RESUMEN
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.
Asunto(s)
Síndrome Hepatopulmonar , Humanos , Síndrome Hepatopulmonar/etiología , Síndrome Hepatopulmonar/patología , Glicocálix/patología , Pulmón/patología , Vasodilatación , LigaduraRESUMEN
AIM: Physical exercise training attenuates pulmonary inflammation, but its effects on impaired respiratory function caused by hepatopulmonary syndrome (HPS) have not been evaluated. We determined if the combination of moderate intensity aerobic and resistance training during HPS development modifies exercise capacity, respiratory system mechanics, and lung inflammation responses. MAIN METHODS: Wistar rats were randomly divided into sham, HPS, and HPS + combined exercise training groups. Fifteen days after HPS induction, a moderate intensity aerobic plus resistance exercise training protocol was performed five times a week for 5 weeks on alternate days. Exercise capacity, respiratory system mechanics, lung inflammation, pulmonary morphology, and immunohistochemistry were evaluated. KEY FINDINGS: Overall, our findings indicated that combined exercise training efficiently increased the maximal running and resistance capacity of HPS animals. The training regimen reduced the expression of P2X7 in parenchymal leukocytes (P < 0.01), partially restored the expression of interleukin-10 in airway epithelium (P < 0.01), and increased the expression of TFPI in the airway epithelium (P < 0.01) as well as reduced its expression in parenchymal leukocytes (P < 0.01). However, exercise training did not attenuate HPS-induced respiratory mechanical derangements or lung tissue remodeling. SIGNIFICANCE: Combined exercise training can elicit adaptation with regard to both maximal running capacity and maximum strength and modify the expression of P2X7 and TFPI in parenchymal leukocytes and that of IL-10 in airway epithelium.
Asunto(s)
Prueba de Esfuerzo/métodos , Tolerancia al Ejercicio/fisiología , Síndrome Hepatopulmonar/terapia , Condicionamiento Físico Animal/métodos , Condicionamiento Físico Animal/fisiología , Neumonía/terapia , Animales , Síndrome Hepatopulmonar/patología , Síndrome Hepatopulmonar/fisiopatología , Masculino , Neumonía/patología , Neumonía/fisiopatología , Ratas , Ratas Wistar , Mecánica Respiratoria/fisiologíaRESUMEN
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-ß1 (TGF-ß1) 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.
Asunto(s)
Síndrome Hepatopulmonar/etiología , Hipoxia/etiología , Pulmón/metabolismo , Macrófagos/metabolismo , Microvasos/metabolismo , Neutrófilos/metabolismo , Fibrosis Pulmonar/etiología , Animales , Compuestos de Bifenilo/sangre , Movimiento Celular , Proliferación Celular , Quimiocina CCL2/metabolismo , Dilatación Patológica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Síndrome Hepatopulmonar/inmunología , Síndrome Hepatopulmonar/metabolismo , Síndrome Hepatopulmonar/patología , Hipoxia/inmunología , Hipoxia/metabolismo , Hipoxia/patología , Mediadores de Inflamación/metabolismo , Leucina/análogos & derivados , Leucina/sangre , Cirrosis Hepática Experimental/complicaciones , Pulmón/inmunología , Pulmón/patología , Macrófagos/inmunología , Masculino , Microvasos/inmunología , Microvasos/patología , Infiltración Neutrófila , Neutrófilos/inmunología , Fenotipo , Fibrosis Pulmonar/inmunología , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Ratas Sprague-Dawley , Receptores CCR2/metabolismo , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Factores de Tiempo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Hepatopulmonary syndrome (HPS) is defined as three distinct features: liver disease, hypoxemia, and intrapulmonary vasodilation. The purpose of this study was to investigate the clinical outcomes of pediatric HPS and to identify the risk factors for HPS in children with biliary atresia (BA). We performed a retrospective cohort study of all children who were diagnosed with HPS between 2000 and 2018 at Seoul National University Hospital. The clinical features and outcomes of the 10 patients diagnosed with HPS were reviewed. To clarify the risk factors of HPS in patients with BA, we reviewed 120 patients diagnosed with BA. Underlying liver disease was BA in 8 patients, portal vein agenesis in 1 patient, and portal vein thrombosis in 1 patient. A total of 7 patients underwent liver transplantation (LT). Currently, all seven patients, including 3 patients with severe HPS, survived after LT. The prevalence of HPS in children with BA was 7%. Polysplenia/interrupted inferior vena was the only risk factor for HPS in BA patients in multivariate analysis. The Pediatric End-Stage Liver Disease score was not associated with the development of HPS. Children with severe HPS undergoing LT had excellent outcomes. Screening for HPS in children with BA is required regardless of the severity of liver diseases.
Asunto(s)
Síndrome Hepatopulmonar/etiología , Síndrome Hepatopulmonar/patología , Atresia Biliar/complicaciones , Atresia Biliar/patología , Niño , Enfermedad Hepática en Estado Terminal/complicaciones , Enfermedad Hepática en Estado Terminal/patología , Humanos , Trasplante de Hígado/métodos , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Seúl , Índice de Severidad de la EnfermedadRESUMEN
The hepatopulmonary syndrome (HPS) is defined by the presence of pulmonary gas exchange abnormalities due to intrapulmonary vascular dilatations in patients with chronic liver disease. Changes in DNA methylation reflect the genomic variation. Since liver transplant (LT) reverts HPS we hypothesized that it may be associated with specific liver epigenetic changes. Thus, the aim of this study was to investigate the role of the liver epigenome in patients with HPS. We extracted DNA from paraffin embedded liver tissue samples from 10 patients with HPS and 10 age-, sex- and MELD (Model for End-stage Liver Disease)-matched controls. DNA methylation was determined using the 850K array (Illumina). Weighted Gene Co-expression Network Analysis (WGCNA) was used to identify modules related to defining physiologic characteristics of HPS. Only 12 out of the 20 liver biopsies (7 HPS and 5 controls) had sufficient quality to be analyzed. None of the 802,688 DNA probes analyzed in the case control comparison achieved a significant False Discovery Rate (FDR). WGCNA identified 5 co-methylated gene-modules associated to HPS markers, mainly related to nervous and neuroendocrine system, apoptotic processes, gut bacterial translocation, angiogenesis and vascular remodeling ontologies. To conclude, HPS is associated with nervous/neuroendocrine system and vascular remodeling related liver epigenetic changes.
Asunto(s)
Epigenoma/genética , Síndrome Hepatopulmonar/genética , Hígado/patología , Adulto , Apoptosis/genética , Estudios de Casos y Controles , Metilación de ADN/genética , Epigenómica/métodos , Femenino , Síndrome Hepatopulmonar/patología , Humanos , Hígado/metabolismo , Pulmón/patología , Masculino , Persona de Mediana Edad , Neovascularización Fisiológica/genética , Células Neuroendocrinas/metabolismo , Proyectos Piloto , Circulación Pulmonar , Intercambio Gaseoso Pulmonar/fisiología , Índice de Severidad de la Enfermedad , Remodelación Vascular/genéticaRESUMEN
BACKGROUND & AIMS: Hepatopulmonary syndrome (HPS) is characterized by pulmonary vasodilation and arterial blood oxygen desaturation in patients with chronic liver disease. Generally, common bile duct ligation (CBDL) rats are a suitable experimental model for studying hepatopulmonary syndrome. Our previous study demonstrated that endotoxin surges markedly, followed by bacterial translocation and the loss of liver immune function in all the stages of CBDL, thereby contributing to the pathogenesis of HPS. However, the mechanisms behind the increase of the endotoxin and how to alleviate it have not yet been elucidated. Pulmonary injury induced by increased bilirubin, endotoxin, and inflammatory mediators occurs in the early and later stages of CBDL. This study assessed the effects of Tea polyphenols (TP) and Levofloxacin on endotoxin reduction and suppression of lung injury in HPS rats in the long and short term, respectively. METHODS: Morphological change of pulmonary injury, HPS relative index, endotoxin concentration, and the activation extent of Malondialdehyde (MDA) and Myeloperoxidase (MPO) were evaluated in CBDL rats with or without TP and Levofloxacin for three weeks or six weeks. The inflammation factors of serum, lung tissue, and BALF were then compared at the same condition for the two time periods. This was followed by adoption of the network pharmacology approach, which was mainly composed of active component gathering, target prediction, HPS gene collection, network analysis, and gene enrichment analysis. Finally, the mRNA and protein levels of the inflammatory factors were studied and relative signaling expression was assessed using RT-PCR and Western blot analysis. RESULTS: The obtained results indicated that the pulmonary injury manifestation was perceived and endotoxin, MDA, and MPO activation were markedly increased in the early and later stages of CBDL. TP and Levofloxacin treatment alleviated endotoxin infection and inflammation factor expression three weeks and six weeks after CBDL. In addition, Levofloxacin displayed a short time anti-bacterial effect, while TP exerted a long period function. TP and Levofloxacin also reduced TNF-α, TGF-ß, IL-1ß, PDGF-BB, NO, ICAM-1, and ET-1 expression on the mRNA or protein expression. With regard to the pharmacological mechanism, the network analysis indicated that 12 targets might be the therapeutic targets of TP and Levofloxacin on HPS, namely ET-1, NOs3, VEGFa, CCl2, TNF, Ptgs2, Hmox1, Alb, Ace, Cav1, and Mmp9. The gene enrichment analysis implied that TP and Levofloxacin probably benefited patients with HPS by modulating pathways associated with the AGE-RAGE signaling pathway, the TNF signaling pathway, the HIF-1 signaling pathway, the VEGF signaling pathway, and the IL-17 signaling pathway, Rheumatoid arthritis, Fluid shear stress, and atherosclerosis. Finally, the TNF-α level was mainly diminished on the protein level following CBDL. CONCLUSIONS: TP and Levofloxacin could alleviate pulmonary injury for short and long period, respectively, while at the same time preventing endotoxin and the development of HPS in CBDL rats. These effects are possibly associated with the regulation of the Endotoxin -TNF-α pathways.
Asunto(s)
Antibacterianos/farmacología , Antiinflamatorios/farmacología , Endotoxinas/metabolismo , Síndrome Hepatopulmonar/prevención & control , Levofloxacino/farmacología , Lesión Pulmonar/prevención & control , Pulmón/efectos de los fármacos , Polifenoles/farmacología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Traslocación Bacteriana , Camellia sinensis , Conducto Colédoco/cirugía , Modelos Animales de Enfermedad , Síndrome Hepatopulmonar/metabolismo , Síndrome Hepatopulmonar/microbiología , Síndrome Hepatopulmonar/patología , Ligadura , Pulmón/metabolismo , Pulmón/patología , Lesión Pulmonar/metabolismo , Lesión Pulmonar/microbiología , Lesión Pulmonar/patología , Masculino , Mapas de Interacción de Proteínas , Ratas Sprague-Dawley , Transducción de Señal , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Hepatopulmonary syndrome (HPS) is a severe complication of hepatic cirrhosis, which is characterized by hypoxia, intrapulmonary vasodilation, inflammation, and angiogenesis. In this study, we aimed to investigate the regulatory effects of diosmin (DS) on selected phosphodiesterase inhibitors against chronic bile duct ligation (CBDL)-induced HPS. Experimentally, Wistar Albino rats were used and HPS was induced by CBDL for 28 days. DS (100 mg/kg, daily, P.O.), sildenafil (Sild; 10 mg/kg, twice daily, P.O.), and pentoxifylline (PTX; 50 mg/kg, daily, P.O.) were evaluated either alone or in combinations for their anti-angiogenic activity. CBDL significantly altered oxidative stress biomarkers and up-regulated pulmonary mRNA expressions of VEGF, IGF-1, ET-1, iNOS, eNOS, and ANG-2 as well as the protein expressions of vWF, FGF-1, PI3K, AKT, p-AKT, TGF-ß, HYP, MPO activity and circulating TNF-α. Treatment with DS, Sild, PTX, and their combinations significantly attenuated molecular and cellular changes due to CBDL. Improvement of histopathological changes was also observed after drug treatment which further supported our results. Furthermore, DS combination with Sild or PTX exhibited an improvement in HPS in comparison to each drug alone. Collectively, DS can augment the anti-angiogenic activity of Sild and PTX during HPS through regulation of TNF-α/VEGF, IGF-1/PI3K/AKT, and FGF-1/ANG-2 signaling pathways.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Diosmina/farmacología , Síndrome Hepatopulmonar/tratamiento farmacológico , Pentoxifilina/farmacología , Transducción de Señal/efectos de los fármacos , Citrato de Sildenafil/farmacología , Angiotensina II/metabolismo , Animales , Sinergismo Farmacológico , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Síndrome Hepatopulmonar/patología , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Liver disorders may be associated with normal pulmonary hemodynamic, hepatopulmonary syndrome (HPS), or portopulmonary hypertension (POPH). In this study, we aimed to investigate the effect of the severity of liver dysfunctions on blood-borne variables, and pulmonary hemodynamic during repeated ventilation with hyperoxic and hypoxic gases. METHODS: Female Sprague Dawley rats were assigned into four groups of Sham (n = 7), portal vein ligation (PPVL, n = 7), common bile duct ligation (CBDL, n = 7), and combination of them (CBDL+ PPVL, n = 7). Twenty-eight days later, right ventricular systolic pressure (RVSP) and systemic blood pressure were recorded in anesthetized animals subjected to repeated maneuvers of hyperoxia (O2 50%) and hypoxia (O2 10%). Besides, we assessed blood parameters and liver histology. RESULTS: Liver histology score, liver enzymes, WBC and plasma malondialdehyde in the CBDL+PPVL group were higher than those in the CBDL group. Also, the plasma platelet level in the CBDL+PPVL group was lower than those in the other groups. On the other hand, the serum estradiol in the CBDL group was higher than that in the CBDL+PPVL group. All the above parameters in the PPVL group were similar to those in the Sham group. During ventilation with hyperoxia gas, RVSP in the CBDL+PPVL group was higher than the ones in the other groups, and in the CBDL group, it was more than those in the PPVL and Sham groups. Hypoxic pulmonary vasoconstriction (HPV) was not detected in both CBDL+PPVL and CBDL groups, whereas, it retained in the PPVL group. CONCLUSION: Severe liver damage increases RVSP in the CBDL+PPVL group linked to the high level of ROS, low levels of serum estradiol and platelets or a combination of them. Furthermore, the high RVSP at the noted group could present a reliable animal model for POPH in female rats.
Asunto(s)
Hemodinámica , Síndrome Hepatopulmonar/fisiopatología , Hiperoxia/fisiopatología , Hipoxia/fisiopatología , Hepatopatías/fisiopatología , Circulación Pulmonar , Anestesia General , Animales , Biomarcadores/sangre , Presión Sanguínea , Conducto Colédoco/cirugía , Modelos Animales de Enfermedad , Estradiol/sangre , Femenino , Síndrome Hepatopulmonar/sangre , Síndrome Hepatopulmonar/patología , Hiperoxia/sangre , Hipoxia/sangre , Ligadura , Hígado/patología , Hepatopatías/sangre , Hepatopatías/patología , Malondialdehído/sangre , Óxido Nítrico/sangre , Vena Porta/cirugía , Ratas Sprague-Dawley , Respiración Artificial , Índice de Severidad de la Enfermedad , Función Ventricular Derecha , Presión VentricularRESUMEN
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.
Asunto(s)
Endotelio Vascular/patología , Exosomas/genética , Hepatocitos/patología , Síndrome Hepatopulmonar/patología , Pulmón/irrigación sanguínea , MicroARNs/genética , Neovascularización Patológica/patología , Animales , Proliferación Celular , Células Cultivadas , Endotelio Vascular/metabolismo , Exosomas/metabolismo , Hepatocitos/metabolismo , Síndrome Hepatopulmonar/genética , Síndrome Hepatopulmonar/metabolismo , Pulmón/metabolismo , Masculino , Neovascularización Patológica/genética , Neovascularización Patológica/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de SeñalRESUMEN
OBJECTIVE: Hepatopulmonary syndrome (HPS) is a kind of pulmonary microvascular disease and occurs in 15%-30% cirrhosis. This study aimed to investigate the effects of pulmonary CX3CR1 on angiogenesis and associated mechanisms in HPS animal models. MATERIALS AND METHODS: CX3CR1GFP/GFP mice were constructed by replacing CX3CR1 with GFP. Common bile duct ligation (CBDL) mouse model was established with surgery. Release of nitric oxide (NO) was evaluated. Hematoxylin-eosin (HE) staining was employed to examine the inflammation of lung tissues. CD31 expression was detected with immunohistochemistry assay. Western blotting was used to evaluate the expression of CX3CL1, CX3CR1, phosphorylated-AKT (p-AKT), phosphorylated-ERK (p-ERK). Quantitative Real Time-PCR (qRT-PCR) assay was used to examine VEGF, PDGF, iNOS, eNOS, and HO-1 expression. RESULTS: CX3CR1-deficiency (CX3CR1GFP/GFP-sham or CX3CR1GFP/GFP-CBDL mice) significantly reduced NO release compared to wide type (WT)-mice or WT-CBDL mice (p<0.05). CX3CR1-deficiency significantly alleviated inflammation compared to wide type (WT)-mice or WT-CBDL mice (p<0.05). CX3CR1-deficiency significantly reduced CD31 expression compared to WT-sham and WT-CBDL mice, respectively (p<0.05). CX3CR1 also participated in anti-angiogenesis efficacy of Bevacizumab. CX3CR1-deficiency significantly down-regulated the ratio of p-AKT/AKT and p-ERK/ERK and inhibited the secretion of VEGF and PDGF compared to WT-mice (p<0.05). CX3CR1-deficiency significantly reduced iNOS, eNOS, and HO-1 expression compared to WT-mice (p<0.05). CONCLUSIONS: CX3CR1 deficiency reduced VEGF and PDGF production, inhibited p-AKT, and p-ERK activation and down-regulated iNOS, eNOS, and HO-1 expression. Therefore, CX3CR1 participates in pulmonary angiogenesis in the experimental HPS mice via inhibiting AKT/ERK signaling pathway and regulating NO/NOS release. These findings would provide a potential insight for clarifying the pathological mechanisms of HPS.
Asunto(s)
Receptor 1 de Quimiocinas CX3C/deficiencia , Síndrome Hepatopulmonar/patología , Pulmón/irrigación sanguínea , Neovascularización Patológica/patología , Animales , Bevacizumab/farmacología , Bevacizumab/uso terapéutico , Receptor 1 de Quimiocinas CX3C/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo , Hemo-Oxigenasa 1/metabolismo , Síndrome Hepatopulmonar/tratamiento farmacológico , Humanos , Pulmón/efectos de los fármacos , Pulmón/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Neovascularización Patológica/tratamiento farmacológico , Óxido Nítrico/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxido Nítrico Sintasa de Tipo III/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
OBJECTIVE: To evaluate the pulmonary alterations of animals with Hepatopulmonary Syndrome (HPS) submitted to Biliary Duct Ligature (BDL), as well as the antioxidant effect of Melatonin (MEL). METHODS: Sixteen male Wistar rats, divided into four Sham groups: BDL group, Sham + MEL group and BDL + MEL. The pulmonary and hepatic histology, lipoperoxidation and antioxidant activity of lung tissue, alveolar-arterial O2 difference and lung / body weight ratio (%) were evaluated. RESULTS: When comparing the groups, could be observed an increase of vasodilation and pulmonary fibrosis in the BDL group and the reduction of this in relation to the BDL + MEL group. It was also observed significant changes in the activity of catalase, ApCO2, ApO2 in the LBD group when compared to the other groups. CONCLUSION: The use of MEL has been shown to be effective in reducing vasodilation, fibrosis levels and oxidative stress as well as gas exchange in an experimental HPS model.
Asunto(s)
Antioxidantes/farmacología , Síndrome Hepatopulmonar/tratamiento farmacológico , Pulmón/efectos de los fármacos , Melatonina/farmacología , Animales , Presión Arterial/efectos de los fármacos , Conductos Biliares/cirugía , Análisis de los Gases de la Sangre , Catalasa/análisis , Modelos Animales de Enfermedad , Glutatión Transferasa/análisis , Síndrome Hepatopulmonar/patología , Síndrome Hepatopulmonar/fisiopatología , Ligadura , Peroxidación de Lípido/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/patología , Hígado/fisiopatología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/patología , Cirrosis Hepática/fisiopatología , Pulmón/patología , Pulmón/fisiopatología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Ratas Wistar , Reproducibilidad de los Resultados , Sustancias Reactivas al Ácido Tiobarbitúrico/análisis , Resultado del TratamientoRESUMEN
One central factor in hepatopulmonary syndrome (HPS) pathogenesis is pulmonary vascular remodelling (PVR) which involves dysregulation of proliferation and migration in pulmonary microvascular endothelial cells (PMVECs). Growing evidence suggests that Apical/basolateral polarity plays an important role in cell proliferation, migration, adhesion and differentiation. In this study, we explored whether cell polarity is involved and critical in experimental HPS rats that are induced by common bile duct ligation (CBDL). Cell polarity related proteins were analysed in CBDL rats lung and PMVECs under the HPS serum stimulation by immunofluorescence assay. Cdc42/PTEN activity, cell proliferation and migration and Annexin A2 (AX2) in PMVECs were determined, respectively. Cell polarity related proteins, lost their specialized luminal localization in PMVECs of the CBDL rat. The loss of cell polarity was induced by abnormal activity of Cdc42, which was strongly enhanced by the interaction between p-PTEN and Annexin A2 in PMVECs, after treatment with serum from CBDL rats. It led to over-proliferation and high migration ability of PMVECs. Down-regulation of PTEN-Cdc42 activity in PMVECs restored cell polarity and thus reduced their ability of migration and proliferation. Our study suggested that the loss of cell polarity plays a critical role in the pathogenesis of HPS-associated PVR and may become a potentially effective therapeutic target.
Asunto(s)
Polaridad Celular , Síndrome Hepatopulmonar/metabolismo , Síndrome Hepatopulmonar/patología , Fosfohidrolasa PTEN/metabolismo , Proteína de Unión al GTP cdc42/metabolismo , Citoesqueleto de Actina/metabolismo , Animales , Anexina A2/metabolismo , Movimiento Celular , Proliferación Celular , Células Cultivadas , Conducto Colédoco/cirugía , Células Endoteliales/metabolismo , Células Endoteliales/patología , Síndrome Hepatopulmonar/sangre , Ligadura , Pulmón/irrigación sanguínea , Masculino , Microvasos/patología , Modelos Biológicos , Ratas Sprague-DawleyRESUMEN
BACKGROUND: Biliary cirrhosis is associated with hepatopulmonary syndrome (HPS), which is related to increased posttransplant morbidity and mortality. AIMS: This study aims to analyze the pathophysiology of biliary cirrhosis and the onset of HPS. METHODS: Twenty-one-day-old Wistar rats were subjected to common bile duct ligation and were allocated to two groups: group A (killed 2, 3, 4, 5, or 6 weeks after biliary obstruction) and group B (subjected to biliodigestive anastomosis 2, 3, 4, 5, or 6 weeks after the first procedure and killed 3 weeks later). At the killing, arterial blood was collected for the analyses, and samples from the liver and lungs were collected for histologic and molecular analyses. The gasometric parameters as well as the expression levels of ET-1, eNOS, and NOS genes in the lung tissue were evaluated. RESULTS: From a total of 42 blood samples, 15 showed hypoxemia (pO2 < 85 mmHg) and 17 showed an increased oxygen gradient [p (A-a) O2 > 18 mmHg]. The liver histology revealed increased ductular proliferation after common bile duct ligation, and reconstruction of bile flow promoted decreased ductular proliferation 5 and 6 weeks post-common bile duct ligation. Pulmonary alterations consisted of decreased parenchymal airspace and increased medial wall thickness. Biliary desobstruction promoted transitory improvements 5 weeks after biliary obstruction (increased parenchymal airspace and decreased MWT-p = 0.003 and p = 0.004, respectively) as well as increased endothelin expression levels (p = 0.009). CONCLUSIONS: The present model showed lung tissue alterations promoted by biliary obstruction. The biliodigestive anastomosis had no clear direct effects on these alterations.
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Conductos Biliares/patología , Modelos Animales de Enfermedad , Síndrome Hepatopulmonar/patología , Cirrosis Hepática Biliar/patología , Anastomosis Quirúrgica/métodos , Animales , Conductos Biliares/cirugía , Femenino , Síndrome Hepatopulmonar/sangre , Ligadura , Cirrosis Hepática Biliar/sangre , Pulmón/patología , Masculino , Ratas , Ratas WistarRESUMEN
Hepatopulmonary syndrome (HPS) is a lethal complication of cirrhosis characterized by hypoxia and overt intrapulmonary shunting. In this study, we investigated the effect of caffeine in rats with common bile duct ligation (CBDL)-induced liver cirrhosis and HPS. CBDL rats were randomly allocated to receive caffeine or vehicle for 14 days. On the 28th day after CBDL, mortality rate, hemodynamics, liver, and renal biochemistry parameters and arterial blood gas analysis were evaluated. Lung and liver were dissected for the evaluation of inflammation, angiogenesis and protein expressions. In another series with parallel groups, the intrapulmonary shunting was determined. Caffeine significantly reduced portal pressure (caffeine vs. control: 10.0 ± 3.7 vs. 17.0 ± 8.1 mmHg, p < 0.05) in CBDL rats. The mortality rate, mean arterial pressure, biochemistry data and hypoxia were similar between caffeine-treated and control groups. Caffeine alleviated liver fibrosis and intrahepatic angiogenesis but intrapulmonary inflammation and angiogenesis were not ameliorated. The hepatic VEGF/Rho-A protein expressions were down-regulated but the pulmonary inflammation- and angiogenesis-related protein expressions were not significantly altered by caffeine. Caffeine did not reduce the intrapulmonary shunting, either. Caffeine has been shown to significantly improve liver fibrosis, intrahepatic angiogenesis and portal hypertension in cirrhotic rats, however, it does not ameliorate HPS.
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Inhibidores de la Angiogénesis/uso terapéutico , Cafeína/uso terapéutico , Síndrome Hepatopulmonar/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Inhibidores de la Angiogénesis/farmacología , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Cafeína/farmacología , Modelos Animales de Enfermedad , Síndrome Hepatopulmonar/complicaciones , Síndrome Hepatopulmonar/patología , Hipertensión Portal/complicaciones , Hipertensión Portal/tratamiento farmacológico , Hipertensión Portal/patología , Hígado/efectos de los fármacos , Hígado/patología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/patología , Pulmón/efectos de los fármacos , Pulmón/patología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Hepatopulmonary syndrome (HPS) is a serious complication in patients with advanced liver disease. The pathological pulmonary angiogenesis contributes to the progression of HPS. Importantly, directional collective migration of endothelial cells is a critical event for pathological angiogenesis. Previously, we have demonstrated that the over-expression of Cyclooxygenase-2 (COX-2) was an important factor in the experimental HPS. However, the role of COX-2 in the directional collective migration of human pulmonary microvascular endothelial cells (HPMVECs) is unclear. Our study aims to evaluate the potential effect of COX-2 in the directional collective migration of HPMVECs under the stimulation of HPS patient serum. In this study, 9 patients with stable liver cirrhosis were screened for presence of HPS. We confirmed that HPS patient serum dramatically promoted the directional collective migration and angiogenesis of HPMVECs, while the COX-2 selective antagonist parecoxib significantly inhibited the directional collective migration of HPMVEC under the stimulation of HPS patient serum. In addition, HPS patient serum significantly upregulated the phosphorylation of PKC and promoted the activation of Rac via COX-2/PGE2 signaling pathway. Notably, silencing PKC activation attenuated the directional collective migration of HPMVEC induced by HPS patient serum. In conclusion, these results indicate that PKC/Rac signaling induced by COX-2 modulates collective directional migration of HPMVEC during pathological pulmonary angiogenesis in HPS patients.
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Ciclooxigenasa 1/metabolismo , Síndrome Hepatopulmonar/patología , Proteína Quinasa C/metabolismo , Proteínas de Unión al GTP rac/metabolismo , Adulto , Estudios de Casos y Controles , Movimiento Celular , Células Cultivadas , Dinoprostona/metabolismo , Células Endoteliales/metabolismo , Células Endoteliales/patología , Endotelio Vascular/patología , Femenino , Síndrome Hepatopulmonar/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Fosforilación , Proteína Quinasa C/genética , Suero , Transducción de SeñalRESUMEN
Respiratory complications before and after liver transplant are common, diverse, and potentially have a negative impact on patient outcomes. In this review, we discuss the most frequent respiratory conditions that patients may develop in the perioperative period. Their prevention and/or treatment may help to maximize the benefit these patients may derive from liver transplant. This review examines diagnostic and therapeutic approaches to these complications for hepatologists, surgeons, and critical care physicians.
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Síndrome Hepatopulmonar/patología , Hepatopatías/complicaciones , Trasplante de Hígado/efectos adversos , Enfermedades Pulmonares/patología , Complicaciones Posoperatorias/patología , Síndrome Hepatopulmonar/etiología , Humanos , Hepatopatías/cirugía , Enfermedades Pulmonares/etiología , Complicaciones Posoperatorias/etiología , Periodo Posoperatorio , Periodo Preoperatorio , Factores de Riesgo , SíndromeRESUMEN
ABSTRACT Objective: To evaluate the pulmonary alterations of animals with Hepatopulmonary Syndrome (HPS) submitted to Biliary Duct Ligature (BDL), as well as the antioxidant effect of Melatonin (MEL). Methods: Sixteen male Wistar rats, divided into four Sham groups: BDL group, Sham + MEL group and BDL + MEL. The pulmonary and hepatic histology, lipoperoxidation and antioxidant activity of lung tissue, alveolar-arterial O2 difference and lung / body weight ratio (%) were evaluated. Results: When comparing the groups, could be observed an increase of vasodilation and pulmonary fibrosis in the BDL group and the reduction of this in relation to the BDL + MEL group. It was also observed significant changes in the activity of catalase, ApCO2, ApO2 in the LBD group when compared to the other groups. Conclusion: The use of MEL has been shown to be effective in reducing vasodilation, fibrosis levels and oxidative stress as well as gas exchange in an experimental HPS model.
RESUMO Objetivo: Avaliar as alterações pulmonares de animais com Síndrome Hepatopulmonar (SHP), submetidos à ligadura de ducto biliar (LDB), bem como o efeito antioxidante da Melatonina (MEL). Métodos: Dezesseis ratos machos da espécie Wistar, divididos em quatro grupos: Sham, Grupo LDB, Grupo Sham + MEL e LDB + MEL. Foram avaliadas a histologia pulmonar e hepática, a lipoperoxidação e atividade antioxidante do tecido pulmonar, diferença álveolo-arterial de O2 e relação peso pulmonar/peso corporal (%). Resultados: Quando comparados os grupos, observamos um aumento da vasodilatação e fibrose pulmonar no grupo LDB e a redução deste em relação ao grupo LDB+MEL. Observamos ainda alterações significativas na atividade da catalase, PaCO2, PaO2 no grupo LBD quando comparado aos demais grupos. Conclusões: A utilização da MEL demonstrou-se eficaz na redução da vasodilatação, níveis de fibrose e estresse oxidativo assim como na troca gasosa em modelo experimental de SHP.
Asunto(s)
Animales , Masculino , Síndrome Hepatopulmonar/tratamiento farmacológico , Pulmón/efectos de los fármacos , Melatonina/farmacología , Antioxidantes/farmacología , Conductos Biliares/cirugía , Análisis de los Gases de la Sangre , Peroxidación de Lípido/efectos de los fármacos , Catalasa/análisis , Síndrome Hepatopulmonar/fisiopatología , Síndrome Hepatopulmonar/patología , Modelos Animales de Enfermedad , Presión Arterial/efectos de los fármacos , Glutatión Transferasa/análisis , Ligadura , Hígado/efectos de los fármacos , Hígado/patologíaRESUMEN
Hepatopulmonary syndrome (HPS) is a frequent pulmonary complication of end-stage liver disease, characterized by impaired arterial oxygenation induced by intrapulmonary vascular dilatation. Its prevalence ranges from 4% to 47% in patients with cirrhosis due to the different diagnostic criteria applied among different studies. Nitric oxide overproduction and angiogenesis seem to be the hallmarks of a complicated pathogenetic mechanism, leading to intrapulmonary shunting and ventilation-perfusion mismatch. A classification of HPS according to the severity of hypoxemia has been suggested. Contrast-enhanced echocardiography represents the gold standard method for the detection of intrapulmonary vascular dilatations which is required, in combination with an elevated alveolar arterial gradient to set the diagnosis. The only effective treatment which can modify the syndrome's natural history is liver transplantation. Although it is usually asymptomatic, HPS imparts a high risk of pretransplantation mortality, independently of the severity of liver disease, while there is variable data concerning survival rates after liver transplantation. The potential of myocardial involvement in the setting of HPS has also gained increasing interest in recent research. The aim of this review is to critically approach the existing literature of HPS and emphasize unclear points that remain to be unraveled by future research.