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1.
J Cell Physiol ; 236(11): 7682-7697, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34041750

RESUMO

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.


Assuntos
Síndrome Hepatopulmonar/etiologia , Hipóxia/etiologia , Pulmão/metabolismo , Macrófagos/metabolismo , Microvasos/metabolismo , Neutrófilos/metabolismo , Fibrose Pulmonar/etiologia , Animais , Compostos de Bifenilo/sangue , Movimento Celular , Proliferação de Células , Quimiocina CCL2/metabolismo , Dilatação Patológica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Síndrome Hepatopulmonar/imunologia , Síndrome Hepatopulmonar/metabolismo , Síndrome Hepatopulmonar/patologia , Hipóxia/imunologia , Hipóxia/metabolismo , Hipóxia/patologia , Mediadores da Inflamação/metabolismo , Leucina/análogos & derivados , Leucina/sangue , Cirrose Hepática Experimental/complicações , Pulmão/imunologia , Pulmão/patologia , Macrófagos/imunologia , Masculino , Microvasos/imunologia , Microvasos/patologia , Infiltração de Neutrófilos , Neutrófilos/imunologia , Fenótipo , Fibrose Pulmonar/imunologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Ratos Sprague-Dawley , Receptores CCR2/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Fatores de Tempo , Fator de Crescimento Transformador beta1/metabolismo
2.
BMJ Case Rep ; 12(4)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30948390

RESUMO

Common variable immune deficiency (CVID) is a primary immunodeficiency disorder that is associated with abnormal liver function tests, however advanced liver disease is uncommon. Hepatopulmonary syndrome (HPS) is a rare but debilitating complication of CVID-associated liver disease. We report a case of CVID complicated by HPS that was successfully treated with orthotopic liver transplant, with the patient recovering to normal hepatic function and successfully weaning off domiciliary oxygen post-transplantation.


Assuntos
Imunodeficiência de Variável Comum/complicações , Síndrome Hepatopulmonar/cirurgia , Transplante de Fígado/métodos , Imunodeficiência de Variável Comum/fisiopatologia , Feminino , Síndrome Hepatopulmonar/imunologia , Humanos , Fígado/fisiopatologia , Pessoa de Meia-Idade , Resultado do Tratamento
3.
Biochem Pharmacol ; 138: 205-215, 2017 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-28642034

RESUMO

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.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Ciclo-Oxigenase 2/metabolismo , Modelos Animais de Doenças , Síndrome Hepatopulmonar/metabolismo , Pulmão/metabolismo , Ativação de Macrófagos , Transdução de Sinais , Animais , Proteína Morfogenética Óssea 2/administração & dosagem , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/uso terapêutico , Proteínas de Transporte/administração & dosagem , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Proteínas de Transporte/uso terapêutico , Células Cultivadas , Ciclo-Oxigenase 2/química , Inibidores de Ciclo-Oxigenase 2/administração & dosagem , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Síndrome Hepatopulmonar/tratamento farmacológico , Síndrome Hepatopulmonar/imunologia , Síndrome Hepatopulmonar/patologia , Injeções Intraperitoneais , Injeções Intravenosas , Isoxazóis/administração & dosagem , Isoxazóis/uso terapêutico , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos Alveolares/efeitos dos fármacos , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/patologia , Microvasos/efeitos dos fármacos , Microvasos/imunologia , Microvasos/metabolismo , Microvasos/patologia , Neovascularização Patológica/fisiopatologia , Neovascularização Patológica/prevenção & controle , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
4.
J Clin Immunol ; 35(3): 302-4, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25708586

RESUMO

Common Variable Immunodeficiency (CVID) comprises a heterogeneous group of primary antibody deficiencies which lead to a range of complications, including infectious, neoplastic and inflammatory disorders. This report describes monozygotic twin brothers with CVID who developed cryptogenic liver disease and subsequently hepatopulmonary syndrome (HPS). This is the second report of the association of HPS and CVID. Its occurrence in two identical twins implicates a genetic basis.


Assuntos
Imunodeficiência de Variável Comum/diagnóstico , Síndrome Hepatopulmonar/diagnóstico , Adolescente , Imunodeficiência de Variável Comum/imunologia , Síndrome Hepatopulmonar/imunologia , Humanos , Masculino , Gêmeos Monozigóticos
5.
Liver Int ; 32(6): 1018-26, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22672643

RESUMO

BACKGROUND/AIM: TNF-α is increased in hepatopulmonary syndrome (HPS). Pentoxifylline (PTX) mitigated experimental HPS through the inhibition of TNF-α. However, PTX has pleiotropic effects besides the inhibition of TNF-α. This study is to neutralize TNF-α with specific monoclonal antibody to TNF-α (TNF-α McAb) to investigate the effect of TNF-α on HPS. MATERIALS AND METHODS: Hepatopulmonary syndrome was induced by common bile duct ligation (CBDL); controls were sham operated. The endpoints were 1, 2, 3, 4 and 5 weeks after surgery. (99m) Technetium-macroaggregated albumin (Tc-MAA) was to evaluate intrapulmonary arteriovenous shunts; Portal venous pressure, cardiac output and mean blood pressure (MAP) were also measured. Serum was for Alanine transaminase (ALT), endotoxin, TNF-α and nitric oxide (NO) measurements, liver for histology, lung for histology and iNOS, PI3K/Akt expression assay. RESULTS: Portal vein pressure was significantly elevated and MAP decreased in CBDL rats. Tc-MAA was mainly located in lung and very weak in brain in sham group and mainly in brain of CBDL rats. TNF-α McAb significantly decreased the radioactivity in the brain, reduced cardiac output, increased MAP and systemic vascular resistance (SVR) in CBDL animals. Serum ALT, endotoxin, TNF-α and NO were significantly increased. TNF-α McAb significantly decreased these serum indices in CBDL rats. TNF-α McAb significantly alleviated liver damage, decreased alveolar-arterial gradient and inhibited iNOS, PI3K/Akt and p-Akt expression in lung tissue. Furthermore, TNF-α McAb significantly attenuated the inflammatory response in lung. CONCLUSION: TNF-α McAb improves HPS in cirrhotic rats; this effect is likely mediated through the inhibition of TNF-α PI3K/Akt-NO pathway.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Síndrome Hepatopulmonar/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Alanina Transaminase/sangue , Animais , Biomarcadores/sangue , Western Blotting , Débito Cardíaco/efeitos dos fármacos , Ducto Colédoco/cirurgia , Modelos Animais de Doenças , Endotoxinas/sangue , Síndrome Hepatopulmonar/sangue , Síndrome Hepatopulmonar/diagnóstico por imagem , Síndrome Hepatopulmonar/etiologia , Síndrome Hepatopulmonar/imunologia , Síndrome Hepatopulmonar/fisiopatologia , Imuno-Histoquímica , Ligadura , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo II/metabolismo , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Pressão na Veia Porta/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Cintilografia , Compostos Radiofarmacêuticos , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacos , Agregado de Albumina Marcado com Tecnécio Tc 99m , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologia
6.
Am J Respir Crit Care Med ; 183(8): 1080-91, 2011 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-21148721

RESUMO

RATIONALE: The etiology of hepatopulmonary syndrome (HPS), a common complication of cirrhosis, is unknown. Inflammation and macrophage accumulation occur in HPS; however, their importance is unclear. Common bile duct ligation (CBDL) creates an accepted model of HPS, allowing us to investigate the cause of HPS. OBJECTIVES: We hypothesized that macrophages are central to HPS and investigated the therapeutic potential of macrophage depletion. METHODS: Hemodynamics, alveolar-arterial gradient, vascular reactivity, and histology were assessed in CBDL versus sham rats (n = 21 per group). The effects of plasma on smooth muscle cell proliferation and endothelial tube formation were measured. Macrophage depletion was used to prevent (gadolinium) or regress (clodronate) HPS. CD68(+) macrophages and capillary density were measured in the lungs of patients with cirrhosis versus control patients (n = 10 per group). MEASUREMENTS AND MAIN RESULTS: CBDL increased cardiac output and alveolar-arterial gradient by causing capillary dilatation and arteriovenous malformations. Activated CD68(+)macrophages (nuclear factor-κB+) accumulated in HPS pulmonary arteries, drawn by elevated levels of plasma endotoxin and lung monocyte chemoattractant protein-1. These macrophages expressed inducible nitric oxide synthase, vascular endothelial growth factor, and platelet-derived growth factor. HPS plasma increased endothelial tube formation and pulmonary artery smooth muscle cell proliferation. Macrophage depletion prevented and reversed the histological and hemodynamic features of HPS. CBDL lungs demonstrated increased medial thickness and obstruction of small pulmonary arteries. Nitric oxide synthase inhibition unmasked exaggerated pulmonary vasoconstrictor responses in HPS. Patients with cirrhosis had increased pulmonary intravascular macrophage accumulation and capillary density. CONCLUSIONS: HPS results from intravascular accumulation of CD68(+)macrophages. An occult proliferative vasculopathy may explain the occasional transition to portopulmonary hypertension. Macrophage depletion may have therapeutic potential in HPS.


Assuntos
Antígenos CD/imunologia , Antígenos de Diferenciação Mielomonocítica/imunologia , Síndrome Hepatopulmonar/imunologia , Macrófagos/imunologia , Animais , Antígenos CD/fisiologia , Antígenos de Diferenciação Mielomonocítica/fisiologia , Malformações Arteriovenosas/etiologia , Malformações Arteriovenosas/fisiopatologia , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Síndrome Hepatopulmonar/etiologia , Humanos , Pulmão/irrigação sanguínea , Pulmão/citologia , Pulmão/imunologia , Macrófagos/fisiologia , Masculino , Músculo Liso Vascular/fisiopatologia , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/fisiologia , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Fator de Crescimento Derivado de Plaquetas/fisiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/fisiologia
7.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 26(7): 657-9, 662, 2010 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-20619089

RESUMO

AIM: To investigate the therapeutic effects of tumor necrosis factor-alpha monoclonal antibody on hepatopulmonary syndrome in rats. METHODS: 60 adult male Sprague-Dawley rats, weighing 250+/-25 g, were randomly divided into 3 groups: sham operation (6 rats) group, CBDL (30 rats) group and CBDL+TNF-alpha mAb (24 rats) group. Then CBDL operation group was divided into 5 subgroups and the CBDL+TNF-alpha mAb group was divided into 4 subgroups. Then the rats were sacrificed and the liver tissues were removed, then HE and Masson staining was performed to observe the extent of fibrosis. The arterial blood were gotten for analysis of blood gas and observing the change of alveoloarterial oxygen difference. The change of liver function, the concentration of endotoxin, TNF-alpha and NO were detected. RESULTS: Compared with the CBDL group, the alveoloarterial oxygen difference decreased significantly in CBDL+TNF-alpha mAb group. And the serum levels of ALT, TBIL decreased obviously. The concentration of ETX, TNF-alpha and NO in CBDL+TNF-alpha mAb group were significantly lower than those in CBDL group. CONCLUSION: There are some therapeutic effects of tumor necrosis factor-alpha antibody on hepatopulmonary syndrome in rats.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Síndrome Hepatopulmonar/tratamento farmacológico , Fator de Necrose Tumoral alfa/imunologia , Animais , Modelos Animais de Doenças , Síndrome Hepatopulmonar/imunologia , Humanos , Masculino , Óxido Nítrico/imunologia , Distribuição Aleatória , Ratos
8.
J Clin Gastroenterol ; 40(2): 135-9, 2006 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-16394874

RESUMO

The association of nodular regenerative hyperplasia with celiac disease is not as well established as it is with hepatopulmonary syndrome and portopulmonary hypertension. IgA anticardiolipin antibodies were reported recently in celiac patients with nodular regenerative hyperplasia. The subject of this study was the description of pulmonary abnormalities and IgA anticardiolipin antibodies in celiac patients with noncirrhotic portal hypertension. Five patients with portal hypertension were investigated to diagnose its etiology. Celiac disease was diagnosed by means of autoantibody reactivity and duodenal biopsies. Liver histology revealed nodular regenerative hyperplasia in four patients and suggested its presence in 1 case. Two cyanotic patients had severe hypoxemia with a confirmed diagnosis of hepatopulmonary syndrome. Another case exhibited features of hepatopulmonary syndrome with increased levels of arterial pulmonary pressure. The remaining 2 cases had slight abnormalities of arterial oxygenation. Three patients had reactivity to IgA anticardiolipin antibodies. The concomitance of celiac disease and nodular regenerative hyperplasia, two infrequent conditions, raises suspicion of there being a nonfortuitous coincidence. Pulmonary abnormalities, and especially hepatopulmonary syndrome, are described for the first time in association with celiac disease and nodular regenerative hyperplasia.


Assuntos
Anticorpos Anticardiolipina/análise , Doença Celíaca/imunologia , Hiperplasia Nodular Focal do Fígado/imunologia , Síndrome Hepatopulmonar/imunologia , Adolescente , Adulto , Doença Celíaca/complicações , Feminino , Hiperplasia Nodular Focal do Fígado/complicações , Síndrome Hepatopulmonar/complicações , Humanos , Fígado/patologia , Masculino , Pessoa de Meia-Idade
9.
Am J Physiol ; 277(5): L919-23, 1999 11.
Artigo em Inglês | MEDLINE | ID: mdl-10564176

RESUMO

Hepatic ischemia and reperfusion cause local and remote organ injury. This injury culminates from an integrated cascade of proinflammatory cytokines, chemokines, and adhesion molecules, many of which are regulated by the transcription factor nuclear factor-kappaB (NF-kappaB). The anti-inflammatory cytokine interleukin-10 (IL-10) has been shown to have inhibitory effects on NF-kappaB. The objective of the current study was to determine whether IL-10 could suppress pulmonary NF-kappaB activation and ensuing lung injury induced by hepatic ischemia-reperfusion. C57BL/6 mice underwent partial hepatic ischemia with or without intravenous administration of IL-10. Hepatic ischemia-reperfusion resulted in pulmonary NF-kappaB activation, increased mRNA expression of tumor necrosis factor-alpha (TNF-alpha), and macrophage inflammatory protein-2 (MIP-2), as well as increased pulmonary neutrophil accumulation and lung edema. Administration of IL-10 suppressed lung NF-kappaB activation, reduced TNF-alpha and MIP-2 mRNA expression, and decreased pulmonary neutrophil recruitment and lung injury. The data suggest that IL-10 protects against hepatic ischemia and reperfusion-induced lung injury by inhibiting lung NF-kappaB activation and the resulting pulmonary production of proinflammatory mediators.


Assuntos
Síndrome Hepatopulmonar/metabolismo , Interleucina-10/farmacologia , NF-kappa B/metabolismo , Pneumonia/metabolismo , Traumatismo por Reperfusão/metabolismo , Animais , Quimiocina CXCL2 , Expressão Gênica/imunologia , Síndrome Hepatopulmonar/etiologia , Síndrome Hepatopulmonar/imunologia , Fígado/irrigação sanguínea , Fígado/imunologia , Hepatopatias/complicações , Hepatopatias/imunologia , Hepatopatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monocinas/genética , Neutrófilos/enzimologia , Neutrófilos/imunologia , Peroxidase/metabolismo , Pneumonia/etiologia , Pneumonia/imunologia , Edema Pulmonar/imunologia , Edema Pulmonar/metabolismo , RNA Mensageiro/análise , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
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