RESUMO
BACKGROUND: Ischemic-reperfusion injury resulting from kidney transplantation declines the post-transplant graft function. Remote ischemic conditioning (RIC) is known to be able to reduce the criticality of ischemic reperfusion injury. This study aimed to meta-analyze whether the application of remote ischemic conditioning to kidney transplantation patients improves clinical outcomes. METHODS: Researchers included randomized controlled studies of the application of RIC to either kidney donors or recipients. Articles were retrieved from PubMed, Embase, Web of Science, and Cochrane Library. The risk of bias was evaluated using RoB 2.0. The primary outcome was mortality after transplantation. Secondary outcomes were the incidence of delayed graft function, graft rejection, and post-transplant laboratory results. All outcomes were integrated by RevMan 5.4.1. RESULTS: Out of 90 papers, 10 articles (8 studies, 1977 patients) were suitable for inclusion criteria. Mortality collected at all time points did not show a significant difference between the groups. Three-month mortality (RR, 3.11; 95% CI, 0.13-75.51, P = 0.49) tended to increase in the RIC group, but 12-month (RR, 0.70; 95% CI, 0.14-3.45, P = 0.67) or final-reported mortality (RR, 0.49; 95% CI, 0.23-1.06, P = 0.07) was higher in the sham group than the RIC group. There was no significant difference between the RIC and sham group in delayed graft function (RR, 0.64; 95% CI, 0.30-1.35, P = 0.24), graft rejection (RR, 1.13; 95% CI, 0.73-1.73, P = 0.59), and the rate of time required for a 50% reduction in baseline serum creatinine concentration of less than 24 h (RR, 0.98; 95% CI, 0.61-1.56, P = 0.93). CONCLUSIONS: It could not be concluded that the application of RIC is beneficial to kidney transplantation patients. However, it is noteworthy that long-term mortality tended to decrease in the RIC group. Since there were many limitations due to the small number of included articles, researchers hope that large-scale randomized controlled trials will be included in the future. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022336565.
Assuntos
Precondicionamento Isquêmico , Transplante de Rim , Ensaios Clínicos Controlados Aleatórios como Assunto , Transplante de Rim/mortalidade , Humanos , Precondicionamento Isquêmico/métodos , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/mortalidade , Rejeição de Enxerto/mortalidade , Rejeição de Enxerto/prevenção & controle , Função Retardada do EnxertoRESUMO
INTRODUCTION: Triggering receptor expressed on myeloid cells-1 (TREM-1) has important implications in sepsis and inflammation and is a novel receptor for extracellular cold-inducible RNA-binding protein (eCIRP). We hypothesize that the inhibition of TREM-1 via its interaction with eCIRP by novel peptide inhibitor M3 or knockout gene will attenuate the inflammation and injury associated with severe hepatic ischemia/reperfusion (I/R). METHODS: Wild-type (WT) C57BL/6 and TREM-1-/- mice underwent 60âmin of 70% hepatic ischemia, with 24âh of reperfusion. Additionally, WT mice underwent hepatic I/R and were treated with M3 (10âmg/kg body weight) or vehicle (normal saline) at the start of reperfusion. Blood and ischemic liver tissues were collected, and analysis was performed using enzymatic assays, enzyme-linked immunosorbent assay, reverse-transcription quantitative polymerase chain reaction, and pathohistology techniques. For survival surgery, mice additionally underwent resection of non-ischemic lobes of the liver and survival was monitored for 10âdays. RESULTS: There was an increase in serum levels of tissue markers including aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase as well as cytokine levels (IL-6) and histological scoring of hematoxylin and eosin sections in WT I/R mice. These markers decreased substantially in TREM-1-/- mice. Additionally, neutrophil infiltration markers and markers of local inflammation (myeloperoxidase, macrophage inflammatory protein-2, cyclooxygenase-2) were attenuated in TREM-1-/- mice. Similarly, we show a significant decrease in injury and inflammation markers with M3 treatment. Additionally, we demonstrate decreased apoptosis with TREM-1 inhibition. Finally, M3 treatment improved the survival rate from 42% to 75% after hepatic I/R. CONCLUSION: TREM-1 is an important eCIRP receptor in the inflammatory response of hepatic I/R, and deficiency of TREM-1 via knockout gene or peptide inhibition attenuated liver injury and inflammation, and improved survival. Inhibition of the TREM-1 and eCIRP interaction in hepatic I/R may have important therapeutic potential.
Assuntos
Inflamação/etiologia , Fígado/irrigação sanguínea , Proteínas de Ligação a RNA/fisiologia , Traumatismo por Reperfusão/mortalidade , Receptor Gatilho 1 Expresso em Células Mieloides/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Taxa de SobrevidaRESUMO
OBJECTIVE: Significant physiologic perturbations can occur in patients with chronic mesenteric ischemia (CMI) undergoing open mesenteric bypass (OMB). These events have frequently been attributed to ischemia-reperfusion events and have been directly implicated in the occurrence of multiple organ dysfunction (MOD). Scoring systems (MOD score [MODS] and sequential organ failure assessment [SOFA]) have been derived within the critical care field to provide a composite metric for these pathophysiologic changes. The purpose of the present study was to describe the early pathophysiologic changes that occur after OMB for CMI and determine whether these are predictive of the outcomes. METHODS: Patients with CMI who had undergone elective OMB from 2002 to 2018 at a single institution were reviewed. Changes in the hemodynamic, pulmonary, hepatic, renal, and hematologic parameters in the first 96 hours postoperatively were analyzed. The MODSs and SOFA scores were calculated. Cox regression was used to determine the association of the MODSs and SOFA scores with the outcomes. RESULTS: The use of OMB was analyzed for 72 patients (age, 66 ± 11 years; 68% women; body mass index, 23.8 ± 6 kg/m2; 48 ± 34-lb weight loss in 59%). Previous mesenteric stent placement or bypass had been performed in 39% [stenting in 21; bypass in 8; (one patient had both)]. An antegrade configuration (93%) was most common (retrograde configuration, 7%), with revascularization of the superior mesenteric artery/celiac vessels in 85% (superior mesenteric artery only in 15%). Postoperative pathophysiologic and metabolic changes were common, and the mean MODSs and SOFA scores were 3.6 ± 2.4 (range, 1-10) and 4.0 ± 2.7 (range, 1-13), respectively. The median length of stay was 14 days (interquartile range, 9-21). The 30-day mortality was 4% (n = 3) and in-hospital morbidity was 53% (n = 38; gastrointestinal, 25%; infectious, 22%; cardiac, 18%; pulmonary, 18%; renal, 11%). The clinical follow-up period was 16 ± 20 months. The MODSs and SOFA scores correlated linearly with overall mortality (MODS: odds ratio [OR], 1.4; 95% confidence interval [CI], 1.2-1.7; P < .01; SOFA score: OR, 1.4; 95% CI, 1.2-1.7; P < .01 per unit), with a score of ≥5 the inflection point most predictive of mortality (MODS: OR, 3.9; 95% CI, 1.6-9.9; P ≤ .01; SOFA score: OR, 2.8; 95% CI, 1.2-6.6; P = .02). The 1- and 3-year primary bypass patency and freedom from reintervention was 91% ± 5% and 83% ± 7%, respectively, with no association with the MODSs or SOFA scores. The 1- and 3-year survival was 86% ± 4% and 71% ± 6% with significantly worse outcomes for patients with higher MODSs and/or SOFA scores. CONCLUSIONS: Most CMI patients undergoing OMB will experience significant metabolic derangements resulting from sequelae of the ischemia-reperfusion phenomenon postoperatively. These can be objectively assessed in the early postoperative period using simply applied scoring systems to reliably predict the early and long-term outcomes. A derivation of the MODS and/or SOFA score after OMB for CMI can identify the most vulnerable patients at the greatest risk of mortality.
Assuntos
Hemodinâmica , Isquemia Mesentérica/cirurgia , Traumatismo por Reperfusão/etiologia , Circulação Esplâncnica , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Idoso , Doença Crônica , Bases de Dados Factuais , Metabolismo Energético , Feminino , Humanos , Masculino , Isquemia Mesentérica/diagnóstico por imagem , Isquemia Mesentérica/mortalidade , Isquemia Mesentérica/fisiopatologia , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/etiologia , Escores de Disfunção Orgânica , Traumatismo por Reperfusão/diagnóstico , Traumatismo por Reperfusão/mortalidade , Traumatismo por Reperfusão/fisiopatologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Grau de Desobstrução Vascular , Procedimentos Cirúrgicos Vasculares/mortalidadeRESUMO
Acute lung injury induced by intestinal ischemia/reperfusion (I/R) is a relevant clinical condition. Acetylcholine (ACh) and the α7 nicotinic ACh receptor (nAChRα-7) are involved in the control of inflammation. Mice with reduced levels of the vesicular ACh transporter (VAChT), a protein responsible for controlling ACh release, were used to test the involvement of cholinergic signaling in lung inflammation due to intestinal I/R. Female mice with reduced levels of VAChT (VAChT-KDHOM) or wild-type littermate controls (WT) were submitted to intestinal I/R followed by 2 h of reperfusion. Mortality, vascular permeability, and recruitment of inflammatory cells into the lung were investigated. Parts of mice were submitted to ovariectomy (OVx) to study the effect of sex hormones or treated with PNU-282,987 (nAChRα-7 agonist). A total of 43.4% of VAChT-KDHOM-I/R mice died in the reperfusion period compared to 5.2% of WT I/R mice. The I/R increased lung inflammation in both genotypes. In VAChT-KDHOM mice, I/R increased vascular permeability and decreased the release of cytokines in the lung compared to WT I/R mice. Ovariectomy reduced lung inflammation and permeability compared to non-OVx, but it did not avoid mortality in VAChT-KDHOM-I/R mice. PNU treatment reduced lung permeability, increased the release of proinflammatory cytokines and the myeloperoxidase activity in the lungs, and prevented the increased mortality observed in VAChT-KDHOM mice. Cholinergic signaling is an important component of the lung protector response against intestinal I/R injury. Decreased cholinergic signaling seems to increase pulmonary edema and dysfunctional cytokine release that increased mortality, which can be prevented by increasing activation of nAChRα-7.
Assuntos
Intestinos/metabolismo , Edema Pulmonar/metabolismo , Edema Pulmonar/mortalidade , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/mortalidade , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo , Animais , Feminino , Mediadores da Inflamação/metabolismo , Intestinos/irrigação sanguínea , Camundongos , Camundongos Transgênicos , Ovariectomia/efeitos adversos , Ovariectomia/mortalidadeRESUMO
Purpose: The present study aimed to determine whether the administration of Acer palmatum thumb. leaf extract (KIOM-2015E) protects against the degeneration of rat retinal ganglion cells after ischemia/reperfusion (I/R) induced by midbrain cerebral artery occlusion (MCAO). Methods: Sprague-Dawley rats were subjected to 90 min of MCAO, which produces transient ischemia in both the retina and brain due to the use of an intraluminal filament that blocks the ophthalmic and middle cerebral arteries. This was followed by reperfusion under anesthesia with isoflurane. The day after surgery, the eyes were treated three times (eye drop) or one time (oral administration) daily with KIOM-2015E for five days. Retinal histology was assessed in flat mounts and vertical sections to determine the effect of KIOM-2015E on I/R injury. Results: A significant loss of brain-specific homeobox/POU domain protein 3A (Brn3a) and neuron-specific class III beta-tubulin (Tuj-1) fluorescence and a marked increase in glial fibrillary acidic protein (GFAP) and glutamine synthetase (GS) expression were observed after five days in the PBS-treated MCAO group compared to the sham-operated control group. However, KIOM-2015E treatment reduced (1) MCAO-induced upregulation of GFAP and GS, (2) retinal ganglion cell loss, (3) nerve fiber degeneration, and (4) the number of TUNEL-positive cells. KIOM-2015E application also increased staining for parvalbumin (a marker of horizontal cell associated calcium-binding protein and amacrine cells) and recoverin (a marker of photoreceptor expression) in rats subjected to MCAO-induced retinal damage. Conclusions: Our findings indicated that KIOM-2015E treatment exerted protective effects against retinal damage following MCAO injury and that this extract may aid in the development of novel therapeutic strategies for retinal diseases, such as glaucoma and age-related macular disease.
Assuntos
Acer/metabolismo , Apoptose/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Traumatismo por Reperfusão/metabolismo , Degeneração Retiniana/prevenção & controle , Células Ganglionares da Retina/efeitos dos fármacos , Acer/química , Animais , Cromatografia Líquida de Alta Pressão , Regulação para Baixo , Proteína Glial Fibrilar Ácida/metabolismo , Glutamato-Amônia Ligase/metabolismo , Masculino , Fibras Nervosas/patologia , Folhas de Planta/química , Folhas de Planta/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/mortalidade , Degeneração Retiniana/complicações , Degeneração Retiniana/metabolismo , Células Ganglionares da Retina/citologia , Células Ganglionares da Retina/patologia , Fator de Transcrição Brn-3B/metabolismo , Tubulina (Proteína)/metabolismo , Regulação para CimaRESUMO
Orthotopic liver transplantation (OLT) using allografts from donation after circulatory death (DCD) is potentially associated with compromised clinical outcomes due to ischemia-reperfusion injury (IRI)-induced organ damage and graft-related complications. The aim of this study was to provide in vivo data on the effects of adenosine A2a receptor stimulation in a clinically relevant large animal model of DCD liver transplantation. Cardiac arrest was induced in German Landrace pigs (n = 10; 20-25 kg). After 30 min of warm ischemia, the donor liver was retrieved following a cold flush with 3 L of histidine-tryptophan-ketoglutarate-HTK solution. Animals of the treatment group (n = 5/group) received a standard dose of the selective adenosine receptor agonist CGS 21680 added to the cold flush. All grafts were stored for 4.5 h at 4 °C in HTK-solution before OLT. Hepatocellular injury, apoptosis, protein kinase A-PKA activity, graft microcirculation, liver function, and animal survival were assessed. Compared to untreated livers, adenosine A2a receptor stimulation resulted in improved tissue microcirculation (103% ± 5% vs. 38% ± 4% compared to baseline; p < 0.05), accelerated functional recovery of the graft (indocyanine green-plasma disappearance rate (ICG-PDR) of 75% ± 18% vs. 40% ± 30% after 3 h), increased PKA activity ratio (56% ± 3% vs. 32% ± 3%; p < 0.001 after 1 h), and consequently reduced tissue necrosis and apoptosis. The potent protective effects were clinically manifested in significantly improved survival in the treatment group after 72 h (100% vs. 40%; p = 0.04). The ex vivo administration of adenosine A2a receptor agonist during the back-table flush mitigates IRI-mediated tissue damage and improves functional graft recovery and survival in a large animal model of DCD liver transplantation.
Assuntos
Agonistas do Receptor A2 de Adenosina/farmacologia , Transplante de Fígado/mortalidade , Receptor A2A de Adenosina/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/mortalidade , Adenosina/análogos & derivados , Adenosina/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Glucose/farmacologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Doadores Vivos , Manitol/farmacologia , Preservação de Órgãos/métodos , Soluções para Preservação de Órgãos/farmacologia , Fenetilaminas/farmacologia , Cloreto de Potássio/farmacologia , Procaína/farmacologia , Traumatismo por Reperfusão/metabolismo , Suínos , Isquemia Quente/métodosRESUMO
Cardiac ischemia/reperfusion (I/R) injury following reperfusion therapy in acute myocardial infarction results in mitochondrial dynamic imbalance and cardiomyocyte apoptosis. Although diabetic patients taking metformin have been shown to have a lower risk of myocardial infarction, the efficacy of the cardioprotection conferred by metformin regarding the mitochondrial function and dynamic in cardiac I/R injury are still inconclusive. In addition, the comparative effects between different doses of metformin given acutely prior to cardiac I/R injury have never been investigated. Fifty 8-week-old male Wistar rats weighing 300-350 g were divided into sham-operated (n = 10) and cardiac I/R-operated (n = 40) groups. In the cardiac I/R group, rats underwent 30-min ischemia followed by 120-min reperfusion and were randomly divided into four subgroups (n = 10/group): control (received normal saline), metformin (100, 200, and 400 mg/kg). The arrhythmia score, cardiac function, infarct size, mortality rate, mitochondrial function and apoptosis, were determined. Metformin (200 mg/kg) exerted the highest level of cardioprotection through reduction in arrhythmia, infarct size, mitochondrial fission, and apoptosis, in addition to preservation of mitochondrial function, leading to the attenuation of cardiac dysfunction. Doses of metformin (100 and 400 mg/kg) also improved mitochondrial and cardiac function, but to a lesser extent than metformin (200 mg/kg). In conclusion, metformin exerts cardioprotection by attenuating mitochondrial dysfunction, mitochondrial dynamic imbalance, and apoptosis. These led to decreased infarct size and eventual improvement in cardiac function in rats with acute cardiac I/R injury. These findings indicate the potential clinical benefits of acute metformin treatment in acute myocardial infarction.
Assuntos
Cardiotônicos/farmacologia , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Mitocôndrias Cardíacas/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Arritmias Cardíacas/tratamento farmacológico , Testes de Função Cardíaca , Masculino , Dinâmica Mitocondrial/efeitos dos fármacos , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/patologia , Infarto do Miocárdio/prevenção & controle , Traumatismo por Reperfusão Miocárdica/mortalidade , Miócitos Cardíacos/efeitos dos fármacos , Ratos , Ratos Wistar , Traumatismo por Reperfusão/mortalidade , Função Ventricular EsquerdaRESUMO
We compared therapeutic properties of natural and engineered chemokine (C-X-C motif) receptor 4 (CXCR4) agonists in a rat acute respiratory distress syndrome (ARDS) model utilizing the PaO2/FiO2-ratio as a clinically relevant primary outcome criterion. Ventilated rats underwent unilateral lung ischemia from t = 0-70 min plus hemorrhage to a mean arterial blood pressure (MAP) of 30 mmHg from t = 40-70 min, followed by reperfusion/fluid resuscitation until t = 300 min. Natural CXCR4 agonists (CXCL12, ubiquitin) and engineered CXCL12 variants (CXCL121, CXCL22, CXCL12K27A/R41A/R47A, CXCL12 (3-68)) were administered within 5 min of fluid resuscitation. Animals treated with vehicle or CXCL12 (3-68) reached criteria for mild and moderate ARDS between t = 90-120 min and t = 120-180 min, respectively, and remained in moderate ARDS until t = 300 min. Ubiquitin, CXCL12, CXCL121 and CXCL122 prevented ARDS development. Potencies of CXCL12/CXCL121/CXCL122 were higher than the potency of ubiquitin. CXCL12K27A/R41A/R47A was inefficacious. CXCL121 > CXCL12 stabilized MAP and reduced fluid requirements. CXCR4 agonists at doses that preserved lung function reduced histological injury of the post-ischemic lung and reduced mortality from 55 to 9%. Our findings suggest that CXCR4 protein agonists prevent development of ARDS and reduce mortality in a rat model, and that development of new engineered protein therapeutics with improved pharmacological properties for ARDS is possible.
Assuntos
Receptores CXCR4/agonistas , Traumatismo por Reperfusão/prevenção & controle , Síndrome do Desconforto Respiratório/prevenção & controle , Ressuscitação/métodos , Choque Hemorrágico/terapia , Ferimentos e Lesões/terapia , Animais , Quimiocina CXCL12/administração & dosagem , Quimiocina CXCL12/genética , Modelos Animais de Doenças , Hidratação/métodos , Humanos , Pulmão/irrigação sanguínea , Pulmão/patologia , Masculino , Engenharia de Proteínas , Ratos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/mortalidade , Traumatismo por Reperfusão/patologia , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/mortalidade , Síndrome do Desconforto Respiratório/patologia , Choque Hemorrágico/etiologia , Choque Hemorrágico/mortalidade , Choque Hemorrágico/patologia , Toracotomia/efeitos adversos , Ubiquitina/administração & dosagem , Ferimentos e Lesões/complicações , Ferimentos e Lesões/mortalidadeRESUMO
OBJECTIVE: To explore clinical outcomes in older adults with acute ischemic stroke treated with endovascular thrombectomy (EVT). METHODS: We included consecutive patients (2014-2016) with an anterior circulation occlusion undergoing EVT from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry. We assessed the effect of age (dichotomized at ≥80 years and as continuous variable) on the modified Rankin Scale (mRS) score at 90 days, symptomatic intracranial hemorrhage (sICH), and reperfusion rate. The association between age and mRS was assessed with multivariable ordinal logistic regression, and a multiplicative interaction term was added to the model to assess modification of reperfusion by age on outcome. RESULTS: Of the 1,526 patients, 380 (25%) were ≥80 years of age (referred to here as older adults). Older adults had a worse functional outcome than younger patients (adjusted common odds ratio [acOR] for an mRS score shift toward better outcome 0.31, 95% confidence interval [CI] 0.24-0.39). Mortality was also higher in older adults (51% vs 22%, adjusted odds ratio 3.12, 95% CI 2.33-4.19). There were no differences in proportion of patients with mRS scores of 4 to 5, sICH, or reperfusion rates. Successful reperfusion was more strongly associated with a shift toward good functional outcome in older adults than in younger patients (acOR 3.22, 95% CI 2.04-5.10 vs 2.00, 95% CI 1.56-2.57, p interaction = 0.026). CONCLUSION: Older age is associated with an increased absolute risk of poor clinical outcome, while the relative benefit of successful reperfusion seems to be higher in these patients. These results should be taken into consideration in the selection of older adults for EVT.
Assuntos
Isquemia Encefálica/cirurgia , Procedimentos Endovasculares/estatística & dados numéricos , Acidente Vascular Cerebral/cirurgia , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/mortalidade , Procedimentos Endovasculares/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Traumatismo por Reperfusão/epidemiologia , Traumatismo por Reperfusão/mortalidade , Acidente Vascular Cerebral/mortalidade , Trombectomia/métodos , Resultado do Tratamento , Adulto JovemRESUMO
Necroptosis is crucially involved in severe cardiac pathological conditions. However, whether necroptosis contributes to age-related intolerance to ischemia/reperfusion (I/R) injury remains elusive. In addition, metformin as a potential anti-aging related injury drug, how it interacts with myocardial necroptosis is not yet clear. Male C57BL/6 mice at 3-4- (young) and 22-24 months of age (aged) and RIPK3-deficient (Ripk3-/- ) mice were used to investigate aging-related I/R injury in vivo. Metformin (125 µg/kg, i.p.), necrostatin-1 (3.5 mg/kg), and adenovirus vector encoding p62-shRNAs (Ad-sh-p62) were used to treat aging mice. I/R-induced myocardial necroptosis was exaggerated in aged mice, which correlated with autophagy defects characterized by p62 accumulation in aged hearts or aged human myocardium. Functionally, blocking autophagic flux promoted H/R-evoked cardiomyocyte necroptosis in vitro. We further revealed that p62 forms a complex with RIP1-RIP3 (necrosome) and promotes the binding of RIP1 and RIP3. In mice, necrostatin-1 treatment (a RIP1 inhibitor), RIP3 deficiency, and cardiac p62 knockdown in vivo demonstrated that p62-RIP1-RIP3-dependent myocardial necroptosis contributes to aging-related myocardial vulnerability to I/R injury. Notably, metformin treatment disrupted p62-RIP1-RIP3 complexes and effectively repressed I/R-induced necroptosis in aged hearts, ultimately reducing mortality in this model. These findings highlight previously unknown mechanisms of aging-related myocardial ischemic vulnerability: p62-necrosome-dependent necroptosis. Metformin acts as a cardioprotective agent that inhibits this unfavorable chain mechanism of aging-related I/R susceptibility.
Assuntos
Envelhecimento/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Metformina/uso terapêutico , Necroptose/efeitos dos fármacos , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Envelhecimento/patologia , Animais , Autofagia/genética , Proteínas Ativadoras de GTPase/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Indóis/farmacologia , Indóis/uso terapêutico , Masculino , Metformina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Necroptose/genética , Ligação Proteica , RNA Interferente Pequeno , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/mortalidade , Proteína Sequestossoma-1/genética , Proteína Sequestossoma-1/metabolismoRESUMO
Reperfusion of the ischemic intestine often leads to drive distant organ injury, especially injuries associated with hepatocellular dysfunction. The precise molecular mechanisms and effective multiple organ protection strategies remain to be developed. In the current study, significant remote liver dysfunction was found after 6 hours of reperfusion according to increased histopathological scores, serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels, as well as enhanced bacterial translocation in a rat intestinal ischemia/reperfusion (I/R) injury model. Moreover, receptor-interacting protein kinase 1/3 (RIP1/3) and phosphorylated-MLKL expressions in tissue were greatly elevated, indicating that necroptosis occurred and resulted in acute remote liver function impairment. Inhibiting the necroptotic pathway attenuated HMGB1 cytoplasm translocation and tissue damage. Meanwhile, macrophage-depletion study demonstrated that Kupffer cells (KCs) are responsible for liver damage. Blocking HMGB1 partially restored the liver function via suppressed hepatocyte necroptosis, tissue inflammation, hepatic KCs, and circulating macrophages M1 polarization. What's more, HMGB1 neutralization further protects against intestinal I/R-associated liver damage in microbiota-depleted rats. Therefore, intestinal I/R is likely associated with acute liver damage due to hepatocyte necroptosis, and which could be ameliorated by Nec-1 administration and HMGB1 inhibition with the neutralizing antibody and inhibitor. Necroptosis inhibition and HMGB1 neutralization/inhibition, may emerge as effective pharmacological therapies to minimize intestinal I/R-induced acute remote organ dysfunction.
Assuntos
Intestinos/patologia , Células de Kupffer/metabolismo , Fígado/metabolismo , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/metabolismo , Animais , Western Blotting , Polaridade Celular/fisiologia , Citometria de Fluxo , Imunofluorescência , Proteína HMGB1/sangue , Hepatócitos/metabolismo , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Marcação In Situ das Extremidades Cortadas , Inflamação/sangue , Inflamação/metabolismo , Lipopolissacarídeos/sangue , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/mortalidade , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND AND OBJECTIVES: Delayed graft function is related to ischemia-reperfusion injury and may be complement dependent. We previously reported from a randomized, placebo-controlled trial that treatment with C1 esterase inhibitor was associated with a shorter duration of delayed graft function and higher eGFR at 1 year. Here, we report longer-term outcomes from this trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This is a post hoc analysis of a phase 1/2, randomized, controlled trial enrolling 70 recipients of deceased donor kidney transplants at risk for delayed graft function (NCT02134314). Subjects were randomized to receive C1 esterase inhibitor 50 U/kg (n=35) or placebo (n=35) intraoperatively and at 24 hours. The cumulative incidence functions method was used to compare graft failure and death over 3.5 years. eGFR slopes were compared using a linear mixed effects model. RESULTS: Three deaths occurred among C1 esterase inhibitor-treated patients compared with none receiving placebo. Seven graft failures developed in the placebo group compared with one among C1 esterase inhibitor-treated recipients; the cumulative incidence of graft failure was lower over 3.5 years among C1 esterase inhibitor-treated recipients compared with placebo (P=0.03). Although no difference in eGFR slopes was observed between groups (P for group-time interaction =0.12), eGFR declined in placebo-treated recipients (-4 ml/min per 1.73 m2 per year; 95% confidence interval, -8 to -0.1) but was stable in C1 esterase inhibitor-treated patients (eGFR slope: 0.5 ml/min per 1.73 m2 per year; 95% confidence interval, -4 to 5). At 3.5 years, eGFR was 56 ml/min per 1.73 m2 (95% confidence interval, 42 to 70) in the C1 esterase inhibitor group versus 35 ml/min per 1.73 m2 (95% confidence interval, 21 to 48) in the placebo group, with an estimated mean eGFR difference of 21 ml/min per 1.73 m2 (95% confidence interval, 2 to 41 ml/min per 1.73 m2). CONCLUSIONS: Treatment of patients at risk for ischemia-reperfusion injury and delayed graft function with C1 esterase inhibitor was associated with a lower incidence of graft failure.
Assuntos
Proteína Inibidora do Complemento C1/uso terapêutico , Função Retardada do Enxerto/prevenção & controle , Taxa de Filtração Glomerular/efeitos dos fármacos , Transplante de Rim , Rim/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Adulto , Proteína Inibidora do Complemento C1/efeitos adversos , Função Retardada do Enxerto/etiologia , Função Retardada do Enxerto/mortalidade , Função Retardada do Enxerto/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Incidência , Rim/fisiopatologia , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/mortalidade , Traumatismo por Reperfusão/fisiopatologia , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Nitric oxide (NO) deficiency is known to play a role in renal ischaemia/reperfusion injury; therefore, kidney-targeting NO donor is expected to prevent renal ischaemia/reperfusion injury. We therefore developed an S-nitrosylated L-serine-modified polyamidoamine dendrimer (SNO-Ser-PAMAM), in which multiple S-nitrosothiols (NO donors) were covalently bound to L-serine-modified dendrimer, as a kidney-targeting NO donor. In the pharmacokinetic study, approximately 76% of 111In-SNO-Ser-PAMAM accumulated in the kidney after intravenous injection in mice. Furthermore, single photon emission computed tomography/computed tomography (SPECT/CT) imaging study showed that 111In-SNO-Ser-PAMAM specifically accumulated in the renal cortex after intravenous injection. SNO-Ser-PAMAM gradually released NO over a day in plasma, indicating that SNO-Ser-PAMAM would show sustained release of NO in vivo. In a mouse model of renal ischaemia/reperfusion injury, increased plasma creatinine, a kidney damage marker, and histological changes were effectively inhibited by intravenous administration of SNO-Ser-PAMAM. These results indicate that SNO-Ser-PAMAM is a promising kidney-targeting NO donor for the efficient prevention of renal ischaemia/reperfusion injury.
Assuntos
Dendrímeros/metabolismo , Rim/patologia , Doadores de Óxido Nítrico/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/prevenção & controle , Animais , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Doadores de Óxido Nítrico/farmacologia , Traumatismo por Reperfusão/mortalidade , Análise de SobrevidaRESUMO
The incidence of stroke recurrence is still higher despite the advanced progression of therapeutic treatment and medical technology. Low intensity pulsed ultrasound (LIPUS) has been demonstrated to possess therapeutic effects on neuronal diseases and stroke via brain-derived neurotrophic factor (BDNF) induction. In this study, we hypothesized that LIPUS treatment possessed therapeutic benefits for the improvement of stroke recurrence. Adult male C57BL/6J mice were subjected to a middle cerebral artery occlusion (MCAO) surgery and then followed to secondary MCAO surgery as a stroke recurrence occurred after nine days from the first MCAO. LIPUS was administered continuously for nine days before secondary MCAO. LIPUS treatment not only decreased the mortality but also significantly moderated neuronal function injury including neurological score, motor activity, and brain pathological score in the recurrent stroke mice. Furthermore, the administration of LIPUS attenuated the apoptotic neuronal cells and increased Bax/Bcl-2 protein expression ratio and accelerated the expression of BDNF in the brain of the recurrent stroke mice. Taken together, these results demonstrate for the first time that LIPUS treatment arouses the expression of BDNF and possesses a therapeutic benefit for the improvement of stroke recurrence in a mouse model. The neuroprotective potential of LIPUS may provide a useful strategy for the prevention of a recurrent stroke.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/administração & dosagem , Traumatismo por Reperfusão/prevenção & controle , Traumatismo por Reperfusão/terapia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Terapia por Ultrassom , Ondas Ultrassônicas , Animais , Apoptose/efeitos dos fármacos , Apoptose/efeitos da radiação , Biomarcadores , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Camundongos , Atividade Motora , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/mortalidade , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/terapiaRESUMO
Progenitor/stem cell-based kidney regenerative strategies are a key step towards the development of novel therapeutic regimens for kidney disease treatment. However, the route of cell delivery, e.g., intravenous, intra-arterial, or intra-parenchymal, may affect the efficiency for kidney repair in different models of acute and chronic injury. Here, we describe a protocol of intra-aorta progenitor/stem cell injection in rats following either acute ischemia-reperfusion injury or acute proteinuria induced by puromycin aminonucleoside (PAN) - the experimental prototype of human minimal change disease and early stages of focal and segmental glomerulosclerosis. Vascular clips were applied across both renal pedicles for 35 min, or a single dose of PAN was injected via intra-peritoneal route, respectively. Subsequently, 2 x 106 stem cells [green fluorescent protein (GFP)-labeled c-Kit+ progenitor/stem cells or GFP-mesenchymal stem cells] or saline were injected into the suprarenal aorta, above the renal arteries, after application of a vascular clip to the abdominal aorta below the renal arteries. This approach contributed to engraftment rates of â¼10% at day 8 post ischemia-reperfusion injury, when c-Kit+ progenitor/stem cells were injected, which accelerated kidney recovery. Similar rates of engraftment were found after PAN-induced podocyte damage at day 21. With practice and gentle surgical technique, 100% of the rats could be injected successfully, and, in the week following injection, â¼ 85% of the injected rats will recover completely. Given the similarities in mammals, much of the data obtained from intra-arterial delivery of progenitor/stem cells in rodents can be tested in translational research and clinical trials with endovascular catheters in humans.
Assuntos
Injúria Renal Aguda/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Proteinúria/terapia , Traumatismo por Reperfusão/terapia , Doença Aguda/terapia , Injúria Renal Aguda/mortalidade , Animais , Feminino , Proteinúria/induzido quimicamente , Proteinúria/mortalidade , Puromicina Aminonucleosídeo , Ratos , Regeneração , Artéria Renal , Traumatismo por Reperfusão/mortalidade , Procedimentos Cirúrgicos Vasculares/métodos , Fluxo de TrabalhoRESUMO
Peroxiredoxin 6 (Prx6) is an important antioxidant enzyme with various functions in the cell. Prx6 reduces a wide range of peroxide substrates, playing a leading role in maintaining the redox homeostasis of mammalian cells. In addition to the peroxidase activity, a phospholipase A2-like activity was demonstrated for Prx6, which plays an important role in the metabolism of membrane phospholipids. Besides that, due to its peroxidase and phospholipase activities, Prx6 participates in intracellular and intercellular signal transduction, thus triggering regenerative processes in the cell, suppressing apoptosis caused by various factors, including ischemia-reperfusion injuries. A nephroprotective effect of exogenous recombinant Prx6 administered before ischemia-reperfusion injury was demonstrated on an animal model. Exogenous Prx6 effectively alleviates the severeness of renal ischemia-reperfusion injuries and facilitates normalization of their structural and functional conditions. Infusion of exogenous Prx6 increases the survival rate of experimental animals by almost 3 times. Application of exogenous Prx6 can be an effective approach in the prevention and treatment of renal ischemia-reperfusion kidney lesions and in preserving isolated kidneys during transplantation.
Assuntos
Rim , Estresse Oxidativo/efeitos dos fármacos , Peroxirredoxina VI/farmacologia , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Modelos Animais de Doenças , Rim/efeitos dos fármacos , Rim/patologia , Camundongos Endogâmicos BALB C , Proteínas Recombinantes/farmacologia , Traumatismo por Reperfusão/mortalidade , Taxa de SobrevidaRESUMO
BACKGROUND: Ischemia-reperfusion injury may compromise the short-term and long-term prognosis after heart transplantation. Experimental studies show that simvastatin administered to the organ donor is vasculoprotective and inhibits cardiac allograft ischemia-reperfusion injury. METHODS: Eighty-four multiorgan donors were randomly assigned to receive 80 mg of simvastatin (42 donors) via nasogastric tube after declaration of brain death and upon acceptance as a cardiac donor, or to receive no simvastatin (42 donors). The primary efficacy end point was postoperative plasma troponin T and I levels during the first 24 hours after heart transplantation. Secondary end points included postoperative hemodynamics, inflammation, allograft function, rejections and rejection treatments, and mortality. Results: Organ donor simvastatin treatment significantly reduced the heart recipient plasma levels of troponin T by 34% (14 900 ± 12 100 ng/L to 9800 ± 7900 ng/L, P=0.047), and troponin I by 40% (171 000 ± 151 000 ng/L to 103 000 ± 109 000 ng/L, P=0.023) at 6 hours after reperfusion, the levels of NT-proBNP (N-terminal pro-B-type natriuretic peptide) by 36% (32 800 ± 24 300 ng/L to 20 900 ± 15 900 ng/L; P=0.011) at 1 week, and the number of rejection treatments with hemodynamic compromise by 53% within the first 30 days (P=0.046). Donor simvastatin treatment did not affect donor lipid levels but was associated with a specific transplant myocardial biopsy gene expression profile, and a decrease in recipient postoperative plasma levels of CXCL10 (C-X-C motif chemokine 10), interleukin-1α, placental growth factor, and platelet-derived growth factor-BB. Postoperative hemodynamics, biopsy-proven acute rejections, and mortality were similar. No adverse effects were seen in recipients receiving noncardiac solid organ transplants from simvastatin-treated donors. CONCLUSIONS: Donor simvastatin treatment reduces biomarkers of myocardial injury after heart transplantation, and-also considering its documented general safety profile-may be used as a novel, safe, and inexpensive adjunct therapy in multiorgan donation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01160978.
Assuntos
Aloenxertos/efeitos dos fármacos , Rejeição de Enxerto/tratamento farmacológico , Transplante de Coração , Inflamação/tratamento farmacológico , Traumatismo por Reperfusão/tratamento farmacológico , Sinvastatina/uso terapêutico , Adolescente , Adulto , Idoso , Quimiocina CXCL10/sangue , Método Duplo-Cego , Feminino , Rejeição de Enxerto/mortalidade , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Traumatismo por Reperfusão/mortalidade , Doadores de Tecidos , Transplante Homólogo , Troponina T/sangue , Adulto JovemRESUMO
Renal ischemia reperfusion injury (IRI) adversely affects clinical outcomes following kidney transplantation. Understanding the cellular mechanisms and the changes in gene/protein expression following IRI may help to improve these outcomes. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), a circulating antiangiogenic protein, is increased in the first week following kidney transplantation. We evaluated the casual relationship of elevated sFlt-1 levels with renal microvascular dysfunction following IRI in a longitudinal study of 93 kidney transplant recipients and in several animal models. Transplant recipients with higher sFlt-1 levels had higher odds of delayed graft function, graft rejection, impaired graft function, and death. In a subgroup of 25 participants who underwent kidney biopsy within 4 months of kidney transplantation, peritubular capillary area was lower in those with elevated serum sFtl-1 levels. The administration of recombinant sFlt-1 into rodents resulted in significant structural and functional changes of the renal microvasculature, including reduced peritubular capillary density and intracapillary blood volume, and lead to increased expression of inflammatory genes and increased fibrosis. In a murine model of IRI, the kidney was a site of sFlt-1 production, and systemic neutralization of sFlt-1 preserved peritubular capillary density and alleviated renal fibrosis. Our data indicate that high sFlt-1 levels after IRI play an important role in the pathogenesis of microvascular dysfunction, thereby contributing to adverse clinical outcomes following kidney transplantation.
Assuntos
Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Traumatismo por Reperfusão/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Aloenxertos/irrigação sanguínea , Aloenxertos/patologia , Animais , Biópsia , Capilares/patologia , Linhagem Celular , Estudos de Coortes , Função Retardada do Enxerto/sangue , Função Retardada do Enxerto/etiologia , Função Retardada do Enxerto/mortalidade , Modelos Animais de Doenças , Feminino , Fibrose , Rejeição de Enxerto/sangue , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/mortalidade , Humanos , Rim/irrigação sanguínea , Rim/patologia , Falência Renal Crônica/mortalidade , Estudos Longitudinais , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/mortalidade , Resultado do Tratamento , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/administração & dosagemRESUMO
Rapid onset of acute inflammation is a hallmark of critical illnesses that bring patients to the intensive care unit (ICU). In critical illness, innate T cells rapidly reach full activation and drive a robust acute inflammatory response. As "cellular adjuvants," innate T cells worsen inflammation and mortality in several common critical illnesses including sepsis, ischemia-reperfusion injury, stroke, and exacerbations of respiratory disease. Interestingly, innate T cell subsets can also promote a protective and anti-inflammatory response in sepsis, ischemia-reperfusion injury, and asthma. Therapies that target innate T cells have been validated in several models of critical illness. Here, we review the role of natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) cells and γδ T cells in clinical and experimental critical illness.
Assuntos
Asma , Imunidade Inata , Unidades de Terapia Intensiva , Células T Matadoras Naturais , Traumatismo por Reperfusão , Sepse , Asma/imunologia , Asma/mortalidade , Asma/patologia , Asma/terapia , Humanos , Células T Matadoras Naturais/imunologia , Células T Matadoras Naturais/patologia , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/mortalidade , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/terapia , Sepse/imunologia , Sepse/mortalidade , Sepse/patologia , Sepse/terapiaRESUMO
Mesenteric ischemia is a surgical emergency caused by a transient reduction in blood perfusion to the bowel. Despite accounting for only 0.1% of hospital admissions and 1-2% of gastrointestinal diseases, its elusive symptoms often lead to dramatically high morbidity and mortality rates. The complex cascade of inflammatory events and mediators triggered by mesenteric ischemia-reperfusion (I/R) accounts for the plethora of proposed pharmacological targets and for the current lack of an efficacious drug strategy for its management. It is hoped that a deeper understanding of its pathogenesis and the preclinical therapeutic strategies identified to date and described herein will improve the translation into the clinical setting of the pharmacological armamentarium against a life-threatening disorder that is currently mainly managed surgically.