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1.
Exp Clin Transplant ; 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34085917

RESUMO

Rabbit antithymocyte globulin is a lymphocytedepleting agent commonly used as induction therapy in kidney transplants. Although its use is generally safe and well tolerated, serious side effects can occur. Here, we describe a case of a severe immune complex hypersensitivity reaction with disseminated intravascular coagulation in response to rabbit antithymocyte globulin infusion. Immediate treatment required return to the operating room, massive transfusion of blood products, and plasmapheresis. The patient's posttransplant course was significant for volume overload, prolonged respiratory failure, and delayed graft function that required hemodialysis, but within 10 weeks the patient had made a full recovery and kidney allograft function had returned to normal.

2.
Clin Transplant ; 35(9): e14399, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34176169

RESUMO

AIM: The use of kidneys donated after circulatory death (DCD) provides an invaluable expansion of the organ supply for transplantation. Here, we investigated the effect of DCD on fibrotic changes on 1 1-year post 1-transplant surveillance kidney allograft biopsy. METHODS: Recipients of a deceased donor kidney transplant between 2013 and 2017 at a single institution, who survived 1 year and underwent surveillance biopsy, were included in the analysis (n = 333: 87 DCD kidneys, 246 kidneys donated after brain death [DBD]). Banff scores for interstitial fibrosis and tubular atrophy were summed as IFTA and compared between the groups. RESULTS: DCD and DBD groups were comparable for baseline characteristics. Delayed graft function was 39% in DCD versus 19% in DBD, P = .0002. Patient and graft survival were comparable for DCD and DBD cohorts. IFTA scores were higher in DCD compared to DBD (2.43±..13 vs. 2.01±..08, P = .0054). On multivariate analysis, the odds of IFTA > 2 in the DCD group was 2.5× higher (95%CI: 1.354.63) than in the DBD group. Within the DCD group, kidneys with IFTA > 2 had inferior 5-year graft survival (P = .037). CONCLUSION: Compared to DBD kidneys, DCD kidneys developed a greater degree of fibrotic changes on 1-year post-transplant surveillance biopsy, which affected graft longevity within the DCD cohort.


Assuntos
Transplante de Rim , Obtenção de Tecidos e Órgãos , Aloenxertos , Biópsia , Morte Encefálica , Morte , Fibrose , Sobrevivência de Enxerto , Humanos , Rim , Transplante de Rim/efeitos adversos , Estudos Retrospectivos , Doadores de Tecidos
3.
Transplantation ; 105(9): 1965-1979, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-33587433

RESUMO

BACKGROUND: Regulatory T cell (Treg) therapy is a promising approach to amelioration of allograft rejection and promotion of organ transplant tolerance. However, the fate of infused Treg, and how this relates to their therapeutic efficacy using different immunosuppressive regimens is poorly understood. Our aim was to analyze the tissue distribution, persistence, replicative activity and phenotypic stability of autologous, donor antigen alloreactive Treg (darTreg) in anti-thymocyte globulin (ATG)-lymphodepleted, heart-allografted cynomolgus monkeys. METHODS: darTreg were expanded ex vivo from flow-sorted, circulating Treg using activated donor B cells and infused posttransplant into recipients of major histocompatibility complex-mismatched heart allografts. Fluorochrome-labeled darTreg were identified and characterized in peripheral blood, lymphoid, and nonlymphoid tissues and the graft by flow cytometric analysis. RESULTS: darTreg selectively suppressed autologous T cell responses to donor antigens in vitro. However, following their adoptive transfer after transplantation, graft survival was not prolonged. Early (within 2 wk posttransplant; under ATG, tacrolimus, and anti-IL-6R) or delayed (6-8 wk posttransplant; under rapamycin) darTreg infusion resulted in a rapid decline in transferred darTreg in peripheral blood. Following their early or delayed infusion, labeled cells were evident in lymphoid and nonlymphoid organs and the graft at low percentages (<4% CD4+ T cells). Notably, infused darTreg showed reduced expression of immunoregulatory molecules (Foxp3 and CTLA4), Helios, the proliferative marker Ki67 and antiapoptotic Bcl2, compared with preinfusion darTreg and endogenous CD4+CD25hi Treg. CONCLUSIONS: Lack of therapeutic efficacy of infused darTreg in lymphodepleted heart graft recipients appears to reflect loss of a regulatory signature and proliferative and survival capacity shortly after infusion.


Assuntos
Transferência Adotiva , Soro Antilinfocitário/farmacologia , Proteínas Reguladoras de Apoptose/metabolismo , Apoptose , Proliferação de Células , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Transplante de Coração , Ativação Linfocitária , Depleção Linfocítica , Linfócitos T Reguladores/transplante , Animais , Células Cultivadas , Modelos Animais de Doenças , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/metabolismo , Transplante de Coração/efeitos adversos , Macaca fascicularis , Masculino , Fenótipo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fatores de Tempo
4.
Abdom Radiol (NY) ; 46(1): 9-16, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32062715

RESUMO

The article describes and illustrates the surgical techniques and the post-operative imaging anatomy in liver transplantation. Special attention is paid to the variant vascular and biliary anatomy that are important for surgical planning. Considering the ever-growing number of liver transplants performed and the key role that imaging plays in the pre-operative planning and post-operative assessment, it is important for the radiologist to be familiar with the surgical techniques and the normal post-operative appearance in these patients.


Assuntos
Sistema Biliar , Transplante de Fígado , Diagnóstico por Imagem , Humanos , Fígado/diagnóstico por imagem , Fígado/cirurgia , Doadores Vivos
6.
J Am Coll Surg ; 231(5): 536-545.e4, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32822886

RESUMO

BACKGROUND: Incisional hernia develops in up to 20% of patients undergoing abdominal operations. We sought to identify characteristics associated with poor outcomes after acute incisional hernia incarceration. STUDY DESIGN: We performed a retrospective cohort study of adult patients with incisional hernias undergoing elective repair or with acute incarceration between 2010 and 2017. The primary end point was 30-day mortality. Logistic regression was used to determine adjusted odds associated with 30-day mortality. The American College of Surgeons Surgical Risk Calculator was used to estimate outcomes had these patients undergone elective repair. RESULTS: A total of 483 patients experienced acute incarceration; 30-day mortality was 9.52%. Increasing age (adjusted odds ratio 1.05; 95% CI, 1.02 to 1.08) and bowel resection (adjusted odds ratio 3.18; 95% CI, 1.45 to 6.95) were associated with mortality. Among those with acute incarceration, 231 patients (47.9%) had no documentation of an earlier surgical evaluation and 252 (52.2%) had been evaluated but had not undergone elective repair. Among patients 80 years and older, 30-day mortality after emergent repair was high (22.9%) compared with estimated 30-day mortality for elective repair (0.73%), based on the American College of Surgeons Surgical Risk Calculator. Estimated mortality was comparable with observed elective repair mortality (0.82%) in an age-matched cohort. Similar mortality trends were noted for patients younger than 60 years and aged 60 to 79 years. CONCLUSIONS: Comparison of predicted elective repair and observed emergent repair mortality in patients with acute incarceration suggests that acceptable outcomes could have been achieved with elective repair. Almost one-half of acute incarceration patients had no earlier surgical evaluation, therefore, targeted interventions to address surgical referral can potentially result in fewer incarceration-related deaths.


Assuntos
Abdome/cirurgia , Herniorrafia , Hérnia Incisional/mortalidade , Hérnia Incisional/cirurgia , Complicações Pós-Operatórias/mortalidade , Complicações Pós-Operatórias/cirurgia , Doença Aguda , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
7.
Ann Surg ; 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773624

RESUMO

OBJECTIVE: The aim of the study was to quantify the risk of incarceration of incisional hernias. BACKGROUND: Operative repair is the definitive treatment for incisional ventral hernias but is often deferred if the perceived risk of elective operation is elevated secondary to comorbid conditions. The risk of incarceration during nonoperative management (NOM) factors into shared decision making by patient and surgeon; however, the incidence of acute incarceration remains largely unknown. METHODS: A retrospective analysis of adult patients with an International Classification of Diseases, Ninth Revision or Tenth Revision diagnosis of incisional hernia was conducted from 2010 to 2017 in 15 hospitals of a single healthcare system. The primary outcome was incarceration necessitating emergent operation. The secondary outcome was 30-, 90-, and 365-day mortality. Univariate and multivariate analyses were used to determine independent predictors of incarceration. RESULTS: Among 30,998 patients with an incisional hernia (mean age 58.1 ±â€Š15.9 years; 52.7% female), 23,022 (78.1%) underwent NOM of whom 540 (2.3%) experienced incarceration, yielding a 1- and 5-year cumulative incidence of 1.24% and 2.59%, respectively. Independent variables associated with incarceration included: age older than 40 years, female sex, current smoker, body mass index 30 or greater, and a hernia-related inpatient admission. All-cause mortality rates at 30, 90, and 365 days were significantly higher in the incarceration group at 7.2%, 10%, and 14% versus 1.1%, 2.3%, and 5.3% in patients undergoing successful NOM, respectively. CONCLUSIONS: Incarceration is an uncommon complication of NOM but is associated with a significant risk of death. Tailored decision making for elective repair and considering the aforementioned risk factors for incarceration provides an initial step toward mitigating the excess morbidity and mortality of an incarceration event.

8.
Front Immunol ; 11: 987, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32528475

RESUMO

Innate immunity can initiate platelet activation during the development of thrombosis through a process, termed immunothrombosis. Neutrophils form neutrophil extracellular traps (NETs) that have been shown to interact directly with platelets and play pro-coagulant roles in a variety of infectious and sterile inflammatory settings. Hepatic surgical stress initiated by ischemia/reperfusion (I/R) injury has wide systemic consequences on distant organs. However, the mechanisms of this remote injury phenomenon are not well-understood. Here, we sought to determine the role of NETs in causing systemic immunothrombosis and distant organ injury following a local inflammatory insult with liver I/R. Postoperative thromboelastographic revealed that the speed of clot formation (alpha-angle) was significantly increased whereas time to clot formation (R-time) were decreased by in patients undergoing liver resection, indicating a hypercoagulable state after surgery. In mice subjected to liver I/R, circulating platelet activation and platelet-neutrophil aggregates were significantly increased. Injured distant organs such as the lung and kidney displayed NETs and platelet-rich micro-thrombi in the microvasculature following liver I/R. The immune-thrombi and organ damage were dramatically decreased when NETs were inhibited by DNase treatment. Depletion of Tlr4 on platelets limited NET-induced activation of platelets but had no effect on NET formation. Furthermore, platelet-specific TLR4 KO mice had significantly reduced distant organ injury with decreased circulating platelet activation, platelet-neutrophil aggregates following liver I/R in comparison to their control counterparts. These data establish that after an acute local inflammatory process, NET-activated platelets can lead to a systemic pro-coagulant state with resultant remote organ injury by immunothrombosis.


Assuntos
Coagulação Sanguínea , Plaquetas/imunologia , Armadilhas Extracelulares/imunologia , Hepatectomia/efeitos adversos , Neutrófilos/imunologia , Ativação Plaquetária , Traumatismo por Reperfusão/imunologia , Trombose/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Plaquetas/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , Modelos Animais de Doenças , Armadilhas Extracelulares/metabolismo , Feminino , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Neutrófilos/metabolismo , Proteína-Arginina Desiminase do Tipo 4/deficiência , Proteína-Arginina Desiminase do Tipo 4/genética , Traumatismo por Reperfusão/sangue , Transdução de Sinais , Estresse Fisiológico , Trombose/sangue , Receptor 4 Toll-Like/deficiência , Receptor 4 Toll-Like/genética , Adulto Jovem
9.
Clin Transplant ; 34(2): e13770, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31829462

RESUMO

Transplantation of kidneys from deceased donors with acute kidney injury (AKI) can expand the donor pool. We investigated the effect of donor AKI on renal function and chronic changes on protocol biopsies at 1-year post-transplant. Donor AKI was defined according to Acute Kidney Injury Network (AKIN) criteria. Between 2013 and 2017, 333 kidneys were transplanted and subsequently biopsied after 1 year. Fifty-three kidneys from AKI donors (AKIN stage I n = 42, stage II n = 8, stage III n = 3) were compared to 280 kidneys from non-AKI donors. At 1-year follow-up, patient and graft survival were comparable. Donor AKI was not predictive of IFTA (Banff interstitial fibrosis plus tubular atrophy scores) at 1-year post-transplant biopsy (2.10 ± 1.28 in AKI, 2.09 ± 1.22 in non-AKI, P = .95). Donor AKI was also not associated with progression of IFTA from 3 to 12 months (P = .69), or inferior glomerular filtration rate (eGFR, P = .94). In a multivariate analysis, the odds of IFTA >2 were comparable between AKI and non-AKI groups. In conclusion, the transplantation of kidneys from donors with predominantly stage I AKI results in comparable function and degree of fibrosis on protocol biopsies 1-year post-transplant. Selected grafts from donors with AKI are a valuable tool for expanding the donor pool for kidney transplantation.


Assuntos
Injúria Renal Aguda , Função Retardada do Enxerto , Injúria Renal Aguda/etiologia , Aloenxertos , Função Retardada do Enxerto/etiologia , Fibrose , Sobrevivência de Enxerto , Humanos , Rim , Estudos Retrospectivos , Doadores de Tecidos
11.
Cancer Res ; 79(21): 5626-5639, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31519688

RESUMO

Neutrophil infiltration and neutrophil extracellular traps (NET) in solid cancers are associated with poorer prognosis, but the mechanisms are incompletely understood. We hypothesized that NETs enhance mitochondrial function in tumor cells, providing extra energy for accelerated growth. Metastatic colorectal cancer tissue showed increased intratumoral NETs and supranormal preoperative serum MPO-DNA, a NET marker. Higher MPO-DNA correlated with shorter survival. In mice, subcutaneous tumor implants and hepatic metastases grew slowly in PAD4-KO mice, genetically incapable of NETosis. In parallel experiments, human cancer cell lines grew slower in nu/nu mice treated with DNAse, which disassembles NETs. PAD4-KO tumors manifested decreased proliferation, increased apoptosis, and increased evidence of oxidative stress. PAD4-KO tumors had decreased mitochondrial density, mitochondrial DNA, a lesser degree of ATP production, along with significantly decreased mitochondrial biogenesis proteins PGC1α, TFAM, and NRF-1. In vitro, cancer cells treated with NETs upregulated mitochondrial biogenesis-associated genes, increased mitochondrial density, increased ATP production, enhanced the percentage of cancer cells with reduced mitochondrial membrane potential, and increased the oxygen consumption rate. Furthermore, NETs increased cancer cells' expression of fission and fusion-associated proteins, DRP-1 and MFN-2, and mitophagy-linked proteins, PINK1 and Parkin. All of which were decreased in PAD4-KO tumors. Mechanistically, neutrophil elastase released from NETs activated TLR4 on cancer cells, leading to PGC1α upregulation, increased mitochondrial biogenesis, and accelerated growth. Taken together, NETs can directly alter the metabolic programming of cancer cells to increase tumor growth. NETs represent a promising therapeutic target to halt cancer progression. SIGNIFICANCE: Neutrophils through the release of NETs facilitate the growth of stressed cancer cells by altering their bioenergetics, the inhibition of which induces cell death.


Assuntos
Proliferação de Células/fisiologia , Armadilhas Extracelulares/fisiologia , Homeostase/fisiologia , Mitocôndrias/fisiologia , Neutrófilos/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Biomarcadores/metabolismo , Linhagem Celular , Linhagem Celular Tumoral , DNA Mitocondrial/metabolismo , Armadilhas Extracelulares/metabolismo , Células HCT116 , Humanos , Elastase de Leucócito/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Infiltração de Neutrófilos/fisiologia , Neutrófilos/metabolismo
12.
HPB (Oxford) ; 20(12): 1181-1188, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30005992

RESUMO

BACKGROUND: The Risk Analysis Index (RAI) for frailty is a rapid survey for comorbidities and performance status, which predicts mortality after general surgery. We aimed to validate the RAI in predicting outcomes after hepatopancreatobiliary surgery. METHODS: Associations of RAI, determined in 162 patients prior to undergoing hepatopancreatobiliary surgery, with prospectively collected 30-day post-operative outcomes were analyzed with multivariate logistic and linear regression. RESULTS: Patients (age 62 ± 14, 51% female) had a median RAI of 7, range 0-25. With every unit increase in RAI, length of stay increased by 5% (95% CI: 2-7%), odds of ICU admission increased by 10% (0-20%), ICU length of stay increased by 21% (9-34%), and odds of discharge to a nursing facility increased by 8% (0-17%) (all P < 0.05). Particularly in patients who suffered a first post-operative complication, RAI was associated with additional complications (1.6 unit increase in Comprehensive Complication Index per unit increase in RAI, P = 0.002). In a direct comparison in a subset of 74 patients, RAI and the ACS-NSQIP Risk Calculator performed comparably in predicting outcomes. CONCLUSION: While RAI and ACS-NSQIP Risk Calculator comparatively predicted short-term outcomes after HPB surgery, RAI has been specifically designed to identify frail patients who can potentially benefit from preoperative prehabilitation interventions.


Assuntos
Técnicas de Apoio para a Decisão , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Fragilidade/diagnóstico , Complicações Pós-Operatórias/etiologia , Idoso , Procedimentos Cirúrgicos do Sistema Biliar/efeitos adversos , Tomada de Decisão Clínica , Feminino , Idoso Fragilizado , Fragilidade/complicações , Hepatectomia/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Pancreatectomia/efeitos adversos , Pancreaticoduodenectomia/efeitos adversos , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
13.
Hepatology ; 68(4): 1347-1360, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29631332

RESUMO

Nonalcoholic steatohepatitis (NASH) is a progressive, inflammatory form of fatty liver disease. It is the most rapidly rising risk factor for the development of hepatocellular carcinoma (HCC), which can arise in NASH with or without cirrhosis. The inflammatory signals promoting the progression of NASH to HCC remain largely unknown. The propensity of neutrophils to expel decondensed chromatin embedded with inflammatory proteins, known as neutrophil extracellular traps (NETs), has been shown to be important in chronic inflammatory conditions and in cancer progression. In this study, we asked whether NET formation occurs in NASH and contributes to the progression of HCC. We found elevated levels of a NET marker in serum of patients with NASH. In livers from STAM mice (NASH induced by neonatal streptozotocin and high-fat diet), early neutrophil infiltration and NET formation were seen, followed by an influx of monocyte-derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with deoxyribonuclease (DNase) or using mice knocked out for peptidyl arginine deaminase type IV (PAD4-/- ), did not affect the development of a fatty liver but altered the consequent pattern of liver inflammation, which ultimately resulted in decreased tumor growth. Mechanistically, we found that commonly elevated free fatty acids stimulate NET formation in vitro. CONCLUSION: Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (Hepatology 2018).


Assuntos
Carcinoma Hepatocelular/patologia , Transformação Celular Neoplásica/patologia , Progressão da Doença , Armadilhas Extracelulares/metabolismo , Neutrófilos/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Animais , Biomarcadores/metabolismo , Biópsia por Agulha , Carcinoma Hepatocelular/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/metabolismo , Prognóstico , Distribuição Aleatória , Medição de Risco
14.
Gene Expr ; 18(2): 89-101, 2018 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-29212576

RESUMO

The increasing prevalence of obesity has made nonalcoholic fatty liver disease (NAFLD) the most common chronic liver disease. As a consequence, NAFLD and especially its inflammatory form nonalcoholic steatohepatitis (NASH) are the fastest increasing etiology of end-stage liver disease and hepatocellular carcinoma. Physical inactivity is related to the severity of fatty liver disease irrespective of body weight, supporting the hypothesis that increasing physical activity through exercise can improve fatty liver disease. This review summarizes the evidence for the effects of physical exercise on NAFLD and NASH. Several clinical trials have shown that both aerobic and resistance exercise reduce the hepatic fat content. From clinical and basic scientific studies, it is evident that exercise affects fatty liver disease through various pathways. Improved peripheral insulin resistance reduces the excess delivery of free fatty acids and glucose for free fatty acid synthesis to the liver. In the liver, exercise increases fatty acid oxidation, decreases fatty acid synthesis, and prevents mitochondrial and hepatocellular damage through a reduction of the release of damage-associated molecular patterns. In conclusion, physical exercise is a proven therapeutic strategy to improve fatty liver disease.


Assuntos
Terapia por Exercício , Hepatopatia Gordurosa não Alcoólica/metabolismo , Animais , Metabolismo Energético , Humanos , Insulina/metabolismo , Metabolismo dos Lipídeos , Hepatopatia Gordurosa não Alcoólica/terapia
15.
J Hepatol ; 2017 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-28943296

RESUMO

BACKGROUND & AIMS: Neutrophils and liver sinusoidal endothelial cells (LSECs) both contribute to sterile inflammatory injury during ischemia/reperfusion (I/R), a well-known liver surgical stress. Interleukin-33 (IL-33) has been shown to drive neutrophil infiltration during inflammatory responses through its receptor ST2. We recently reported that infiltrating neutrophils form neutrophil extracellular traps (NETs), which exacerbate sterile inflammatory injury in liver I/R. Here, we sought to determine the role of IL-33 in NET formation during liver sterile inflammation. METHODS: Evaluation of IL-33 forming NETs was investigated using a partial liver I/R model to generate sterile injury in healthy WT, IL-33 and ST2 knockouts. Serum levels of IL-33 and myeloperoxidase (MPO)-DNA complex were measured in both humans and mice after the first surgery. Liver damage was assessed. Mouse neutrophil depletion was performed by intraperitoneal injection of anti-Ly6G antibody before I/R. RESULTS: Patients undergoing liver resection showed a significant increase in serum IL-33 compared to healthy volunteers. This coincided with higher serum MPO-DNA complexes. NET formation was decreased in IL-33 and ST2 knockout mice compared with control mice, after liver I/R. IL-33 or ST2 deficiency protected livers from I/R injury, whereas rIL-33 administration during I/R exacerbated hepatotoxicity and systemic inflammation. In vitro, IL-33 is released from LSECs to promote NET formation. IL-33 deficient LSECs failed to induce NETs. ST2 deficient neutrophils limited their capacity to form NETs in vitro and adoptive transfer of ST2 knockout neutrophils to neutrophil-depleted WT mice significantly decreased NET formation. CONCLUSIONS: Data establish that IL-33, mainly released from LSECs, causes excessive sterile inflammation after hepatic I/R by inducing NET formation. Therapeutic targeting of IL-33/ST2 might extend novel strategies to minimize organ damage in various clinical settings associated with sterile inflammation. LAY SUMMARY: Liver ischemia and reperfusion injury results in the formation of neutrophil extracellular traps, which contribute to organ damage in liver surgeries. Herein, we show that IL-33 is released from liver sinusoidal endothelial cells to promote NET formation during liver I/R, which exacerbates inflammatory cascades and sterile inflammation.

16.
Hepatology ; 66(1): 182-197, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28370295

RESUMO

The ability of cancer cells to survive and grow under hypoxic conditions has been known for decades, but the mechanisms remain poorly understood. Under certain conditions, cancer cells undergo changes in their bioenergetic profile to favor mitochondrial respiration by activating the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and up-regulating mitochondrial biogenesis. In this study, we hypothesized that augmented mitochondrial biogenesis plays a critical role for cancer cells to survive hypoxia. Consistent with this hypothesis, both hypoxic human hepatocellular carcinoma (HCC) tumors and HCC cell lines subjected to hypoxia increase mitochondrial biogenesis. Silencing of PGC-1α in hypoxic HCC cell lines halts their proliferation. Mechanistic investigations in vitro indicated that intracellular high mobility group box 1 (HMGB1) protein, a nuclear protein overexpressed in HCC, is essential for the process. Silencing of HMGB1 in hypoxic HCC cell lines resulted in a significant decrease in PGC-1α activation and mitochondrial biogenesis. Without HMGB1, hypoxic HCC cells had significantly reduced adenosine triphosphate production, decreased cellular proliferation, and increased apoptosis. In a diethylnitrosamine-induced murine model of HCC, genetic blocking of HMGB1 in hypoxic tumors resulted in a significant decrease in tumor growth. Tumors lacking HMGB1 had a significant reduction in mitochondrial biogenesis and a significant increase in mitochondrial dysfunction. Further in vitro mechanistic experiments indicated that during hypoxia HMGB1 translocates from the nucleus to the cytoplasm and binds to cytoplasmic Toll-like receptor-9. This binding leads to activation of p38 and subsequent phosphorylation of PGC-1α, with resultant up-regulation of mitochondrial biogenesis. CONCLUSION: Taken together, our findings suggest that during hypoxia HMGB1 up-regulates mitochondrial biogenesis in HCC cancer cells, promoting tumor survival and proliferation. (Hepatology 2017;66:182-197).


Assuntos
Carcinoma Hepatocelular/genética , Proteína HMGB1/genética , Neoplasias Hepáticas/genética , Biogênese de Organelas , Receptor Toll-Like 9/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Hipóxia Celular , Sobrevivência Celular , Humanos , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas Experimentais/genética , Neoplasias Hepáticas Experimentais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Distribuição Aleatória , Transdução de Sinais , Ativação Transcricional , Células Tumorais Cultivadas
17.
Xenotransplantation ; 21(5): 397-419, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25176336

RESUMO

BACKGROUND: The pig-to-non-human primate model is the standard choice for in vivo studies of organ and cell xenotransplantation. In 1998, Lambrigts and his colleagues surveyed the entire world literature and reported all experimental studies in this model. With the increasing number of genetically engineered pigs that have become available during the past few years, this model is being utilized ever more frequently. METHODS: We have now reviewed the literature again and have compiled the data we have been able to find for the period January 1, 1998 to December 31, 2013, a period of 16 yr. RESULTS: The data are presented for transplants of the heart (heterotopic and orthotopic), kidney, liver, lung, islets, neuronal cells, hepatocytes, corneas, artery patches, and skin. Heart, kidney, and, particularly, islet xenograft survival have increased significantly since 1998. DISCUSSION: The reasons for this are briefly discussed. A comment on the limitations of the model has been made, particularly with regard to those that will affect progression of xenotransplantation toward the clinic.


Assuntos
Transplante de Células/métodos , Modelos Animais , Transplante de Órgãos/métodos , Primatas , Suínos , Transplante Heterólogo/métodos , Animais
19.
Transplantation ; 94(12): 1187-91, 2012 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-23128998

RESUMO

BACKGROUND: Large animals treated with immunosuppressive drugs for preclinical experiments of transplantation have increased risks of infection, which can be compounded by the induction of diabetes if islet transplantation is planned. METHODS: We report our experience with severe sepsis in two young cynomolgus monkeys and five pigs that were subjected to diabetes induction, immunosuppressive therapy, or islet allotransplantation. RESULTS: In two monkeys and five pigs, infection was associated with a syndrome of profound hypoglycemia accompanied by severe acidosis, which was resistant to treatment. We do not believe that this syndrome has been reported previously by others. CONCLUSIONS: Despite treatment, this syndrome complicated the interpretation of blood glucose readings as a measure of islet graft function and resulted in death or the need for euthanasia in all seven animals. We tentatively suggest that the syndrome may be related to the presence of microorganisms that metabolize glucose and produce lactate.


Assuntos
Acidose/imunologia , Diabetes Mellitus Experimental/imunologia , Hipoglicemia/imunologia , Imunossupressores/farmacologia , Transplante das Ilhotas Pancreáticas/imunologia , Sepse/imunologia , Acidose/metabolismo , Animais , Bactérias/metabolismo , Glicemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/cirurgia , Modelos Animais de Doenças , Rejeição de Enxerto/tratamento farmacológico , Rejeição de Enxerto/imunologia , Hipoglicemia/metabolismo , Transplante das Ilhotas Pancreáticas/efeitos adversos , Ácido Láctico/sangue , Macaca fascicularis , Sepse/metabolismo , Índice de Gravidade de Doença , Suínos , Síndrome , Transplante Homólogo
20.
Cell Transplant ; 21(8): 1791-802, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22776064

RESUMO

Currently, islet transplantation as a cell therapeutic option for type 1 diabetes occurs via islet injection into the portal vein. Direct contact between islets and blood is a pathophysiological "provocation" that results in the instant blood-mediated inflammatory reaction (IBMIR) and is associated with early islet loss. However, the nature of the various insults on the islets in the blood stream remains mostly unknown. To gain insight into the mechanisms, we utilized a simplified in vitro model in which islets were exposed to blood in different clinically relevant but increasingly challenging, autologous, allogeneic, and xenogeneic combinations. Irrespective of the blood type and species compatibility, islets triggered blood clotting. Islet damage was worse as islet, and blood compatibility diminished, with substantial islet injury after exposure of porcine islets to human blood. Islet damage involved membrane leakage, antibody deposition, complement activation, positive staining for the membrane attack complex, and mitochondrial dysfunction. Islet damage occurred even after exposure to plasma only, and specific complement inactivation and neutralization of IgM substantially prevented islet damage, indicating the importance of humoral immunity. Efficacious measures are needed to reduce this injury, especially in view of a potential clinical use of porcine islets to treat diabetes.


Assuntos
Imunidade Humoral , Ilhotas Pancreáticas/imunologia , Animais , Coagulação Sanguínea/imunologia , Peptídeo C/metabolismo , Membrana Celular/metabolismo , Ativação do Complemento/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/metabolismo , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Ilhotas Pancreáticas/patologia , Mitocôndrias/metabolismo , Suínos
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