RESUMO
SUMMARY: One of the reasons for acute kidney damage is renal ischemia. Nevertheless, there are limited protective and therapeutic approaches for this problem. Diacerein is an anti-inflammatory drug characterized by numerous biological activities. We aimed to determine the ameliorative impact of diacerein on renal ischemia/reperfusion injury (I/R) condition, exploring the underlying mechanisms. Twenty-four male rats were allotted into four groups (n= 6): sham group; Diacerein (DIA) group; I/R group, in which a non-crushing clamp occluded the left renal pedicle for 45 min, and the right kidney was nephrectomized for 5 min before the reperfusion process; I/R + diacerein group, injected intraperitoneally with 50 mg diacerein/kg i.m 30 minutes prior to I/R operation. Ischemia/ reperfusion was found to affect renal function and induce histopathological alterations. The flow cytometry analysis demonstrated an elevated expression of innate and mature dendritic cells in I/R renal tissues. Moreover, upregulation in the expression of the inflammatory genes (TLR4, Myd88, and NLRP3), and overexpression of the pro-inflammatory cytokines (IL-1β), apoptotic (caspase-3) and pyroptotic (caspase-1) markers were observed in I/R-experienced animals. The aforementioned deteriorations were mitigated by pre-I/R diacerein treatment. Diacerein alleviated I/R-induced inflammation and apoptosis. Thus, it could be a promising protective agent against I/R.
La isquemia renal es una de los motivos del daño renal agudo. Sin embargo, los enfoques protectores y terapéuticos para este problema son limitados. La diacereína es un fármaco antiinflamatorio caracterizado por numerosas actividades biológicas. Nuestro objetivo fue determinar el impacto de mejora de la diacereína en la condición de lesión por isquemia/ reperfusión renal (I/R), explorando los mecanismos subyacentes. Veinticuatro ratas macho se distribuyeron en cuatro grupos (n= 6): grupo simulado; grupo de diacereína (DIA); grupo I/R, en el que una pinza no aplastante ocluyó el pedículo renal izquierdo durante 45 min, y el riñón derecho fue nefrectomizado durante 5 min antes del proceso de reperfusión; Grupo I/R + diacereína, inyectado por vía intraperitoneal con 50 mg de diacereína/kg i.m. 30 min antes de la operación I/R. Se encontró que la isquemia/ reperfusión afecta la función renal e induce alteraciones histopatológicas. El análisis de citometría de flujo demostró una expresión elevada de células dendríticas innatas y maduras en tejidos renales I/R. Además, se observó una regulación positiva en la expresión de los genes inflamatorios (TLR4, Myd88 y NLRP3) y una sobreexpresión de las citoquinas proinflamatorias (IL-1β), marcadores apoptóticos (caspasa-3) y piroptóticos (caspasa-1) en animales con experiencia en I/R. Los deterioros antes mencionados fueron mitigados por el tratamiento previo a la diacereína I/R. La diacereína alivió la inflamación y la apoptosis inducidas por I/R. Por lo tanto, podría ser un agente protector prometedor contra I/R.
Assuntos
Animais , Ratos , Traumatismo por Reperfusão/tratamento farmacológico , Antraquinonas/administração & dosagem , Nefropatias/tratamento farmacológico , Anti-Inflamatórios/administração & dosagem , Células Dendríticas/efeitos dos fármacos , Traumatismo por Reperfusão/imunologia , Transdução de Sinais , NF-kappa B/metabolismo , Antraquinonas/imunologia , Apoptose/efeitos dos fármacos , Estresse Oxidativo , Receptor 4 Toll-Like/metabolismo , Interleucina-1beta/metabolismo , Citometria de Fluxo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Inflamação , Injeções Intraperitoneais , Nefropatias/imunologiaRESUMO
BACKGROUND AND AIMS: Liver ischemia/reperfusion injury (IRI) induces local and systemic inflammation in which neutrophil extracellular traps (NETs) are major drivers. IRI markedly augments metastatic growth, which is consistent with the notion that the liver IRI can serve as a premetastatic niche. Exercise training (ExT) confers a sustainable protection, reducing IRI in some animal models, and has been associated with improved survival in patients with cancer; however, the impact of ExT on liver IRI or development of hepatic metastases is unknown. APPROACH AND RESULTS: Mice were randomized into exercise (ExT) and sedentary groups before liver IRI and tumor injection. Computerized dynamic network analysis of 20 inflammatory mediators was used to dissect the sequence of mediator interactions after ischemia/reperfusion (I/R) that induce injury. ExT mice showed a significant decrease in hepatic IRI and tissue necrosis. This coincided with disassembly of complex networks among inflammatory mediators seen in sedentary mice. Neutrophil infiltration and NET formation were decreased in the ExT group, which suppressed the expression of liver endothelial cell adhesion molecules. Concurrently, ExT mice revealed a distinct population of infiltrating macrophages expressing M2 phenotypic genes. In a metastatic model, fewer metastases were present 3 weeks after I/R in the ExT mice, a finding that correlated with a marked increase in tumor-suppressing T cells within the tumor microenvironment. CONCLUSIONS: ExT preconditioning mitigates the inflammatory response to liver IRI, protecting the liver from injury and metastases. In light of these findings, potential may exist for the reduction of liver premetastatic niches induced by liver IRI through the use of ExT as a nonpharmacologic therapy before curative surgical approaches.
Assuntos
Armadilhas Extracelulares/imunologia , Inflamação , Hepatopatias , Metástase Neoplásica , Infiltração de Neutrófilos/imunologia , Condicionamento Físico Animal/métodos , Traumatismo por Reperfusão , Animais , Proliferação de Células , Modelos Animais de Doenças , Imunidade , Inflamação/etiologia , Inflamação/imunologia , Inflamação/terapia , Hepatopatias/imunologia , Hepatopatias/patologia , Hepatopatias/terapia , Camundongos , Metástase Neoplásica/imunologia , Metástase Neoplásica/terapia , Fatores de Proteção , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/terapia , Resultado do TratamentoRESUMO
Innate immune cells can develop exacerbated immunologic response and long-term inflammatory phenotype following brief exposure to endogenous or exogenous insults, which leads to an altered response towards a second challenge after the return to a nonactivated state. This phenomenon is known as trained immunity (TI). TI is not only important for host defense and vaccine response but also for chronic inflammations such as cardiovascular and metabolic diseases such as atherosclerosis. TI can occur in innate immune cells such as monocytes/macrophages, natural killer cells, endothelial cells (ECs), and nonimmune cells, such as fibroblast. In this brief review, we analyze the significance of TI in ECs, which are also considered as innate immune cells in addition to macrophages. TI can be induced by a variety of stimuli, including lipopolysaccharides, BCG (bacillus Calmette-Guerin), and oxLDL (oxidized low-density lipoprotein), which are defined as risk factors for cardiovascular and metabolic diseases. Furthermore, TI in ECs is functional for inflammation effectiveness and transition to chronic inflammation. Rewiring of cellular metabolism of the trained cells takes place during induction of TI, including increased glycolysis, glutaminolysis, increased accumulation of tricarboxylic acid cycle metabolites and acetyl-coenzyme A production, as well as increased mevalonate synthesis. Subsequently, this leads to epigenetic remodeling, resulting in important changes in chromatin architecture that enables increased gene transcription and enhanced proinflammatory immune response. However, TI pathways and inflammatory pathways are separated to ensure memory stays when inflammation undergoes resolution. Additionally, reactive oxygen species play context-dependent roles in TI. Therefore, TI plays significant roles in EC and macrophage pathology and chronic inflammation. However, further characterization of TI in ECs and macrophages would provide novel insights into cardiovascular disease pathogenesis and new therapeutic targets. Graphic Abstract: A graphic abstract is available for this article.
Assuntos
Células Endoteliais/imunologia , Macrófagos/imunologia , Animais , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/imunologia , Citocinas/biossíntese , Metabolismo Energético , Epigênese Genética , Humanos , Imunidade Inata , Memória Imunológica , Infecções/etiologia , Infecções/imunologia , Inflamação/etiologia , Inflamação/imunologia , Doenças Metabólicas/etiologia , Doenças Metabólicas/imunologia , Redes e Vias Metabólicas/imunologia , Modelos Imunológicos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/imunologia , Fatores de RiscoRESUMO
BACKGROUND: Oxidative stress and the inflammatory process are involved in ischemia-reperfusion (I/R) injury. Juglans mollis has been reported as having antioxidant activity, which could attenuate the damage caused by I/R. We evaluated whether a methanolic extract of Juglans mollis (JM) exhibits nephroprotective activity in a Wistar rat model of I/R injury. METHODS: Four groups of six rats were used: Sham, I/R, JM, and JM + I/R. Two groups were dosed with JM (300 mg/kg) for 7 days before I/R. I/R injury was induced by clamping the renal hilums for 45 min and then reperfusing the kidneys for 15 h. Blood samples were taken to evaluate the levels of alanine aminotransferase (ALT), blood urea nitrogen, creatinine, superoxide dismutase (SOD), malondialdehyde (MDA), interleukin 1ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF-α). RESULTS: The levels of creatinine, ALT, MDA, IL-1ß, IL-6, and TNF-α were lower in JM + I/R than in I/R rats, whereas SOD level only was higher in JM + I/R than in Sham rats. No biochemical or histological damage was observed in JM rats compared with Sham rats; however, less histological damage was observed in JM + I/R rats compared with I/R rats. CONCLUSIONS: To our knowledge, this is the first report of nephroprotective activity of J. mollis against damage induced by I/R. This activity may be related to decreased levels of proinflammatory cytokines (IL-1ß, IL-6, and TNF-α) and modulation of oxidative stress markers (SOD and MDA) observed in the present study.
Assuntos
Anti-Inflamatórios/administração & dosagem , Juglans/química , Extratos Vegetais/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Creatinina/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/imunologia , Rim/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo , Superóxido Dismutase/genética , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
AIMS: Cardiac arrhythmias are one of the most important remote complications after kidney injury. Renal ischemia reperfusion (I/R) is a major cause of acute renal injury predisposing to several remote dysfunctions, including cardiac electrical disturbance. Since IL-1ß production dependent on NLRP3 represents a link between tissue malfunctioning and cardiac arrhythmias, here we tested the hypothesis that longer ventricular repolarization and arrhythmias after renal I/R depend on this innate immunity sensor. METHODS AND RESULTS: Nlrp3-/- and Casp1-/- mice reacted to renal I/R with no increase in plasma IL-1ß, different from WT (wild-type) I/R. A prolonged QJ interval and an increased susceptibility to ventricular arrhythmias were found after I/R compared to Sham controls in wild-type mice at 15â¯days post-perfusion, but not in Nlrp3-/- or CASP1-/- I/R, indicating that the absence of NLRP3 or CASP1 totally prevented longer QJ interval after renal I/R. In contrast with WT mice, we found no renal atrophy and no renal dysfunction in Nlrp3-/- and Casp1-/- mice after renal I/R. Depletion of macrophages in vivo after I/R and a day before IL-1ß peak (at 7â¯days post-perfusion) totally prevented prolongation of QJ interval, suggesting that macrophages might participate as sensors of tissue injury. Moreover, treatment of I/R-WT mice with IL-1r antagonist (IL-1ra) from 8 to 15â¯days post perfusion did not interfere with renal function, but reversed QJ prolongation, prevented the increase in susceptibility to ventricular arrhythmias and rescued a close to normal duration and amplitude of calcium transient. CONCLUSION: Taken together, these results corroborate the hypothesis that IL-1ß is produced after sensing renal injury through NRLP3-CASP1, and IL-1ß on its turn triggers longer ventricular repolarization and increase susceptibility to cardiac arrhythmias. Still, they offer a therapeutic approach to treat cardiac arrhythmias that arise after renal I/R.
Assuntos
Arritmias Cardíacas/etiologia , Arritmias Cardíacas/metabolismo , Interleucina-1beta/metabolismo , Nefropatias/complicações , Nefropatias/metabolismo , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/metabolismo , Animais , Caspase 1/genética , Caspase 1/metabolismo , Imunidade Inata/fisiologia , Nefropatias/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Traumatismo por Reperfusão/imunologia , Transdução de Sinais/fisiologiaRESUMO
Complement plays important roles in both ischemia-reperfusion injury (IRI) and antibody-mediated rejection (AMR) of solid organ allografts. One approach to possibly improve outcomes after transplantation is the use of C1 inhibitor (C1-INH), which blocks the first step in both the classical and lectin pathways of complement activation and also inhibits the contact, coagulation, and kinin systems. C1-INH can also directly block leukocyte-endothelial cell adhesion. C1-INH contrasts with eculizumab and other distal inhibitors, which do not affect C4b or C3b deposition or noncomplement pathways. Authors of reports on trials in kidney transplant recipients have suggested that C1-INH treatment may reduce IRI and delayed graft function, based on decreased requirements for dialysis in the first month after transplantation. This effect was particularly marked with grafts with Kidney Disease Profile Index ≥ 85. Other clinical studies and models suggest that C1-INH may decrease sensitization and donor-specific antibody production and might improve outcomes in AMR, including in patients who are refractory to other modalities. However, the studies have been small and often only single-center. This article reviews clinical data and ongoing trials with C1-INH in transplant recipients, compares the results with those of other complement inhibitors, and summarizes potentially productive directions for future research.
Assuntos
Ativação do Complemento/efeitos dos fármacos , Proteína Inibidora do Complemento C1/uso terapêutico , Complemento C1s/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Função Retardada do Enxerto/prevenção & controle , Rejeição de Enxerto/prevenção & controle , Transplante de Órgãos , Traumatismo por Reperfusão/prevenção & controle , Aloenxertos , Animais , Proteína Inibidora do Complemento C1/efeitos adversos , Complemento C1s/imunologia , Inativadores do Complemento/efeitos adversos , Função Retardada do Enxerto/imunologia , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Transplante de Órgãos/efeitos adversos , Traumatismo por Reperfusão/imunologia , Fatores de Risco , Resultado do TratamentoRESUMO
Ischemia-reperfusion (IR) is a deleterious condition associated with liver transplantation or resection that involves pro-oxidant and pro-inflammatory mechanisms. Considering that Rosa Mosqueta (RM) oil composition is rich in protective components such as α-linolenic acid (ALA) and tocopherols, we studied the effects of RM oil supplementation given prior to an IR protocol. Male Sprague-Dawley rats receiving RM oil (0.4 mL d-1) for 21 days were subjected to 1 h of ischemia followed by 20 h reperfusion. Parameters of liver injury (serum transaminases, histology), oxidative stress [liver contents of protein carbonyls, thiobarbituric acid reactants, Nrf2 activity and its target mRNA expression of heme oxygenase-1 (HO-1) and NADPH-quinone oxidoreductase-1 (NQO-1)] and inflammation [nuclear factor-κB (NF-κB) and its target mRNA expression of tumor necrosis factor-α (TNF-α) and interleukine-1ß (IL-1ß)] were studied. RM oil increased liver ALA and its derived EPA and DHA fatty acids' contents, with enhancement in those of α- and γ-tocopherols. IR induced inflammatory liver injury, with enhancement in serum transaminases, oxidative stress-related parameters with reduced Nrf2 signaling, and higher pro-inflammatory cytokines, indexes that were attenuated or abrogated by RM oil pretreatment. It is concluded that RM oil supplementation represents a novel non-invasive preconditioning strategy against liver injury induced by IR that has potential clinical applications in metabolic stress conditions.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/uso terapêutico , Suplementos Nutricionais , Fígado/metabolismo , Óleos Voláteis/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Rosa/química , Animais , Ácidos Docosa-Hexaenoicos/metabolismo , Ácido Eicosapentaenoico/metabolismo , Regulação da Expressão Gênica , Fígado/irrigação sanguínea , Fígado/imunologia , Fígado/patologia , Masculino , Fator 2 Relacionado a NF-E2/antagonistas & inibidores , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Distribuição Aleatória , Ratos Sprague-Dawley , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Sementes/química , Transdução de Sinais , Desmame , Ácido alfa-Linolênico/metabolismo , Ácido alfa-Linolênico/uso terapêutico , alfa-Tocoferol/metabolismo , alfa-Tocoferol/uso terapêutico , gama-Tocoferol/metabolismo , gama-Tocoferol/uso terapêuticoRESUMO
Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycaemia and high morbidity worldwide. The detrimental effects of hyperglycaemia include an increase in the oxidative stress (OS) response and an enhanced inflammatory response. DM compromises the ability of the liver to regenerate and is particularly associated with poor prognosis after ischaemia-reperfusion (I/R) injury. Considering the growing need for knowledge of the impact of DM on the liver following a surgical procedure, this review aims to present recent publications addressing the effects of DM (hyperglycaemia) on OS and the inflammatory process, which play an essential role in I/R injury and impaired hepatic regeneration after liver surgery.
Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/metabolismo , Animais , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Fígado/imunologia , Fígado/metabolismo , Fígado/cirurgia , Estresse Oxidativo/fisiologia , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismoRESUMO
A large number of researches have led to a substantial growth of knowledge about exercise and oxidative stress. Initial investigations reported that physical exercise generates free radical-mediated damages to cells; however, in recent years, studies have shown that regular exercise can upregulate endogenous antioxidants and reduce oxidative damage. Yet, strenuous exercise perturbs the antioxidant system by increasing the reactive oxygen species (ROS) content. These alterations in the cellular environment seem to occur in an exercise type-dependent manner. The source of ROS generation during exercise is debatable, but now it is well established that both contracting and relaxing skeletal muscles generate reactive oxygen species and reactive nitrogen species. In particular, exercises of higher intensity and longer duration can cause oxidative damage to lipids, proteins, and nucleotides in myocytes. In this review, we summarize the ROS effects and interplay of antioxidants in skeletal muscle during physical exercise. Additionally, we discuss how ROS-mediated signaling influences physical exercise in antioxidant system.
Assuntos
Antioxidantes/uso terapêutico , Exercício Físico , Estilo de Vida Saudável , Músculo Esquelético/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/antagonistas & inibidores , Traumatismo por Reperfusão/prevenção & controle , Animais , Anti-Inflamatórios não Esteroides/metabolismo , Anti-Inflamatórios não Esteroides/uso terapêutico , Antioxidantes/metabolismo , Sobrevivência Celular , Dieta Saudável , Suplementos Nutricionais , Humanos , Mitocôndrias Musculares/enzimologia , Mitocôndrias Musculares/imunologia , Mitocôndrias Musculares/metabolismo , Fadiga Muscular , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/imunologia , Músculo Esquelético/fisiopatologia , Mialgia/etiologia , Mialgia/prevenção & controle , Miosite/imunologia , Miosite/prevenção & controle , Consumo de Oxigênio , Esforço Físico , Espécies Reativas de Nitrogênio/antagonistas & inibidores , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologiaRESUMO
Ischemia-reperfusion injury (IRI) is the main cause of morbidity and mortality due to graft rejection after liver transplantation. During IRI, an intense inflammatory process occurs in the liver. This hepatic inflammation is initiated by the ischemic period but occurs mainly during the reperfusion phase, and is characterized by a large neutrophil recruitment to the liver. Production of cytokines, chemokines, and danger signals results in activation of resident hepatocytes, leukocytes, and Kupffer cells. The role of neutrophils as the main amplifiers of liver injury in IRI has been recognized in many publications. Several studies have shown that elimination of excessive neutrophils or inhibition of their function leads to reduction of liver injury and inflammation. However, the mechanisms involved in neutrophil recruitment during liver IRI are not well known. In addition, the molecules necessary for this type of migration are poorly defined, as the liver presents an atypical sinusoidal vasculature in which the classical leukocyte migration paradigm only partially applies. This review summarizes recent advances in neutrophil-mediated liver damage, and its application to liver IRI. Basic mechanisms of activation of neutrophils and their unique mechanisms of recruitment into the liver vasculature are discussed. In particular, the role of danger signals, adhesion molecules, chemokines, glycosaminoglycans (GAGs), and metalloproteinases is explored. The precise definition of the molecular events that govern the recruitment of neutrophils and their movement into inflamed tissue may offer new therapeutic alternatives for hepatic injury by IRI and other inflammatory diseases of the liver.