RESUMO
INTRODUCTION: Experimental hepatopulmonary syndrome (HPS) is best reproduced in the rat common bile duct ligation (CBDL) model. Vildagliptin (Vild) is an anti-hyperglycemic drug that exerts beneficial anti-inflammatory, anti-oxidant and anti-fibrotic effects. Therefore, the present search aimed to explore the possible effectiveness of Vild in CBDL-induced HPS model. METHODS: Four groups of male Wistar rats which weigh 220-270 g were used, including the normal control group, the sham control group, the CBDL group and CBDL+Vild group. The first three groups received i.p. saline, while the last group was treated with i.p. Vild (10 mg/kg/day) from the 15th to 28th day of the experiment. RESULTS: CBDL decreased the survivability and body weight of rats, increased diameter of the pulmonary vessels, and altered the arterial blood gases and the liver function parameters. Additionally, it increased the pulmonary expressions of endothelin-1 (ET-1) and tumor necrosis factor-α (TNF-α) mRNA as well as endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor-A (VEGF-A) proteins. The CBDL rats also exhibited elevation of the pulmonary interleukin-6 (IL-6), dipeptidyl peptidase-4 (DPP-4) and nitric oxide (NO) levels along with reduction of the pulmonary total anti-oxidant capacity and glucagon-like peptide-1 (GLP-1) levels. Vild mitigated these alterations and improved the histopathological abnormalities caused by CBDL. CONCLUSION: Vild effectively attenuated CBDL-induced HPS through its anti-oxidant and anti-inflammatory effects along with its modulatory effects on ET-1/NOS/NO and TNF-α/IL-6/VEGF-A signaling implicated in the regulation of intrapulmonary vasodilatation and angiogenesis, respectively.
Assuntos
Ducto Colédoco , Síndrome Hepatopulmonar , Ratos Wistar , Vasodilatação , Vildagliptina , Animais , Síndrome Hepatopulmonar/tratamento farmacológico , Vildagliptina/farmacologia , Masculino , Ligadura , Ducto Colédoco/cirurgia , Ratos , Vasodilatação/efeitos dos fármacos , Modelos Animais de Doenças , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/metabolismo , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Adamantano/análogos & derivados , Adamantano/farmacologia , Adamantano/uso terapêutico , AngiogêneseRESUMO
Pulmonary arterial hypertension-targeted therapies in portopulmonary hypertension (PoPH) are scarce, let alone for patients with chronic liver failure (CLF) and hepatopulmonary syndrome (HPS). A 48-year male was admitted to the hospital because of cirrhosis for 18 years, systemic oedema, and chest distress after exercise for 1 week. He was diagnosed with CLF, PoPH, and HPS. After 7 weeks of macitentan treatment, the patient's activity tolerance, pulmonary artery systolic pressure, arterial partial pressure of oxygen (PaO2 ), cTNI, and NT-proBNP changes indicated gradual recovery, without hepatic safety concerns. This case indicated that administering macitentan in patients diagnosed as PoPH (with CLF and HPS) may be efficient and safe enough in a clinical setting.
Assuntos
Síndrome Hepatopulmonar , Hipertensão Portal , Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Humanos , Masculino , Síndrome Hepatopulmonar/complicações , Síndrome Hepatopulmonar/diagnóstico , Síndrome Hepatopulmonar/tratamento farmacológico , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Portal/complicações , Hipertensão Portal/tratamento farmacológico , Hipertensão Portal/diagnósticoRESUMO
BACKGROUND & AIMS: Hepatopulmonary syndrome (HPS) is characterised by a defect in arterial oxygenation induced by pulmonary vascular dilatation in patients with liver disease. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, suppresses vasodilation by reducing nitric oxide (NO) production. We investigated the role of S1P in patients with HPS and the role of fingolimod as a therapeutic option in an experimental model of HPS. METHODS: Patients with cirrhosis with HPS (n = 44) and without HPS (n = 89) and 25 healthy controls were studied. Plasma levels of S1P, NO, and markers of systemic inflammation were studied. In a murine model of common bile duct ligation (CBDL), variations in pulmonary vasculature, arterial oxygenation, liver fibrosis, and inflammation were estimated before and after administration of S1P and fingolimod. RESULTS: Log of plasma S1P levels was significantly lower in patients with HPS than in those without HPS (3.1 ± 1.4 vs. 4.6 ± 0.2; p <0.001) and more so in severe intrapulmonary shunting than in mild and moderate intrapulmonary shunting (p <0.001). Plasma tumour necrosis factor-α (76.5 [30.3-91.6] vs. 52.9 [25.2-82.8]; p = 0.02) and NO (152.9 ± 41.2 vs. 79.2 ± 29.2; p = 0.001) levels were higher in patients with HPS than in those without HPS. An increase in Th17 (p <0.001) and T regulatory cells (p <0.001) was observed; the latter inversely correlated with plasma S1P levels. In the CBDL HPS model, fingolimod restored pulmonary vascular injury by increasing the arterial blood gas exchange and reducing systemic and pulmonary inflammation, resulting in improved survival (p = 0.02). Compared with vehicle treatment, fingolimod reduced portal pressure (p <0.05) and hepatic fibrosis and improved hepatocyte proliferation. It also induced apoptotic death in hepatic stellate cells and reduced collagen formation. CONCLUSIONS: Plasma S1P levels are low in patients with HPS and even more so in severe cases. Fingolimod, by improving pulmonary vascular tone and oxygenation, improves survival in a murine CBDL HPS model. IMPACT AND IMPLICATIONS: A low level of plasma sphingosine-1-phosphate (S1P) is associated with severe pulmonary vascular shunting, and hence, it can serve as a marker of disease severity in patients with hepatopulmonary syndrome (HPS). Fingolimod, a functional agonist of S1P, reduces hepatic inflammation, improves vascular tone, and thus retards the progression of fibrosis in a preclinical animal model of HPS. Fingolimod is being proposed as a potential novel therapy for management of patients with HPS.
Assuntos
Síndrome Hepatopulmonar , Ratos , Camundongos , Animais , Síndrome Hepatopulmonar/tratamento farmacológico , Cloridrato de Fingolimode/farmacologia , Cloridrato de Fingolimode/uso terapêutico , Ratos Sprague-Dawley , Cirrose Hepática/complicações , Niacinamida/uso terapêutico , Inflamação/complicaçõesRESUMO
BACKGROUND: Common bile duct ligation (BDL) is a rat experimental model to induce biliary cirrhosis. Lung fibrosis and pulmonary vascular angiogenesis and congestion are the most common complications of biliary cirrhosis that is known as hepatopulmonary syndrome. The aim of the present work is to investigate the acute lung injury in a BDL model and to investigate the possible protective effect of quercetin on this injury. METHODS: Twenty-four adult male albino rats of the Wister strain (weighing 150-250 g). Animals were divided into 3 groups, with 8 rats each: Group I: Sham-operated group (control). Group II: Bile duct ligation group (BDL) sacrificed after 28 days from the surgery. Group III: Quercetin-treated bile duct ligation group (Q-BDL) was given orally by gastric gavage in a dose of 50 mg/kg/day, starting from the 4th day of the operation until the 28th day. At the end of the experiment, at day 28, all rats were sacrificed. Lung specimens were processed to measure Endothelin B receptor gene expression by PCR, lung surfactant by ELISA, "eNO" s by immunohistochemistry. Histological assessment was done using; H&E, Masson's trichrome, PAS, toluidine blue-stained semi-thin sections, transmission electron microscope. Histomorphometric and statistical studies were done. RESULTS: BDL group showed significant increase in lung index together with mononuclear cellular infiltration denoting lung inflammatory state. Also, the significant increase in pulmonary endothelial nitric oxide synthase ("eNO" s) area percent and endothelin B receptor (ETB) gene expression indicates enhanced angiogenesis. Pulmonary surfactant concentration was significantly decreased together with thickening of interalveolar septa denoting lung injury and fibrosis. Quercetin led to significant decrease in lung index, pulmonary "eNO" s area percent, ETB gene expression and significant increase in pulmonary surfactant concentration. Quercetin treatment improved histological changes and morphometric measurements, limited mononuclear cellular infiltration and decreased perivascular and perialveolar collagen deposition. CONCLUSION: Quercetin ameliorates the hepatopulmonary syndrome-induced lung injury through its anti-inflammatory, antioxidative and antifibrotic effects.
Assuntos
Lesão Pulmonar Aguda , Síndrome Hepatopulmonar , Cirrose Hepática Biliar , Surfactantes Pulmonares , Masculino , Ratos , Animais , Ratos Wistar , Síndrome Hepatopulmonar/tratamento farmacológico , Quercetina/farmacologia , Receptor de Endotelina B , Lesão Pulmonar Aguda/tratamento farmacológicoRESUMO
The hepatopulmonary syndrome (HPS) is defined by liver dysfunction, intrapulmonary vasodilatation and abnormal oxygenation. Hypoxaemia is progressive and liver transplant is the only effective treatment. Severe hypoxaemia is a life-threatening HPS complication, particularly after transplant. We evaluated gas-exchange and haemodynamic effects of invasive therapies in a consecutive sample of 26 pre-transplant patients. Inhaled nitric oxide significantly improved partial pressure of oxygen (12.4 mm Hg; p=0.001) without deleterious effects on cardiac output. Trendelenburg positioning resulted in a small improvement, and methylene blue did not, though individual responses were variable. Future studies should prospectively evaluate these strategies in severe post-transplant hypoxaemia.
Assuntos
Síndrome Hepatopulmonar , Transplante de Fígado , Síndrome Hepatopulmonar/tratamento farmacológico , Humanos , Hipóxia/tratamento farmacológico , Óxido Nítrico , OxigênioRESUMO
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.
Assuntos
Inibidores da Angiogênese/farmacologia , Diosmina/farmacologia , Síndrome Hepatopulmonar/tratamento farmacológico , Pentoxifilina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Citrato de Sildenafila/farmacologia , Angiotensina II/metabolismo , Animais , Sinergismo Farmacológico , Fator 1 de Crescimento de Fibroblastos/metabolismo , Síndrome Hepatopulmonar/patologia , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is a high-mortality form of EBV infection. However, chronic hypoxemia is rare in these patients. We herein reported a case of severe hypoxemia due to intrapulmonary shunting in CAEBV. A 17-year-old girl presented with fever, dyspnea, cyanosis, and hepatosplenomegaly. Laboratory tests showed mild liver dysfunction and high copy numbers of EBV-DNA in the peripheral blood. A left supratrochlear lymph node biopsy showed infiltration of highly proliferative T lymphocytes with positive EBV encoded small RNA by in situ hybridization. Technetium-99m-labeled macroaggregated albumin and contrast-enhanced echocardiography confirmed the existence of intrapulmonary shunting, which was probably related to hepatopulmonary syndrome. The final diagnosis was CAEBV with intrapulmonary shunting. The patient was treated with cyclosporine A, etoposide, and dexamethasone. Finally, the patient died of respiratory failure. Intrapulmonary shunting is a rare complication of CAEBV. Early recognition and exploring the cause of hypoxemia should be highlighted in patients with CAEBV.
Assuntos
Infecções por Vírus Epstein-Barr/complicações , Hipóxia/etiologia , Circulação Pulmonar , Adolescente , Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , Biópsia/métodos , Doença Crônica , DNA Viral/sangue , Dexametasona/uso terapêutico , Ecocardiografia/métodos , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/tratamento farmacológico , Evolução Fatal , Feminino , Síndrome Hepatopulmonar/diagnóstico , Síndrome Hepatopulmonar/tratamento farmacológico , Síndrome Hepatopulmonar/etiologia , Herpesvirus Humano 4/genética , Humanos , Hipóxia/diagnóstico , Hipóxia/tratamento farmacológico , Linfonodos/patologia , Troca Gasosa PulmonarRESUMO
BACKGROUND: Rapamycin is a type of immunosuppressive agent that acts through inhibition of mammalian target of rapamycin (mTOR). Hepatopulmonary syndrome (HPS) is a lethal complication in cirrhotic patients. It is characterized by hypoxia and increased intrapulmonary shunts, in which pulmonary inflammation and angiogenesis play important roles. The current study aimed to evaluate the effect of rapamycin on HPS using the experimental model of common bile duct ligation (CBDL)-induced cirrhosis in rats. METHODS: The rats received low-dose (0.5 mg/kg), high-dose (2 mg/kg) rapamycin, or vehicle from the 15th to the 28th day post CBDL. Then the mortality rate, hemodynamics, biochemistry parameters, arterial blood gas and plasma levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor (TNF)-α were evaluated on the 28th day post CBDL. Pulmonary histopathological stains were performed, and protein expression was examined. In parallel groups, the intrapulmonary shunts of CBDL rats were measured. RESULTS: Compared with the control, a high-dose rapamycin treatment decreased portal pressure and improved hypoxia in CBDL rats. It also reduced the plasma level of VEGF and TNF-α and decreased intrapulmonary shunts. Meanwhile, it ameliorated pulmonary inflammation and angiogenesis and downregulated the protein expression of mTOR, P70S6K, nuclear factor kappa B (NFκB), VEGF, and VEGF receptor 2. In contrast, low-dose rapamycin did not attenuate intrapulmonary shunts despite ameliorating portal hypertension. CONCLUSION: High-dose rapamycin ameliorates HPS in cirrhotic rats as evidenced by the alleviated hypoxia and decreased intrapulmonary shunts. Downregulation of the mTOR/P70S6K, NFκB, and VEGF signaling pathways might play a key role.
Assuntos
Síndrome Hepatopulmonar/tratamento farmacológico , Cirrose Hepática/complicações , Sirolimo/uso terapêutico , Animais , Antígenos CD/análise , Antígenos de Diferenciação Mielomonocítica/análise , Modelos Animais de Doenças , Síndrome Hepatopulmonar/mortalidade , Masculino , NF-kappa B/antagonistas & inibidores , Ratos , Ratos Sprague-Dawley , Sirolimo/efeitos adversos , Serina-Treonina Quinases TOR/antagonistas & inibidores , Fator de Necrose Tumoral alfa/análise , Fator A de Crescimento do Endotélio Vascular/análise , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidoresAssuntos
Síndrome Hepatopulmonar/diagnóstico , Oxigênio/administração & dosagem , Dispneia/tratamento farmacológico , Dispneia/etiologia , Coração/diagnóstico por imagem , Síndrome Hepatopulmonar/complicações , Síndrome Hepatopulmonar/tratamento farmacológico , Humanos , Cirrose Hepática/etiologia , Masculino , Pessoa de Meia-Idade , Osteoartropatia Hipertrófica Primária/etiologia , Oxigênio/uso terapêuticoRESUMO
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.
Assuntos
Receptor 1 de Quimiocina CX3C/deficiência , Síndrome Hepatopulmonar/patologia , Pulmão/irrigação sanguínea , Neovascularização Patológica/patologia , Animais , Bevacizumab/farmacologia , Bevacizumab/uso terapêutico , Receptor 1 de Quimiocina CX3C/genética , Modelos Animais de Doenças , Regulação para Baixo , Heme Oxigenase-1/metabolismo , Síndrome Hepatopulmonar/tratamento farmacológico , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Neovascularização Patológica/tratamento farmacológico , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
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.
Assuntos
Antioxidantes/farmacologia , Síndrome Hepatopulmonar/tratamento farmacológico , Pulmão/efeitos dos fármacos , Melatonina/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Ductos Biliares/cirurgia , Gasometria , Catalase/análise , Modelos Animais de Doenças , Glutationa Transferase/análise , Síndrome Hepatopulmonar/patologia , Síndrome Hepatopulmonar/fisiopatologia , Ligadura , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Cirrose Hepática/fisiopatologia , Pulmão/patologia , Pulmão/fisiopatologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos Wistar , Reprodutibilidade dos Testes , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Resultado do TratamentoRESUMO
The tyrosine kinase inhibitor sorafenib improves hepatopulmonary syndrome (HPS) in an experimental model. However, the efficacy and adverse effect profile in patients with HPS are unknown. We aimed to determine the effect of sorafenib on the alveolar-arterial oxygen gradient (AaPO2 ) at 3 months in patients with HPS. We performed a randomized, double-blind, placebo-controlled parallel trial of sorafenib in patients with HPS at 7 centers. A total of 28 patients with HPS were randomized to sorafenib 400 mg by mouth daily or a matching placebo in a 1:1 ratio. We found no statistically significant difference in the median change in AaPO2 from baseline to 12 weeks between the patients allocated to sorafenib (4.5 mm Hg; IQR, -3.8 to 7.0 mm Hg) and those allocated to placebo (-2.4 mm Hg; IQR, -4.8 to 8.2 mm Hg; P = 0.70). There was also no difference between the groups in terms of degree of intrapulmonary shunting by contrast echocardiography. Sorafenib significantly reduced circulating levels of angiogenic markers, including vascular endothelial growth factor receptors (P < 0.01) and TIE2-expressing M2 monocytes (P = 0.03), but it reduced the mental component scores of the Short Form 36 (P = 0.04), indicating a worse quality of life. In conclusion, sorafenib did not change the AaPO2 or other disease markers at 3 months in patients with HPS. Alternative antiangiogenic therapies or treatments targeting other pathways should be investigated.
Assuntos
Síndrome Hepatopulmonar/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Qualidade de Vida , Sorafenibe/administração & dosagem , Biomarcadores/sangue , Método Duplo-Cego , Ecocardiografia , Feminino , Síndrome Hepatopulmonar/sangue , Síndrome Hepatopulmonar/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Neovascularização Patológica/sangue , Neovascularização Patológica/diagnóstico , Placebos/administração & dosagem , Placebos/efeitos adversos , Estudo de Prova de Conceito , Inibidores de Proteínas Quinases/efeitos adversos , Sorafenibe/efeitos adversos , Resultado do TratamentoRESUMO
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.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Cafeína/uso terapêutico , Síndrome Hepatopulmonar/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Inibidores da Angiogênese/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Cafeína/farmacologia , Modelos Animais de Doenças , Síndrome Hepatopulmonar/complicações , Síndrome Hepatopulmonar/patologia , Hipertensão Portal/complicações , Hipertensão Portal/tratamento farmacológico , Hipertensão Portal/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/complicações , Cirrose Hepática/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
AMD3100 (plerixafor, Mozobil®) was first identified as an anti-HIV agent specifically active against the T4-lymphotropic HIV strains, as it selectively blocked the CXCR4 receptor. Through interference with the interaction of CXCR4 with its natural ligand, SDF-1 (also named CXCL12), it also mobilized the CD34+stem cells from the bone marrow into the peripheral blood stream. In December 2008, AMD3100 was formally approved by the US FDA for autologous transplantation in patients with Non-Hodgkin's Lymphoma or multiple myeloma. It may be beneficially used in various other malignant diseases as well as hereditary immunological disorders such as WHIM syndrome, and physiopathological processes such as hepatopulmonary syndrome.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Aprovação de Drogas/legislação & jurisprudência , Compostos Heterocíclicos/uso terapêutico , Animais , Fármacos Anti-HIV/farmacologia , Antineoplásicos/uso terapêutico , Benzilaminas , Ciclamos , Reposicionamento de Medicamentos , Infecções por HIV/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/métodos , Síndrome Hepatopulmonar/tratamento farmacológico , Compostos Heterocíclicos/farmacologia , Humanos , Síndromes de Imunodeficiência/tratamento farmacológico , Camundongos , Doenças da Imunodeficiência Primária , Receptores CXCR4/antagonistas & inibidores , Fatores de Tempo , Estados Unidos , United States Food and Drug Administration , Verrugas/tratamento farmacológicoRESUMO
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.
Assuntos
Animais , Masculino , Síndrome Hepatopulmonar/tratamento farmacológico , Pulmão/efeitos dos fármacos , Melatonina/farmacologia , Antioxidantes/farmacologia , Ductos Biliares/cirurgia , Gasometria , Peroxidação de Lipídeos/efeitos dos fármacos , Catalase/análise , Síndrome Hepatopulmonar/fisiopatologia , Síndrome Hepatopulmonar/patologia , Modelos Animais de Doenças , Pressão Arterial/efeitos dos fármacos , Glutationa Transferase/análise , Ligadura , Fígado/efeitos dos fármacos , Fígado/patologiaRESUMO
The patient was a 23-year-old man who was diagnosed with severe hypoxemia and liver dysfunction after suffering from sudden difficulty breathing. At 2 years of age, he had been diagnosed with hypopituitarism, and had received hormone-replacement until he was 18 years of age. Echocardiography using micro bubbles and pulmonary scintigraphy indicated intrapulmonary shunt and a liver biopsy showed steatohepatitis. He was diagnosed with hepatopulmonary syndrome associated with nonalcoholic steatohepatitis. Hormone-replacement therapy was re-started. After 5 months, a second liver biopsy revealed the amelioration of nonalcoholic steatohepatitis, which improved his respiratory condition. This case suggested that early effective therapy for chronic liver diseases might improve the pathological and clinical conditions of hepatopulmonary syndrome.
Assuntos
Síndrome Hepatopulmonar/complicações , Síndrome Hepatopulmonar/tratamento farmacológico , Terapia de Reposição Hormonal/métodos , Hipopituitarismo/tratamento farmacológico , Hipopituitarismo/etiologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/etiologia , Corticosteroides/uso terapêutico , Adulto , Hormônio do Crescimento/uso terapêutico , Humanos , Masculino , Testosterona/uso terapêutico , Hormônios Tireóideos/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
Hepatopulmonary syndrome (HPS) is a relatively common and potentially severe pulmonary complication of cirrhosis with increased risk of mortality. In experimental models, a complex interaction between pulmonary endothelial cells, monocytes, and the respiratory epithelium, which produces chemokines, cytokines, and angiogenic growth factors, causes alterations in the alveolar microvasculature, resulting in impaired oxygenation. Model systems are critical for evaluating mechanisms and for preclinical testing in HPS, due to the challenges of evaluating the lung in the setting of advanced liver disease in humans. This review provides an overview of current knowledge and recent findings in the rodent common bile duct ligation model of HPS, which recapitulates many features of human disease. We focus on the concepts of endothelial derangement, monocyte infiltration, angiogenesis, and alveolar type II cell dysfunction as main contributors and potential targets for therapy.
Assuntos
Síndrome Hepatopulmonar/fisiopatologia , Fígado/fisiopatologia , Pulmão/fisiopatologia , Animais , Modelos Animais de Doenças , Células Endoteliais/patologia , Síndrome Hepatopulmonar/tratamento farmacológico , Humanos , Camundongos , Monócitos/patologia , Neovascularização Patológica/fisiopatologia , RatosRESUMO
Recent studies have shown that pulmonary angiogenesis is an important pathological process in the development of hepatopulmonary syndrome (HPS), and growing evidence has indicated that Stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4) axis is involved in pulmonary vascular disease by mediating the accumulation of c-kit+ cells. This study aimed to test the effect of AMD3100, an antagonist of CXCR4, in HPS pulmonary angiogenesis. Common bile duct ligation (CBDL) rats were used as experimental HPS model and were treated with AMD3100 (1.25mg/kg/day, i.p.) or 0.9% saline for 3weeks. The sham rats underwent common bile duct exposure without ligation. The c-kit+ cells accounts and its angiogenic-related functions, prosurvival signals, pulmonary angiogenesis and arterial oxygenation were analysed in these groups. Our results showed that pulmonary SDF-1/CXCR4, Akt, Erk and VEGF/VEGFR2 were significantly activated in CBDL rats, and the numbers of circulating and pulmonary c-kit+ cells were increased in CBDL rats compared with control rats. Additionally, the angiogenic-related functions of c-kit+ cells and pulmonary microvessel counts were also elevated in CBDL rats. CXCR4 inhibition reduced pulmonary c-kit+ cells and microvessel counts and improved arterial oxygenation within 3weeks in CBDL rats. The pulmonary prosurvival signals and pro-angiogenic activity of c-kit+ cells were also down-regulated in AMD3100-treated rats. In conclusion, AMD3100 treatment attenuated pulmonary angiogenesis in CBDL rats and prevented the development of HPS via reductions in pulmonary c-kit+ cells and inhibition of the prosurvival signals. Our study provides new insights in HPS treatment.
Assuntos
Síndrome Hepatopulmonar/patologia , Compostos Heterocíclicos/farmacologia , Pulmão/efeitos dos fármacos , Neovascularização Patológica/prevenção & controle , Proteínas Proto-Oncogênicas c-kit/metabolismo , Animais , Benzilaminas , Células Cultivadas , Ducto Colédoco/patologia , Ducto Colédoco/cirurgia , Ciclamos , Regulação para Baixo/efeitos dos fármacos , Síndrome Hepatopulmonar/tratamento farmacológico , Síndrome Hepatopulmonar/metabolismo , Compostos Heterocíclicos/uso terapêutico , Ligadura , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Neovascularização Patológica/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: Hepatopulmonary syndrome (HPS) is characterized by oxygen desaturation and increased intrapulmonary shunting formation in cirrhosis. Due to an unclarified mechanism, there is still no effective therapy except liver transplantation. Recent studies revealed that pulmonary angiogenesis may participate in pathogenesis, in which nitric oxide (NO) and vascular endothelial growth factor (VEGF) play roles. Pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, exerts anti-angiogenesis effect. However, whether pioglitazone influences pulmonary angiogenesis, shunting and HPS remains unexplored. METHODS: Cirrhosis with HPS was induced in Spraque-Dawley rats with common bile duct ligation (CBDL). Pioglitazone (10 mg/kg/day, oral gavage) or vehicle was administered from 8th to 28th day post CBDL. On the 28th day, the mortality rate, hemodynamic parameters, concentrations of plasma glucose and liver biochemistry parameters, and arterial blood gas data were evaluated. Lungs were dissected for protein expression analyses. In another series, intrapulmonary shunting degree was determined by color microsphere method in paralleled groups. RESULTS: The survival rates were similar in HPS rats with or without pioglitazone administration. Pioglitazone did not influence the hemodynamic parameters, glucose and liver biochemistry levels, oxygen saturation and alveolar arterial gradient, but significantly down-regulated pulmonary VEGF protein expression, endothelial NO synthase (eNOS) activation, and decreased intrapulmonary shunts. Pioglitazone significantly decreased intrapulmonary shunts as compared with the vehicle (18.1 ± 4.5 vs. 9.8 ± 3.6, p = 0.015). CONCLUSION: Pioglitazone down-regulated VEGF, eNOS and decreased intrapulmonary shunts without improving oxygenation. The current finding suggests a multifactorial mechanism of HPS that could not be successfully overcome merely by pioglitazone-induced anti-angiogenesis and shunting reduction.
Assuntos
Inibidores da Angiogênese/uso terapêutico , Síndrome Hepatopulmonar/tratamento farmacológico , Cirrose Hepática/tratamento farmacológico , Tiazolidinedionas/uso terapêutico , Animais , Endotelina-1/sangue , Masculino , Óxido Nítrico/fisiologia , Pioglitazona , Ratos , Ratos Sprague-Dawley , Fator A de Crescimento do Endotélio Vascular/fisiologiaRESUMO
BACKGROUND AND AIMS: One central factor in hepatopulmonary syndrome (HPS) pathogenesis is intravascular accumulation of activated macrophages in small pulmonary arteries. However, molecular mechanism underlying the macrophage accumulation in HPS is unknown. In this study, we aimed to explore whether elevated COX-2 induces the Bone morphogenic protein-2 (BMP-2)/Crossveinless-2 (CV-2) imbalance and then activation of BMP signaling pathway promotes the macrophage accumulation in Common Bile Duct Ligation (CBDL) rat lung. METHODS: The COX-2/PGE2 signaling activation, the BMP-2/CV-2 imbalance and the activation of Smad1 were evaluated in CBDL rat lung and in cultured pulmonary microvascular endothelial cells (PMVECs) under the HPS serum stimulation. The effects of Parecoxib (COX-2 inhibitor), BMP-2 and CV-2 recombinant proteins on 4-week CBDL rat lung were determined, respectively. RESULTS: The COX-2/PGE2 signaling pathway was activated in CBDL rat lung in vivo and PMVECs in vitro, which was due to the activation of NF-κB P65. The inhibition of COX-2 by Parecoxib reduced macrophage accumulation, decreased lung angiogenesis and improved HPS. Meanwhile, the CBDL rat lung secreted more BMP-2 but less CV-2, and the imbalance between BMP-2 and CV-2 exacerbated the BMP signaling activation thus promoting the macrophage accumulation and lung angiogenesis. The BMP-2/CV-2 imbalance is dependent on the COX-2/PGE2 signaling pathway, and thus the effects of this imbalance can be reversed by adminstration of Parecoxib. CONCLUSION: Our findings indicate that inhibition of COX-2 by parecoxib can improve the HPS through the repression of BMP signaling and macrophage accumulation.