythropoietin (EPO) signaling in the lung recruits endothelial progenitor cells, promotes cell maturation and angiogenesis, and is upregulated during canine postpneumonectomy (PNX) compensatory lung growth. To determine whether inhalational delivery of exogenous EPO augments endogenous post-PNX lung growth, adult canines underwent right PNX and received, via a permanent tracheal stoma, weekly nebulization of recombinant human EPO-containing nanoparticles or empty nanoparticles (control) for 16 wk. Lung function was assessed under anesthesia pre- and post-PNX. The remaining lobes were fixed for detailed morphometric analysis. Compared with control treatment, EPO delivery significantly increased serum EPO concentration without altering systemic hematocrit or hemoglobin concentration and abrogated post-PNX lipid oxidative stress damage. EPO delivery modestly increased post-PNX volume densities of the alveolar septum per unit of lung volume and type II epithelium and endothelium per unit of septal tissue volume in selected lobes. EPO delivery also augmented the post-PNX increase in alveolar double-capillary profiles, a marker of intussusceptive capillary formation, in all remaining lobes. EPO treatment did not significantly alter absolute resting lung volumes, lung and membrane diffusing capacities, alveolar-capillary blood volume, pulmonary blood flow, lung compliance, or extravascular alveolar tissue volumes or surface areas. Results established the feasibility of chronic inhalational delivery of growth-modifying biologics in a large animal model. Exogenous EPO selectively enhanced cytoprotection and alveolar angiogenesis in remaining lobes but not whole-lung extravascular tissue growth or resting function; the nonuniform response contributes to structure-function discrepancy, a major challenge for interventions aimed at amplifying the innate potential for compensatory lung growth.
Collapse
Affiliation(s)
- D Merrill Dane
- Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Cuneyt Yilmaz
- Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Dipendra Gyawali
- Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Roshni Iyer
- Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Jyothi Menon
- Department of Bioengineering, University of Texas at Arlington , Arlington, Texas
| | - Kytai T Nguyen
- Department of Bioengineering, University of Texas at Arlington , Arlington, Texas
| | - Priya Ravikumar
- Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Aaron S Estrera
- Department of Cardiothoracic Surgery, University of Texas Southwestern Medical Center , Dallas, Texas
| | - Connie C W Hsia
- Department of Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas
| |
Collapse
|
|
38
|
Lejealle C, Paradis V, Bruno O, de Raucourt E, Francoz C, Soubrane O, Lebrec D, Bedossa P, Valla D, Mal H, Vilgrain V, Durand F, Rautou PE. Evidence for an Association Between Intrahepatic Vascular Changes and the Development of Hepatopulmonary Syndrome. Chest 2019; 155:123-136. [DOI: 10.1016/j.chest.2018.09.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Revised: 08/21/2018] [Accepted: 09/05/2018] [Indexed: 02/06/2023] Open
|
|
39
|
Fernandez M. Placental growth factor: New treatment target bringing hope for hepatopulmonary syndrome. Hepatology 2018; 68:404-407. [PMID: 29356037 DOI: 10.1002/hep.29795] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 01/11/2018] [Accepted: 01/16/2018] [Indexed: 12/17/2022]
Affiliation(s)
- Mercedes Fernandez
- IDIBAPS Biomedical Research Institute, Hospital Clinic, University of Barcelona.,Biomedical Research Networking Center, on Hepatic and Digestive Disease (CIBERehd), Spanish National Institute of Health, Madrid, Spain
| |
Collapse
|
|
40
|
Lee WS, Wong SY, Ivy DD, Sokol RJ. Hepatopulmonary Syndrome and Portopulmonary Hypertension in Children: Recent Advances in Diagnosis and Management. J Pediatr 2018. [PMID: 29514741 DOI: 10.1016/j.jpeds.2017.12.068] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Way Seah Lee
- Department of Pediatrics, University Malaya Medical Centre, Kuala Lumpur, Malaysia; University Malaya Pediatrics and Child Health Research Group, University Malaya, Kuala Lumpur, Malaysia.
| | - Shin Yee Wong
- Department of Pediatrics, University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - D Dunbar Ivy
- Section of Pediatric Cardiology, Department of Pediatrics, and the Heart Institute, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO
| | - Ronald J Sokol
- Pediatric Liver Center, Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, and the Digestive Health Institute, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO
| |
Collapse
|