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1.
Immunology ; 159(2): 167-177, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31646612

RESUMO

Immune checkpoint inhibition with monoclonal antibodies is becoming increasingly commonplace in cancer medicine, having contributed to a widening of therapeutic options across oncological indications. Disruption of immune tolerance is the key mechanism of action of checkpoint inhibitors and although immune-related adverse events are a typical class effect of these compounds, the relationship between toxicity and response is not fully understood. Awareness and vigilance are paramount in recognizing potentially life-threatening toxicities and managing them in a timely manner. In this review article, we provide an overview of the clinical features, pathological findings and management principles of common immune-related toxicities, attempting to provide mechanistic insight into an increasingly common complication of cancer therapy.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doenças do Sistema Endócrino/induzido quimicamente , Gastroenteropatias/induzido quimicamente , Tolerância Imunológica/efeitos dos fármacos , Imunoterapia/efeitos adversos , Pneumopatias/induzido quimicamente , Terapia de Alvo Molecular/efeitos adversos , Neoplasias/tratamento farmacológico , Animais , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/terapia , Doenças do Sistema Endócrino/imunologia , Doenças do Sistema Endócrino/metabolismo , Doenças do Sistema Endócrino/terapia , Gastroenteropatias/imunologia , Gastroenteropatias/metabolismo , Gastroenteropatias/terapia , Humanos , Pneumopatias/imunologia , Pneumopatias/metabolismo , Pneumopatias/terapia , Neoplasias/imunologia , Neoplasias/metabolismo , Fatores de Risco , Evasão Tumoral/efeitos dos fármacos
2.
Hepatology ; 69(2): 785-802, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30055117

RESUMO

Hepatic stellate cells (HSCs) are essential perisinusoidal cells in both healthy and diseased liver. HSCs modulate extracellular matrix (ECM) homeostasis when quiescent, but in liver fibrosis, HSCs become activated and promote excess deposition of ECM molecules and tissue stiffening via force generation and mechanosensing. In hepatocellular carcinoma (HCC), activated HSCs infiltrate the stroma and migrate to the tumor core to facilitate paracrine signaling with cancer cells. Because the function of HSCs is known to be modulated by retinoids, we investigated the expression profile of retinoic acid receptor beta (RAR-ß) in patients with cirrhosis and HCC, as well as the effects of RAR-ß activation in HSCs. We found that RAR-ß expression is significantly reduced in cirrhotic and HCC tissues. Using a comprehensive set of biophysical methods combined with cellular and molecular biology, we have elucidated the biomechanical mechanism by which all trans-retinoic acid promotes HSC deactivation via RAR-ß-dependent transcriptional downregulation of myosin light chain 2 expression. Furthermore, this also abrogated mechanically driven migration toward stiffer substrates. Conclusion: Targeting mechanotransduction in HSCs at the transcriptional level may offer therapeutic options for a range of liver diseases.

3.
Front Immunol ; 9: 2948, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619308

RESUMO

Acute and acute-on-chronic liver failure (ALF and ACLF), though distinct clinical entities, are considered syndromes of innate immune dysfunction. Patients with ALF and ACLF display evidence of a pro-inflammatory state with local liver inflammation, features of systemic inflammatory response syndrome (SIRS) and vascular endothelial dysfunction that drive progression to multi-organ failure. In an apparent paradox, these patients are concurrently immunosuppressed, exhibiting acquired immune defects that render them highly susceptible to infections. This paradigm of tissue injury succeeded by immunosuppression is seen in other inflammatory conditions such as sepsis, which share poor outcomes and infective complications that account for high morbidity and mortality. Monocyte and macrophage dysfunction are central to disease progression of ALF and ACLF. Activation of liver-resident macrophages (Kupffer cells) by pathogen and damage associated molecular patterns leads to the recruitment of innate effector cells to the injured liver. Early monocyte infiltration may contribute to local tissue destruction during the propagation phase and results in secretion of pro-inflammatory cytokines that drive SIRS. In the hepatic microenvironment, recruited monocytes mature into macrophages following local reprogramming so as to promote resolution responses in a drive to maintain tissue integrity. Intra-hepatic events may affect circulating monocytes through spill over of soluble mediators and exposure to apoptotic cell debris during passage through the liver. Hence, peripheral monocytes show numerous acquired defects in acute liver failure syndromes that impair their anti-microbial programmes and contribute to enhanced susceptibility to sepsis. This review will highlight the cellular and molecular mechanisms by which monocytes and macrophages contribute to the pathophysiology of ALF and ACLF, considering both hepatic inflammation and systemic immunosuppression. We identify areas for further research and potential targets for immune-based therapies to treat these devastating conditions.


Assuntos
Insuficiência Hepática Crônica Agudizada/imunologia , Falência Hepática/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Doença Aguda , Insuficiência Hepática Crônica Agudizada/patologia , Hepatite/imunologia , Hepatite/patologia , Humanos , Falência Hepática/patologia , Modelos Imunológicos , Sepse/imunologia , Sepse/patologia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Síndrome de Resposta Inflamatória Sistêmica/patologia
4.
Gut ; 67(2): 333-347, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-28450389

RESUMO

OBJECTIVE: Acute liver failure (ALF) is characterised by overwhelming hepatocyte death and liver inflammation with massive infiltration of myeloid cells in necrotic areas. The mechanisms underlying resolution of acute hepatic inflammation are largely unknown. Here, we aimed to investigate the impact of Mer tyrosine kinase (MerTK) during ALF and also examine how the microenvironmental mediator, secretory leucocyte protease inhibitor (SLPI), governs this response. DESIGN: Flow cytometry, immunohistochemistry, confocal imaging and gene expression analyses determined the phenotype, functional/transcriptomic profile and tissue topography of MerTK+ monocytes/macrophages in ALF, healthy and disease controls. The temporal evolution of macrophage MerTK expression and its impact on resolution was examined in APAP-induced acute liver injury using wild-type (WT) and Mer-deficient (Mer-/-) mice. SLPI effects on hepatic myeloid cells were determined in vitro and in vivo using APAP-treated WT mice. RESULTS: We demonstrate a significant expansion of resolution-like MerTK+HLA-DRhigh cells in circulatory and tissue compartments of patients with ALF. Compared with WT mice which show an increase of MerTK+MHCIIhigh macrophages during the resolution phase in ALF, APAP-treated Mer-/- mice exhibit persistent liver injury and inflammation, characterised by a decreased proportion of resident Kupffer cells and increased number of neutrophils. Both in vitro and in APAP-treated mice, SLPI reprogrammes myeloid cells towards resolution responses through induction of a MerTK+HLA-DRhigh phenotype which promotes neutrophil apoptosis and their subsequent clearance. CONCLUSIONS: We identify a hepatoprotective, MerTK+, macrophage phenotype that evolves during the resolution phase following ALF and represents a novel immunotherapeutic target to promote resolution responses following acute liver injury.


Assuntos
Falência Hepática Aguda/imunologia , Falência Hepática Aguda/metabolismo , Macrófagos/metabolismo , Inibidor Secretado de Peptidases Leucocitárias/farmacologia , c-Mer Tirosina Quinase/metabolismo , Acetaminofen , Adulto , Idoso , Animais , Estudos de Casos e Controles , Feminino , Expressão Gênica , Genes MHC da Classe II , Antígenos HLA-DR/metabolismo , Humanos , Macrófagos do Fígado/imunologia , Macrófagos do Fígado/metabolismo , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Macrófagos/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Neutrófilos/fisiologia , Fenótipo , Inibidor Secretado de Peptidases Leucocitárias/metabolismo , Inibidor Secretado de Peptidases Leucocitárias/uso terapêutico , Transcriptoma , c-Mer Tirosina Quinase/deficiência , c-Mer Tirosina Quinase/genética
5.
Gastroenterology ; 153(1): 263-276.e8, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28363639

RESUMO

BACKGROUND & AIMS: Patients with acute liver failure (ALF) have defects in innate immune responses to microbes (immune paresis) and are susceptible to sepsis. Cytotoxic T-lymphocyte-associated protein 4 (CTLA4), which interacts with the membrane receptor B7 (also called CD80 and CD86), is a negative regulator of T-cell activation. We collected T cells from patients with ALF and investigated whether inhibitory signals down-regulate adaptive immune responses in patients with ALF. METHODS: We collected peripheral blood mononuclear cells from patients with ALF and controls from September 2013 through September 2015 (45 patients with ALF, 20 patients with acute-on-chronic liver failure, 15 patients with cirrhosis with no evidence of acute decompensation, 20 patients with septic shock but no cirrhosis or liver disease, and 20 healthy individuals). Circulating CD4+ T cells were isolated and analyzed by flow cytometry. CD4+ T cells were incubated with antigen, or agonist to CD3 and dendritic cells, with or without antibody against CTLA4; T-cell proliferation and protein expression were quantified. We measured levels of soluble B7 molecules in supernatants of isolated primary hepatocytes, hepatic sinusoidal endothelial cells, and biliary epithelial cells from healthy or diseased liver tissues. We also measured levels of soluble B7 serum samples from patients and controls, and mice with acetaminophen-induced liver injury using enzyme-linked immunosorbent assays. RESULTS: Peripheral blood samples from patients with ALF had a higher proportion of CD4+ CTLA4+ T cells than controls; patients with infections had the highest proportions. CD4+ T cells from patients with ALF had a reduced proliferative response to antigen or CD3 stimulation compared to cells from controls; incubation of CD4+ T cells from patients with ALF with an antibody against CTLA4 increased their proliferative response to antigen and to CD3 stimulation, to the same levels as cells from controls. CD4+ T cells from controls up-regulated expression of CTLA4 after 24-48 hours culture with sera from patients with ALF; these sera were found to have increased concentrations of soluble B7 compared to sera from controls. Necrotic human primary hepatocytes exposed to acetaminophen, but not hepatic sinusoidal endothelial cells and biliary epithelial cells from patients with ALF, secreted high levels of soluble B7. Sera from mice with acetaminophen-induced liver injury contained high levels of soluble B7 compared to sera from mice without liver injury. Plasma exchange reduced circulating levels of soluble B7 in patients with ALF and expression of CTLA4 on T cells. CONCLUSIONS: Peripheral CD4+ T cells from patients with ALF have increased expression of CTLA4 compared to individuals without ALF; these cells have a reduced response to antigen and CD3 stimulation. We found sera of patients with ALF and from mice with liver injury to have high concentrations of soluble B7, which up-regulates CTLA4 expression by T cells and reduces their response to antigen. Plasma exchange reduces levels of B7 in sera from patients with ALF and might be used to restore antimicrobial responses to patients.


Assuntos
Imunidade Adaptativa , Antígeno B7-1/sangue , Linfócitos T CD4-Positivos/metabolismo , Antígeno CTLA-4/metabolismo , Falência Hepática Aguda/imunologia , Acetaminofen/toxicidade , Insuficiência Hepática Crônica Agudizada/imunologia , Adulto , Animais , Anticorpos/farmacologia , Antígeno B7-1/metabolismo , Complexo CD3/farmacologia , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/imunologia , Antígeno CTLA-4/imunologia , Proliferação de Células , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/sangue , Técnicas de Cocultura , Células Dendríticas , Hepatócitos/metabolismo , Humanos , Cirrose Hepática/imunologia , Ativação Linfocitária , Camundongos , Pessoa de Meia-Idade , Choque Séptico/imunologia
6.
Gut ; 66(3): 519-529, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-26860769

RESUMO

OBJECTIVE: In order to explain the increased susceptibility to serious infection in alcoholic hepatitis, we evaluated monocyte phagocytosis, aberrations of associated signalling pathways and their reversibility, and whether phagocytic defects could predict subsequent infection. DESIGN: Monocytes were identified from blood samples of 42 patients with severe alcoholic hepatitis using monoclonal antibody to CD14. Phagocytosis and monocyte oxidative burst (MOB) were measured ex vivo using flow cytometry, luminometry and bacterial killing assays. Defects were related to the subsequent development of infection. Intracellular signalling pathways were investigated using western blotting and PCR. Interferon-γ (IFN-γ) was evaluated for its therapeutic potential in reversing phagocytic defects. Paired longitudinal samples were used to evaluate the effect of in vivo prednisolone therapy. RESULTS: MOB, production of superoxide and bacterial killing in response to Escherichia coli were markedly impaired in patients with alcoholic hepatitis. Pretreatment MOB predicted development of infection within two weeks with sensitivity and specificity that were superior to available clinical markers. Accordingly, defective MOB was associated with death at 28 and 90 days. Expression of the gp91 phox subunit of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was reduced in patients with alcoholic hepatitis demonstrating defective MOB. Monocytes were refractory to IFN-γ stimulation and showed high levels of a negative regulator of cytokine signalling, suppressor of cytokine signalling-1. MOB was unaffected by 7 days in vivo prednisolone therapy. CONCLUSIONS: Monocyte oxidative burst and bacterial killing is impaired in alcoholic hepatitis while bacterial uptake by phagocytosis is preserved. Defective MOB is associated with reduced expression of NADPH oxidase in these patients and predicts the development of infection and death.


Assuntos
Infecções Bacterianas/imunologia , Hepatite Alcoólica/fisiopatologia , Monócitos/fisiologia , NADPH Oxidases/metabolismo , Fagocitose , Explosão Respiratória , Adulto , Anti-Inflamatórios/uso terapêutico , Estudos de Casos e Controles , Células Cultivadas , Técnicas de Cocultura , Contagem de Colônia Microbiana , Escherichia coli/imunologia , Feminino , Hepatite Alcoólica/tratamento farmacológico , Hepatite Alcoólica/enzimologia , Humanos , Interferon gama/farmacologia , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , NADPH Oxidase 2 , Valor Preditivo dos Testes , Prednisolona/uso terapêutico , Explosão Respiratória/efeitos dos fármacos , Transdução de Sinais , Proteína 1 Supressora da Sinalização de Citocina/metabolismo
7.
Liver Int ; 35(3): 764-73, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25244648

RESUMO

BACKGROUND & AIMS: Variations in intestinal microbiota may influence acetaminophen metabolism. This study aimed to determine whether intestinal microbiota are a source of differential susceptibility to acetaminophen-induced hepatotoxicity. METHODS: Conventionally housed C3H/HeH (CH) and C3H/HeH germ-free (GF) mice were administered a 200 mg/kg IP dose of acetaminophen. The severity of hepatotoxicity at 8 h was assessed by histology and biochemical indices. A urinary metabolic profile was obtained using (1) H-NMR. Baseline hepatic glutathione content and CYP2E1 expression were quantified. An additional group of C3H/HeJ (LPS-r) mice were assessed to determine the contribution of LPS/TLR4 signalling. RESULTS: Baseline glutathione levels were significantly reduced (P = 0.03) in GF mice. CYP2E1 mRNA expression and protein levels were not altered. Interindividual variability did not differ between GF and CH groups. No significant differences in the extent of hepatocellular injury (ALT or percentage necrosis) were demonstrated. However, a milder acute liver failure (ALF) phenotype was shown in GF compared with CH mice, with reduced plasma bilirubin and creatinine and increased blood glucose. Differential acetaminophen metabolism was demonstrated. GF mice displayed a higher urinary acetaminophen-sulphate:glucuronide ratio compared with CH (P = 0.01). Urinary analysis showed metabolic differentiation of GF and CH groups at baseline and 8 h (cross-validated anova P = 1 × 10(-22) ). Interruption of TLR4 signalling in LPS-r mice had additional protective effects. CONCLUSION: Variations in intestinal microbiota do not fully explain differential susceptibility to acetaminophen-induced hepatotoxicity. GF mice experienced some protection from secondary complications following acetaminophen overdose and this may be mediated through reduced TLR4/LPS signalling.


Assuntos
Acetaminofen/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Intestinos/microbiologia , Fígado/patologia , Microbiota , Alanina Transaminase/sangue , Animais , Doença Hepática Induzida por Substâncias e Drogas/microbiologia , Citocromo P-450 CYP2E1/sangue , Citocinas/sangue , Modelos Animais de Doenças , Glutationa/sangue , Masculino , Camundongos , Camundongos Endogâmicos C3H , Espectroscopia de Prótons por Ressonância Magnética
9.
J Hepatol ; 61(2): 439-45, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24703954

RESUMO

Acute liver failure (ALF) is a condition with a high mortality and morbidity for which new treatments are desperately required. We contend that although the initial event in ALF is liver cell death, the clinical syndrome of ALF and its complications including multi-organ dysfunction and sepsis, are largely generated by the immune response to liver injury. Hepatic macrophages fulfil a diversity of roles in ALF, from pro-inflammatory to pro-resolution. Their inherent plasticity means the same macrophages may have a variety of functions depending on the local tissue environment at different stages of disease. A better understanding of the mechanisms that regulate macrophage plasticity during ALF will be an essential step towards realising the potential of immune-modulating therapies that re-orientate macrophages to promote the desirable functions of attenuating liver injury and promoting liver repair/regenerative responses. The key dynamics: temporal (early vs. late phase), regional (hepatic vs. systemic), and activation (pro-inflammatory vs. pro-resolution) are discussed and the potential for novel ALF therapies that modulate monocyte/macrophage function are described.


Assuntos
Falência Hepática Aguda/imunologia , Macrófagos/fisiologia , Monócitos/fisiologia , Animais , Polaridade Celular , Microambiente Celular , Humanos , Imunidade Inata , Falência Hepática Aguda/terapia , Regeneração Hepática , Síndrome de Resposta Inflamatória Sistêmica/imunologia
10.
Hepatology ; 59(4): 1564-76, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24282114

RESUMO

UNLABELLED: Acetaminophen-induced acute liver failure (AALF) is characterized both by activation of innate immune responses and susceptibility to sepsis. Circulating monocytes and hepatic macrophages are central mediators of inflammatory responses and tissue repair processes during human AALF. Secretory leukocyte protease inhibitor (SLPI) modulates monocyte/macrophage function through inhibition of nuclear factor kappa B (NF-κB) signaling. The aims of this study were to establish the role of SLPI in AALF. Circulating levels of SLPI, monocyte cluster of differentiation 163 (CD163), human leukocyte antigen-DR (HLA-DR), and lipopolysaccharide (LPS)-stimulated levels of NF-κBp65, tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6 were determined in patients with AALF, chronic liver disease, and healthy controls. Immunohistochemistry and multispectral imaging of AALF explant tissue determined the cellular sources of SLPI and hepatic macrophage phenotype. The phenotype and function of monocytes and macrophages was determined following culture with recombinant human (rh)-SLPI, liver homogenates, and plasma derived from AALF patients in the presence and absence of antihuman (α)SLPI. Hepatic and circulatory concentrations of SLPI were elevated in AALF and immunohistochemistry revealed SLPI expression in biliary epithelial cells and within hepatic macrophages (h-mψ) in areas of necrosis. H-mψ and circulating monocytes in AALF exhibited an anti-inflammatory phenotype and functional characteristics; typified by reductions in NF-κBp65, TNF-α, and IL-6 and preserved IL-10 secretion following LPS challenge. Culture of healthy monocytes with AALF liver homogenates, plasma, or rhSLPI induced monocytes with strikingly similar anti-inflammatory characteristics which were reversed by inhibiting the activity of SLPI. CONCLUSION: SLPI is a pivotal mediator of anti-inflammatory responses in AALF through modulation of monocyte/macrophage function, which may account for the susceptibility to sepsis in AALF.


Assuntos
Acetaminofen/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Inflamação/prevenção & controle , Inflamação/fisiopatologia , Macrófagos/fisiologia , Monócitos/fisiologia , Inibidor Secretado de Peptidases Leucocitárias/fisiologia , Adolescente , Adulto , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Estudos de Casos e Controles , Doença Hepática Induzida por Substâncias e Drogas/sangue , Antígenos HLA-DR/sangue , Humanos , Inflamação/sangue , Interleucina-6/sangue , Pessoa de Meia-Idade , NF-kappa B/sangue , Fenótipo , Receptores de Superfície Celular/sangue , Inibidor Secretado de Peptidases Leucocitárias/sangue , Transdução de Sinais/fisiologia , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
11.
Crit Care Med ; 41(11): 2543-50, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23949472

RESUMO

OBJECTIVE: To evaluate the role of hepatocellular and extrahepatic apoptosis during the evolution of acetaminophen-induced acute liver failure. DESIGN AND SETTING: A prospective observational study in two tertiary liver transplant units. PATIENTS: Eighty-eight patients with acetaminophen-induced acute liver failure were recruited. Control groups included patients with nonacetaminophen-induced acute liver failure (n = 13), nonhepatic multiple organ failure (n = 28), chronic liver disease (n = 19), and healthy controls (n = 11). MEASUREMENTS: Total and caspase-cleaved cytokeratin-18 (M65 and M30) measured at admission and sequentially on days 3, 7, and 10 following admission. Levels were also determined from hepatic vein, portal vein, and systemic arterial blood in seven patients undergoing transplantation. Protein arrays of liver homogenates from patients with acetaminophen-induced acute liver failure were assessed for apoptosis-associated proteins, and histological assessment of liver tissue was performed. MAIN RESULTS: Admission M30 levels were significantly elevated in acetaminophen-induced acute liver failure and non-acetaminophen induced acute liver failure patients compared with multiple organ failure, chronic liver disease, and healthy controls. Admission M30 levels correlated with outcome with area under receiver operating characteristic of 0.755 (0.639-0.885, p < 0.001). Peak levels in patients with acute liver failure were seen at admission then fell significantly but did not normalize over 10 days. A negative gradient of M30 from the portal to hepatic vein was demonstrated in patients with acetaminophen-induced acute liver failure (p = 0.042) at the time of liver transplant. Analysis of protein array data demonstrated lower apoptosis-associated protein and higher catalase concentrations in acetaminophen-induced acute liver failure compared with controls (p < 0.05). Explant histological analysis revealed evidence of cellular proliferation with an absence of histological evidence of apoptosis. CONCLUSIONS: Hepatocellular apoptosis occurs in the early phases of human acetaminophen-induced acute liver failure, peaking on day 1 of hospital admission, and correlates strongly with poor outcome. Hepatic regenerative/tissue repair responses prevail during the later stages of acute liver failure where elevated levels of M30 are likely to reflect epithelial cell death in extrahepatic organs.


Assuntos
Acetaminofen/toxicidade , Analgésicos não Entorpecentes/toxicidade , Apoptose/fisiologia , Doença Hepática Induzida por Substâncias e Drogas/fisiopatologia , Estado Terminal , APACHE , Adulto , Idoso , Feminino , Humanos , Queratina-18/sangue , Fígado , Falência Hepática Aguda/fisiopatologia , Testes de Função Hepática , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/fisiopatologia , Fragmentos de Peptídeos/sangue , Estudos Prospectivos , Fatores de Tempo
12.
Hepatology ; 56(2): 735-46, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22334567

RESUMO

UNLABELLED: Acetaminophen-induced acute liver failure (AALF) is associated with innate immunity activation, which contributes to the severity of hepatic injury and clinical outcome. A marked increase in hepatic macrophages (h-mφ) is observed in experimental models of AALF, but controversy exists regarding their role, implicating h-mφ in both aggravation and resolution of liver injury. The role of h-mφ in human AALF is virtually unexplored. We sought to investigate the role of chemokine (C-C motif) ligand 2 (CCL2) in the recruitment of circulating monocytes to the inflamed liver and to determine how the h-mφ infiltrate and liver microenvironment may contribute to tissue repair versus inflammation in AALF. We evaluated circulating monocytes, their chemokine (C-C motif) receptor 2 (CCR2) expression, and serum CCL2 levels in patients with AALF. Cell subsets and numbers of circulation-derived (MAC387+) or resident proliferating (CD68/Ki67+) h-mφ in hepatic immune infiltrates were determined by immunohistochemistry. Inflammatory cytokine levels were determined in whole and laser microdissected liver tissue by proteome array. In AALF, circulating monocytes were depleted, with the lowest levels observed in patients with adverse outcomes. CCL2 levels were high in AALF serum and hepatic tissue, and circulating monocyte subsets expressed CCR2, suggesting CCL2-dependent hepatic monocyte recruitment. Significant numbers of both MAC387+ and CD68+ h-mφ were found in AALF compared with control liver tissue with a high proportion expressing the proliferation marker Ki67. Levels of CCL2, CCL3, interleukin (IL)-6, IL-10, and transforming growth factor-ß1 were significantly elevated in AALF liver tissue relative to chronic liver disease controls. CONCLUSION: In AALF, the h-mφ population is expanded in areas of necrosis, both through proliferation of resident cells and CCL2-dependent recruitment of circulating monocytes. The presence of h-mφ within an anti-inflammatory/regenerative microenvironment indicates that they are implicated in resolution of inflammation/tissue repair processes during AALF.


Assuntos
Acetaminofen/envenenamento , Doença Hepática Induzida por Substâncias e Drogas/patologia , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/patologia , Macrófagos/patologia , Adulto , Analgésicos não Entorpecentes/envenenamento , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Quimiocina CCL2/metabolismo , Quimiocina CCL3/metabolismo , Quimiotaxia/imunologia , Feminino , Humanos , Interleucina-10/metabolismo , Interleucina-8/metabolismo , Antígeno Ki-67/metabolismo , Falência Hepática Aguda/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/patologia , Receptores CCR2/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
13.
World J Gastroenterol ; 16(15): 1811-9, 2010 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-20397256

RESUMO

Acute liver failure (ALF) is a devastating clinical syndrome characterised by progressive encephalopathy, coagulopathy, and circulatory dysfunction, which commonly leads to multiorgan failure and death. Central to the pathogenesis of ALF is activation of the immune system with mobilisation of cellular effectors and massive production of cytokines. As key components of the innate immune system, monocytes and macrophages are postulated to play a central role in the initiation, progression and resolution of ALF. ALF in humans follows a rapidly progressive clinical course that poses inherent difficulties in delineating the role of these pivotal immune cells. Therefore, a number of experimental models have been used to study the pathogenesis of ALF. Here we consider the evidence from experimental and human studies of ALF on the role of monocytes and macrophages in acute hepatic injury and the ensuing extrahepatic manifestations, including functional monocyte deactivation and multiple organ failure.


Assuntos
Falência Hepática/sangue , Macrófagos/citologia , Monócitos/citologia , Animais , Quimiocina CCL2/metabolismo , Citocinas/metabolismo , Humanos , Sistema Imunitário , Inflamação , Fígado/lesões , Fígado/metabolismo , Fígado/patologia , Falência Hepática/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Ratos
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