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1.
J Surg Res ; 246: 568-583, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31653415

RESUMO

BACKGROUND: Coagulation disturbances in several liver diseases lead to thrombin generation, which triggers intracellular injury via activation of protease-activated receptor-1 (PAR-1). Little is known about the thrombin/PAR-1 pathway in hepatic ischemia-reperfusion injury (IRI). The present study aimed to clarify whether a newly selective PAR-1 antagonist, vorapaxar, can attenuate liver damage caused by hepatic IRI, with a focus on apoptosis and the survival-signaling pathway. METHODS: A 60-min hepatic partial-warm IRI model was used to evaluate PAR-1 expression in vivo. Subsequently, IRI mice were treated with or without vorapaxar (with vehicle). In addition, hepatic sinusoidal endothelial cells (SECs) pretreated with or without vorapaxar (with vehicle) were incubated during hypoxia-reoxygenation in vitro. RESULTS: In naïve livers, PAR-1 was confirmed by immunohistochemistry and immunofluorescence analysis to be located on hepatic SECs, and IRI strongly enhanced PAR-1 expression. In IRI mice models, vorapaxar treatment significantly decreased serum transaminase levels, improved liver histological damage, reduced the number of apoptotic cells as evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling staining (median: 135 versus 25, P = 0.004), and induced extracellular signal-regulated kinase 1/2 (ERK 1/2) cell survival signaling (phospho-ERK/total ERK 1/2: 0.96 versus 5.34, P = 0.004). Pretreatment of SECs with vorapaxar significantly attenuated apoptosis and induced phosphorylation of ERK 1/2 in vitro (phospho-ERK/total ERK 1/2: 0.66 versus 3.04, P = 0.009). These changes were abolished by the addition of PD98059, the ERK 1/2 pathway inhibitor, before treatment with vorapaxar. CONCLUSIONS: The results of the present study revealed that hepatic IRI induces significant enhancement of PAR-1 expression on SECs, which may be associated with suppression of survival signaling pathways such as ERK 1/2, resulting in severe apoptosis-induced hepatic damage. Thus, the selective PAR-1 antagonist attenuates hepatic IRI through an antiapoptotic effect by the activation of survival-signaling pathways.


Assuntos
Apoptose/efeitos dos fármacos , Lactonas/administração & dosagem , Fígado/irrigação sanguínea , Piridinas/administração & dosagem , Receptor PAR-1/antagonistas & inibidores , Traumatismo por Reperfusão/prevenção & controle , Animais , Modelos Animais de Doenças , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Receptor PAR-1/metabolismo , Traumatismo por Reperfusão/etiologia , Trombina/metabolismo
2.
J Surg Res ; 246: 512-518, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31630883

RESUMO

BACKGROUND: Acute mesenteric ischemia carries a significant morbidity. Measures to improve blood flow parameters to the intestine may ameliorate the disease. Sildenafil, a phosphodiesterase 5 inhibitor, increases cyclic guanosine monophosphate and has been shown to prevent the effects of ischemia when given before injury. However, its effects as a rescue agent have not been established. We therefore hypothesized that sildenafil, when given as a rescue agent for intestinal ischemia, would improve mesenteric perfusion, limit intestinal epithelial injury, and decrease intestinal leukocyte chemoattractants. METHODS: Eight to 12 wk-old-male C57BL/6J mice underwent laparotomy and temporary occlusion of the superior mesenteric artery for 60 min. Following ischemia, reperfusion was permitted, and before closing the abdomen, sildenafil was injected intraperitoneally in a variety of concentrations. After 24 h, reperfusion was reassessed. Animals were euthanized and intestines evaluated for histologic injury and leukocyte chemoattractants. RESULTS: Postischemic administration of sildenafil did not improve mesenteric perfusion following intestinal ischemia and reperfusion injury. However, sildenafil did improve histologic injury scores in dose ranges of 0.01 to 10 mg/kg. No difference was noted in histological injury with 100 mg/kg dose, and all members of the 1000 mg/kg group died within 24 h of injury. Epithelial protection was not facilitated by the leukocyte chemoattractants Regulated on Activation, Normal T Cell Expressed, and Secreted, macrophage inflammatory protein 1 alpha, monocyte chemoattractant protein, neutrophil activating protein, or granulocyte colony stimulating factor. CONCLUSIONS: Administration of sildenafil following intestinal ischemia may limit intestinal mucosal injury but does not appear to alter mesenteric perfusion or leukocyte chemoattractant influx. TYPE: Basic science. LEVEL OF EVIDENCE: N/A.


Assuntos
Mucosa Intestinal/irrigação sanguínea , Isquemia Mesentérica/tratamento farmacológico , Inibidores da Fosfodiesterase 5/administração & dosagem , Traumatismo por Reperfusão/tratamento farmacológico , Citrato de Sildenafila/administração & dosagem , Animais , Modelos Animais de Doenças , Humanos , Injeções Intraperitoneais , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Masculino , Artéria Mesentérica Superior/cirurgia , Isquemia Mesentérica/complicações , Mesentério/irrigação sanguínea , Mesentério/efeitos dos fármacos , Camundongos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Resultado do Tratamento
3.
Life Sci ; 241: 117160, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31837331

RESUMO

AIMS: Theanine, as a naturally occurring component in tea, has been shown to deliver benefits against various diseases. However, the exact molecular mechanisms underlying theanine's protective actions against cerebral ischemia/reperfusion (IR) injury still remains largely unknown. MAIN METHODS: In this study, rat cerebral IR injury model was established and were randomly divided into the following five groups: Sham (SH), IR, IR + Theanine (TH), IR + TH+ heme oxygenase-1 (HO-1) inducer cobalt protoporphyrin (Copp), and IR + Copp groups. KEY FINDINGS: We found that theanine significantly inhibited neuron damage and apoptosis in the hippocampus during the 48 h detection period, as detected by hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. Meanwhile, reduced levels of malondialdehyde (MDA) and elevated activities of superoxide dismutase (SOD), glutathione (GSH), and glutathione peroxidase (GSH-PX) were observed in the theanine-treated group. Enzyme-linked immunosorbent (ELISA) assay also revealed that theanine markedly decreased the levels of inflammatory cytokines, such as IL-6, IL-1ß, and TNF-α, in IR rats. The anti-apoptotic effect of theanine on IR injury was further verified by flow cytometry assay. Besides, theanine dramatically inhibited HO-1 expression and activity but increased extracellular signal-regulated kinase 1/2 (ERK1/2) activity in hippocampal tissue from rats with cerebral IR injury. However, co-treatment with Copp remarkably abolished the protective effects of theanine on cerebral IR injury. SIGNIFICANCE: These findings demonstrated that the neuroprotective role of theanine was associated with its anti-oxidative, anti-inflammatory, and anti-apoptotic properties, which might be through regulation of HO-1 activation in rats with cerebral IR injury.


Assuntos
Isquemia Encefálica/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Glutamatos/farmacologia , Heme Oxigenase (Desciclizante)/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Traumatismo por Reperfusão/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia
4.
Exp Mol Pathol ; 111: 104325, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31669130

RESUMO

BACKGROUND: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) has been reported to be critical in the onset and progression of acute myocardial ischemia (AMI). This study attempted to reveal the biological function of MALAT1 in AMI. METHODS: Expression of MALAT1 in H9c2 cells was silenced by shRNA-mediated transfection, following which cells were suffered from oxygen-glucose deprivation and reperfusion (OGD/R). CCK-8, flow cytometry and western blot were carried out to evaluate the effects of MALAT1 against OGD/R injury. Further, the correlation between MALAT1, miR-122 and AKT/GSK-3ß/ß-catenin signaling was studied to decode the underlying mechanisms. RESULTS: MALAT1 expression was highly expressed following OGD/R. Suppression of MALAT1 attenuated OGD/R-induced cardiomyocyte apoptosis, as evidenced by the increase of cell viability and the decrease of apoptosis rate. Besides that, miR-122 was found to be positive regulated by MALAT1. The protective effects of MALAT1 knockdown were flattened by miR-122 overexpression. Furthermore, AKT/GSK-3ß/ß-catenin signaling was activated by MALAT1 knockdown. The effects of MALAT1 knockdown on the signaling were flattened when miR-122 was overexpressed. CONCLUSION: Our finding revealed protective effects of MALAT1 knockdown on OGD/R induced cardiomyocyte apoptosis. MALAT1 exerted its function possibly through regulating AKT/GSK-3ß/ß-catenin signaling through up-regulating miR-122.


Assuntos
Apoptose/efeitos dos fármacos , Glucose/deficiência , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos , Oxigênio/toxicidade , RNA Longo não Codificante/genética , Traumatismo por Reperfusão/prevenção & controle , Animais , Sobrevivência Celular , Células Cultivadas , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos , Ratos Wistar , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais
5.
Medicine (Baltimore) ; 98(48): e18244, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31770287

RESUMO

BACKGROUND: We investigated the effects of propofol vs desflurane on ischemia and reperfusion injury (IRI)-induced inflammatory responses, especially in matrix metalloproteinase-9 (MMP-9) downregulation and heme oxygenase-1 (HO-1) upregulation, which may result in different clinical outcomes in liver transplant recipients. METHODS: Fifty liver transplant recipients were randomized to receive propofol-based total intravenous anesthesia (TIVA group, n = 25) or desflurane anesthesia (DES group, n = 25). We then measured the following: perioperative serum cytokine concentrations (interleukin 1 receptor antagonist [IL-1RA], IL-6, IL-8, and IL-10); MMP-9 and HO-1 mRNA expression levels at predefined intervals. Further, postoperative outcomes were compared between the 2 groups. RESULTS: The TIVA group showed a significant HO-1 level increase following the anhepatic phase and a significant MMP-9 reduction after reperfusion, in addition to a significant increase in IL-10 levels after the anhepatic phase and IL-1RA levels after reperfusion. Compared to DES patients, TIVA patients showed a faster return of the international normalized ratio to normal values, lower plasma alanine aminotransferase concentrations 24 hours after transplantation, and fewer patients developing acute lung injury. Moreover, compared with DES patients, TIVA patients showed a significant reduction in serum blood lactate levels. However, there were no differences in postoperative outcomes between the two groups. CONCLUSION: Propofol-based TIVA attenuated inflammatory response (elevated IL-1RA and IL-10 levels), downregulated MMP-9 response, and increased HO-1 expression with improved recovery of graft function and better microcirculation compared with desflurane anesthesia in liver transplant recipients.


Assuntos
Desflurano , Transplante de Fígado , Propofol , Traumatismo por Reperfusão , Adulto , Anestésicos Inalatórios/administração & dosagem , Anestésicos Inalatórios/efeitos adversos , Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/efeitos adversos , Desflurano/administração & dosagem , Desflurano/efeitos adversos , Feminino , Heme Oxigenase-1/análise , Humanos , Proteína Antagonista do Receptor de Interleucina 1/análise , Interleucina-10/análise , Transplante de Fígado/efeitos adversos , Transplante de Fígado/métodos , Masculino , Metaloproteinase 9 da Matriz/análise , Período Pós-Operatório , Propofol/administração & dosagem , Propofol/efeitos adversos , Traumatismo por Reperfusão/sangue , Traumatismo por Reperfusão/etiologia , Imunologia de Transplantes
6.
Scand J Trauma Resusc Emerg Med ; 27(1): 104, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31752982

RESUMO

BACKGROUND: Tourniquet is the most widely used and effective first-aid equipment for controlling hemorrhage of injured limb in battlefield. However, time-out application of tourniquets leads to ischemic-necrosis of skeletal muscles and ischemia-reperfusion injury. Regional hypothermia (RH) on wounded limb can relieve the injury on local tissue and distant organs. We aimed to investigate the protective effects of RH on rabbits' limbs injured by a steel-ball combined with hemorrhagic-shock, and then employed tourniquet over-time, tried to identify the optimal treatment RH. METHODS: Thirty rabbits were randomly divided into 5 groups. All rabbits were anesthetized, intubated femoral artery and vein in right-hind limbs. Sham operation group (Sham): only femoral arteriovenous cannula in right-hind limb. None RH group (NRH): rabbits were intubated as Sham group, then the soft tissues of rabbits' left-hinds were injured by a steel-ball shooting, and were exsanguinated until shock, then bundled with rubber tourniquets for 4 h. Three RH subgroups: rabbits were injured as mentioned above, the injured limbs were bundled with rubber tourniquets and treated with different temperature (5 ± 1 °C, 10 ± 1 °C, and 20 ± 1 °C, respectively) for 4 h. The injury severity of lung and regional muscle was assessed by histologic examination. Activity of adenosine triphosphatase (ATPase) and content of malondialdehyde (MDA) in muscle, inflammatory cytokines, myoglobin, creatine kinase-MM (CK-MM), Heme, Heme oxygenase 1 (HO-1), lactic acid (Lac), and lectrolyte ion in serum were detected. RESULTS: Following with RH treatment, the injury of lung and local muscle tissue was alleviated evidencing by mitigation of histopathological changes, significant decrease of water-content and MDA content, and increase of ATPase activity. Lower level of Lac, Potassium (K+), inflammatory cytokines, Heme, CK-MM, myoglobin content, and higher level of Calcium (Ca2+), HO-1 content were shown in RH treatment. 10 °C was the most effective RH to increase ATPase activity, and decrease MDA, myoglobin, CK-MM content. CONCLUSION: Transient RH (4 h) had a "long-term mitigation effects" (continued for 6 h) on time-out application of tourniquet with the fluid resuscitation and core temperature maintenance, and the most effective temperature for reducing the side effects on tourniquet time-out application was 10 °C.


Assuntos
Hipotermia Induzida , Extremidade Inferior/irrigação sanguínea , Músculo Esquelético/irrigação sanguínea , Traumatismo por Reperfusão/prevenção & controle , Adenosina Trifosfatases/metabolismo , Animais , Gasometria , Citocinas/sangue , Modelos Animais de Doenças , Pulmão/patologia , Lesão Pulmonar/prevenção & controle , Malondialdeído/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Coelhos , Traumatismo por Reperfusão/etiologia , Choque Hemorrágico/complicações , Torniquetes
7.
Molecules ; 24(19)2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31597329

RESUMO

The neuroprotective role of schizandrin (SA) in cerebral ischemia-reperfusion (I/R) was recently highlighted. However, whether SA plays a regulatory role on autophagy in cerebral I/R injury is still unclear. This study aimed to explore whether the neuroprotective mechanisms of SA were linked to its regulation of AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR)/autophagy pathway in vivo and in vitro. The present study confirmed that SA significantly improved oxygen-glucose deprivation/re-oxygenation (OGD/R)-induced PC12 cells injury. The results of immunoblotting and confocal microscope showed that SA decreased autophagy in OGD/R-injured PC12 cells, which was reflected by the decreased Beclin-1 and LC3-II expression, autophagy flux level, and LC3 puncta formation. In addition, the autophagy inducer rapamycin partially prevented the effects of SA on cell viability and autophagy after OGD/R, whereas the autophagy inhibitor 3-methyladenine (3-MA) exerted the opposite effect. The results of Western blotting showed that SA markedly decreased the phosphorylation of AMPK (p-AMPK), whereas the phosphor-mTOR (p-mTOR) levels increased in the presence of OGD/R insult. Furthermore, pretreatment with the AMPK inducer AICAR partially reversed the protective effects and autophagy inhibition of SA. However, AMPK inhibitor Compound C pretreatment further promoted the inhibition of SA on autophagy induction and cell damage induced by OGD/R. Taken together, these findings demonstrate that SA protects against OGD/R insult by inhibiting autophagy through the regulation of the AMPK-mTOR pathway and that SA may have therapeutic value for protecting neurons from cerebral ischemia.


Assuntos
Autofagia/efeitos dos fármacos , Ciclo-Octanos/farmacologia , Glucose/metabolismo , Lignanas/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxirredução , Oxigênio/metabolismo , Compostos Policíclicos/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Ciclo-Octanos/química , Modelos Animais de Doenças , Lignanas/química , Camundongos , Modelos Biológicos , Estrutura Molecular , Fármacos Neuroprotetores/química , Compostos Policíclicos/química , Ratos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo , Serina-Treonina Quinases TOR/metabolismo
8.
Transplant Proc ; 51(8): 2808-2813, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31563248

RESUMO

INTRODUCTION: Prostaglandin E1 (PGE1) administered to patients in the immediate post-transplant period has been known to reduce ischemic reperfusion injuries (IRIs), but the effect on IRI of PGE1 administered to the donor is unknown. The purpose of this study was to determine the effect on IRI of PGE1 injected into donor rats during heterotopic heart transplantation. METHODS: Genetically identical male Sprague Dawley rats with a body weight of 300-320 g at 8-9 weeks of age were used for the study. Experimental methods were the same in the control (G0, n = 6) and experimental groups (G1, n = 6), but only the donor rats in the experimental group received an intramuscular injection of PGE1 (5 µg/kg) prior to the donor surgery. On day 1 the animals were sacrificed with the removal of the transplanted heart. Histologic analysis was performed in the hematoxylin-eosin-stained slides to assess interstitial edema and neutrophil infiltration by a pathologist. RESULTS: Median times of the donor organ procurement, cold ischemia, and warm ischemia were 37, 69, and 35 minutes, respectively, in the G0 group and 38, 76.5, and 33 minutes respectively in G1 group; there were no statistical differences. Heartbeats were observed in the transplanted graft in 2 of the G0 group and 2 of G1 group immediately after heart transplantation, but in all transplanted grafts on day 1 after surgery. Histologic scores for neutrophil infiltration showed significantly lower in the G1 group than in the G0 group. CONCLUSION: PGE1 administration to donors in a rat heart transplantation model may significantly reduce IRI.


Assuntos
Alprostadil/uso terapêutico , Transplante de Coração/efeitos adversos , Traumatismo por Reperfusão/prevenção & controle , Vasodilatadores/uso terapêutico , Alprostadil/administração & dosagem , Animais , Masculino , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Doadores de Tecidos , Transplante Heterotópico , Vasodilatadores/administração & dosagem
9.
Int J Mol Sci ; 20(19)2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31557793

RESUMO

Coronary heart diseases are of high relevance for health care systems in developed countries regarding patient numbers and costs. Disappointingly, the enormous effort put into the development of innovative therapies and the high numbers of clinical studies conducted are counteracted by the low numbers of therapies that become clinically effective. Evidently, pre-clinical research in its present form does not appear informative of the performance of treatments in the clinic and, even more relevant, it appears that there is hardly any consent about how to improve the predictive capacity of pre-clinical experiments. According to the steadily increasing relevance that pig models have gained in biomedical research in the recent past, we anticipate that research in pigs can be highly predictive for ischemia-reperfusion injury (IRI) therapies as well. Thus, we here describe the significance of pig models in IRI, give an overview about recent developments in evaluating such models by clinically relevant methods and present the latest insight into therapies applied to pigs under IRI.


Assuntos
Biomarcadores , Suscetibilidade a Doenças , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Animais , Biomimética , Modelos Animais de Doenças , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Óxido Nítrico/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Suínos
10.
Exp Mol Pathol ; 111: 104305, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31491367

RESUMO

Testicular torsion is a pathological condition which leads to sever scrotal pain and ischemia. After surgical reperfusion, oxidative stress factors cause to germ cell apoptosis. Thus, adjuvant therapy to surgery should be useful to decrease of ischemia/reperfusion (I/R) injury of testis. Modafinil, a drug to treat sleepiness, has been indicated to have anti-inflammatory effects. The aim was to evaluate the efficiency of modafinil administration after reperfusion surgery in a rat model of testicular torsion/detorsion (T/D). Male wistar rats were divided into three groups and each group contained 10 animals. To induce torsion right testis was rotated 720° clockwise and was left for 1 h. Modafinil group received modafinil (10 mg/kg) once daily intraperitoneally for 7 days after the surgery and the control group received physiologic saline once daily intraperitoneally for 7 days after the surgery. Thereafter, MDA, IL-1ß and TNF-α levels and histopathological changes were investigated. MDA, IL-1ß and TNF-α levels significantly increased in T/D group compared to the control group (⁎⁎P < .01 and ⁎⁎⁎P < .001, respectively). Moreover, modafinil administration significantly reduced these values compared to T/D group (#P < .05 and ##P < .01, respectively). Histopathological changes such as degeneration in germinal cells were detected in testis T/D group of rats whereas modafinil administration prevented degeneration in germinal cells, edema and hemorrhage compared with T/D group. In conclusion, administration of modafinil after reperfusion surgery had protective role on testicular torsion in rat and reduced ischemia/reperfusion cellular injury via anti-inflammatory and decrease of oxidative stress.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Modafinila/farmacologia , Substâncias Protetoras/farmacologia , Traumatismo por Reperfusão/tratamento farmacológico , Torção do Cordão Espermático/tratamento farmacológico , Testículo/efeitos dos fármacos , Animais , Apoptose , Masculino , Modafinila/administração & dosagem , Estresse Oxidativo , Ratos , Ratos Wistar , Traumatismo por Reperfusão/etiologia , Torção do Cordão Espermático/complicações , Testículo/metabolismo , Testículo/patologia
11.
Int J Mol Sci ; 20(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398927

RESUMO

Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects that contribute to maintain water-salt balance and regulate blood pressure. Besides these systemic properties, ANP displays important pleiotropic effects in the heart and in the vascular system that are independent of blood pressure regulation. These functions occur through autocrine and paracrine mechanisms. Previous works examining the cardiac phenotype of loss-of-function mouse models of ANP signaling showed that both mice with gene deletion of ANP or its receptor natriuretic peptide receptor A (NPR-A) developed cardiac hypertrophy and dysfunction in response to pressure overload and chronic ischemic remodeling. Conversely, ANP administration has been shown to improve cardiac function in response to remodeling and reduces ischemia-reperfusion (I/R) injury. ANP also acts as a pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic factor in the vascular system. Pleiotropic effects regarding brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were also reported. In this review, we discuss the current evidence underlying the pleiotropic effects of NPs, underlying their importance in cardiovascular homeostasis.


Assuntos
Sistema Cardiovascular/metabolismo , Peptídeos Natriuréticos/metabolismo , Animais , Sistema Cardiovascular/efeitos dos fármacos , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Peptídeo Natriurético Encefálico/metabolismo , Peptídeo Natriurético Encefálico/farmacologia , Peptídeos Natriuréticos/farmacologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Remodelação Vascular/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
12.
Nutrients ; 11(8)2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31374900

RESUMO

Systemic and localized ischemia and reperfusion injury remain clinically relevant issues after organ transplantation and contribute to organ dysfunctions, among which acute kidney injury is one of the most common. An in vitro test-circuit for normothermic perfusion of porcine kidneys after warm ischemia was used to investigate the antioxidant properties of vitamin C during reperfusion. Vitamin C is known to enhance microcirculation, reduce endothelial permeability, prevent apoptosis, and reduce inflammatory reactions. Based on current evidence about the pleiotropic effects of vitamin C, we hypothesize that the antioxidant properties of vitamin C might provide organ-protection and improve the kidney graft function in this model of ischemia and reperfusion. METHODS: 10 porcine kidneys from 5 Landrace pigs were perfused in vitro for 6 h. For each experiment, both kidneys of one animal were perfused simultaneously with a 1:1 mixture of autologous blood and modified Ringer's solution at 38 °C and 75 mmHg continuous perfusion pressure. One kidney was treated with a 500 mg bolus injection of vitamin C into the perfusate, followed by continuous infusion of 60 mg/h vitamin C. In the control test circuit, an equal volume of Ringer's solution was administered as a placebo. Perfusate samples were withdrawn at distinct points in time during 6 h of perfusion for blood gas analyses as well as measurement of serum chemistry, oxidative stress and antioxidant capacity. Hemodynamic parameters and urine excretion were monitored continuously. Histological samples were analyzed to detect tubular- and glomerular-injury. RESULTS: vitamin C administration to the perfusate significantly reduced oxidative stress (49.8 ± 16.2 vs. 118.6 ± 23.1 mV; p = 0.002) after 6 h perfusion, and increased the antioxidant capacity, leading to red blood cell protection and increased hemoglobin concentrations (5.1 ± 0.2 vs. 3.9 ± 0.6 g/dL; p = 0.02) in contrast to placebo treatment. Kidney function was not different between the groups (creatinine clearance vit C: 2.5 ± 2.1 vs. placebo: 0.5 ± 0.2 mL/min/100 g; p = 0.9). Hypernatremia (187.8 ± 4.7 vs. 176.4 ± 5.7 mmol/L; p = 0.03), and a lower, but not significant decreased fractional sodium excretion (7.9 ± 2 vs. 27.7 ± 15.3%; p = 0.2) were observed in the vitamin C group. Histological analysis did not show differences in tubular- and glomerular injury between the groups. CONCLUSION: Vitamin C treatment increased the antioxidant capacity of in vitro perfused kidney grafts, reduced oxidative stress, preserved red blood cells as oxygen carrier in the perfusate, but did not improve clinically relevant parameters like kidney function or attenuate kidney damage. Nevertheless, due to its antioxidative properties vitamin C might be a beneficial supplement to clinical kidney graft perfusion protocols.


Assuntos
Antioxidantes/farmacologia , Ácido Ascórbico/farmacologia , Rim/efeitos dos fármacos , Preservação de Órgãos , Estresse Oxidativo/efeitos dos fármacos , Perfusão , Traumatismo por Reperfusão/prevenção & controle , Animais , Citocinas/metabolismo , Feminino , Hemoglobinas/metabolismo , Técnicas In Vitro , Rim/metabolismo , Rim/patologia , Preservação de Órgãos/efeitos adversos , Perfusão/efeitos adversos , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Sus scrofa
13.
Andrologia ; 51(9): e13358, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31286549

RESUMO

This study was planned to evaluate the effects of sumatriptan, 5-HT1B/1D receptors agonist, on ischaemia/reperfusion injury in bilateral testes after unilateral testicular torsion/detorsion in rats. Male Wistar rats (n = 42) were allocated into a sham-operated group, a control group and treatment groups which were injected sumatriptan (0.1, 0.3 and 1 mg/kg), GR-127935 (0.01 mg/kg)-5-HT1B/1D receptors antagonist-and sumatriptan (0.1 mg/kg) + GR-127935 (0.01 mg/kg). Torsion was induced for 1 hr by rotating right testis 7200 in the clockwise direction, and after 7 days of detorsion, bilateral orchiectomy was conducted. While the level of TNF-α rose in testicular tissue after inducing torsion/detorsion, sumatriptan injection notably lowered TNF-α level in ipsilateral (torted) and contralateral (nontorted) testes (p < 0.001). Moreover, after inducing testicular torsion/detorsion, SOD activity was decreased, whereas administration of sumatriptan significantly increased SOD activity in bilateral testes (p < 0.001). After induction of torsion/detorsion, macroscopic and histological analyses also showed severe damages which were improved by sumatriptan injection. Interestingly, co-administration of sumatriptan with GR-127935 reversed the beneficial impacts of sumatriptan on macroscopic appearance, microscopic pattern and biochemical markers. It is concluded that sumatriptan presumably via stimulation of 5-HT1B/1D receptors decreased inflammation, oxidative stress and deteriorations induced by ischaemia/reperfusion injury following testicular torsion/detorsion.


Assuntos
Traumatismo por Reperfusão/tratamento farmacológico , Agonistas do Receptor 5-HT1 de Serotonina/administração & dosagem , Torção do Cordão Espermático/complicações , Sumatriptana/administração & dosagem , Testículo/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Humanos , Masculino , Oxidiazóis/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Piperazinas/administração & dosagem , Ratos , Ratos Wistar , Receptor 5-HT1B de Serotonina/metabolismo , Receptor 5-HT1D de Serotonina/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Antagonistas da Serotonina/administração & dosagem , Superóxido Dismutase/metabolismo , Testículo/patologia , Fator de Necrose Tumoral alfa/metabolismo
14.
J Surg Res ; 243: 363-370, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31277013

RESUMO

BACKGROUND: Intestinal ischemia/reperfusion (I/R) is a grave condition related to high morbidity and mortality. Autophagy, which can induce a new cell death named type II programmed cell death, has been reported in some intestinal diseases, but little is known in I/R-induced intestinal injury. In this study, we aimed to explore the role of autophagy in intestinal injury induced by I/R and its potential mechanisms. MATERIALS AND METHODS: The rats pretreated with rapamycin or 3-methyladenine had intestinal I/R injury. After reperfusion, intestinal injury was measured by Chiu's score, intestinal mucosal wet-to-dry ratio, and lactic acid level. Intestinal mucosal oxidative stress level was measured by malondialdehyde and superoxide dismutase. Autophagosome, LC3, and p62 were detected to evaluate autophagy level. Mammalian target of rapamycin (mTOR) was detected to explore potential mechanism. RESULTS: Chiu's score, intestinal mucosal wet-to-dry ratio, lactic acid level, malondialdehyde level, autophagosomes, and LC3-II/LC3-I were significantly increased, and superoxide dismutase level and expression of p62 were significantly decreased in intestinal mucosa after intestinal ischemia/reperfusion. Pretreatment with rapamycin significantly aggravated intestinal injury evidenced by increased Chiu's score, intestinal mucosal wet-to-dry ratio and lactic acid level, increased autophagy level evidenced by increased autophagosomes and LC3-II/LC3-I and decreased expression of p62, and downregulated expression of p-mTOR/mTOR. On the contrary, pretreatment with 3-methyladenine significantly attenuated intestinal injury and autophagy level and upregulated expression of p-mTOR/mTOR. CONCLUSIONS: In summary, autophagy was significantly enhanced in intestinal mucosa after intestinal ischemia/reperfusion, and inhibition of autophagy attenuated intestinal injury induced by I/R through activating mTOR signaling.


Assuntos
Adenina/análogos & derivados , Autofagia/efeitos dos fármacos , Enteropatias/prevenção & controle , Traumatismo por Reperfusão/prevenção & controle , Adenina/farmacologia , Adenina/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Enteropatias/enzimologia , Enteropatias/etiologia , Enteropatias/patologia , Mucosa Intestinal/enzimologia , Mucosa Intestinal/ultraestrutura , Masculino , Malondialdeído/metabolismo , Distribuição Aleatória , Ratos Sprague-Dawley , Traumatismo por Reperfusão/enzimologia , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Sirolimo , Superóxido Dismutase/metabolismo , Serina-Treonina Quinases TOR/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo
15.
Int J Mol Sci ; 20(14)2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31330934

RESUMO

Ischemia-reperfusion injury (IRI) plays a significant role in the pathogenesis of acute kidney injury (AKI). The complicated interaction between injured tubular cells, activated endothelial cells, and the immune system leads to oxidative stress and systemic inflammation, thereby exacerbating the apoptosis of renal tubular cells and impeding the process of tissue repair. Stem cell therapy is an innovative approach to ameliorate IRI due to its antioxidative, immunomodulatory, and anti-apoptotic properties. Therefore, it is crucial to understand the biological effects and mechanisms of action of stem cell therapy in the context of acute ischemic AKI to improve its therapeutic benefits. The recent finding that treatment with conditioned medium (CM) derived from stem cells is likely an effective alternative to conventional stem cell transplantation increases the potential for future therapeutic uses of stem cell therapy. In this review, we discuss the recent findings regarding stem cell-mediated cytoprotection, with a focus on the anti-inflammatory effects via suppression of oxidative stress and uncompromised immune responses following AKI. Stem cell-derived CM represents a favorable approach to stem cell-based therapy and may serve as a potential therapeutic strategy against acute ischemic AKI.


Assuntos
Lesão Renal Aguda/etiologia , Lesão Renal Aguda/metabolismo , Apoptose , Estresse Oxidativo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Células-Tronco/metabolismo , Lesão Renal Aguda/patologia , Lesão Renal Aguda/terapia , Animais , Estudos Clínicos como Assunto , Meios de Cultivo Condicionados/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Humanos , Inflamação , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia , Leucócitos/metabolismo , Transplante de Células-Tronco Mesenquimais , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/terapia , Células-Tronco/citologia , Resultado do Tratamento
16.
J Surg Res ; 244: 241-250, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31301480

RESUMO

BACKGROUND: Ischemic preconditioning (IPC) can provide a defense against ischemia-reperfusion (IR)-induced acute inflammation and barrier dysfunction in many organs. Because nitric oxide (NO) has been implicated as a trigger or mediator in the IPC mechanism and because neuronal NO synthase (nNOS) is a dominant isoform of NOS in the gastrointestinal tract, our aim was to investigate the role of nNOS in IPC-induced protection after mesenteric IR. MATERIALS AND METHODS: Intestinal IR was induced in sodium pentobarbital-anesthetized dogs by clamping the superior mesenteric artery for 60 min followed by 2 h of reperfusion (IR group; n = 7). In further groups, IPC was used (three cycles of 5-min ischemia/5-min reperfusion periods) before IR in the presence or absence of selective inhibition of nNOS with 7-nitroindazole (5 mg/kg, intravenously, in a bolus 15 min before IPC, n = 6 each). Changes in mesenteric vascular resistance, intramucosal pH (pHi), and small bowel motility were monitored. Plasma nitrite/nitrate levels, intestinal NO synthase activity, leukocyte accumulation, mast cell degranulation, and histologic injury were also determined. RESULTS: Ischemia significantly decreased mesenteric vascular resistance and pHi, whereas IR induced a temporary bowel hypermotility and acute inflammatory reaction. IPC facilitated pHi recovery, attenuated motility dysfunction, elevated NOS-dependent NO production, and reduced leukocyte accumulation, mast cell degranulation, and mucosal injury. Pretreatment with 7-nitroindazole halted the IPC-induced increase in NO availability, pHi recovery, and the anti-inflammatory and morphologic effects. CONCLUSIONS: Our data demonstrate that NO generated by intestinal nNOS plays a pivotal role in IPC-linked tissue protection by inhibiting an IR-related acute inflammatory response.


Assuntos
Mucosa Intestinal/imunologia , Precondicionamento Isquêmico/métodos , Óxido Nítrico Sintase Tipo I/metabolismo , Óxido Nítrico/imunologia , Traumatismo por Reperfusão/prevenção & controle , Animais , Degranulação Celular/imunologia , Modelos Animais de Doenças , Cães , Feminino , Humanos , Mucosa Intestinal/irrigação sanguínea , Mucosa Intestinal/metabolismo , Masculino , Mastócitos/imunologia , Artéria Mesentérica Superior/cirurgia , Óxido Nítrico/metabolismo , Traumatismo por Reperfusão/etiologia
17.
Transplant Proc ; 51(6): 2076-2080, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31303405

RESUMO

BACKGROUND: Renal ischemia/reperfusion (I/R) injury (RI/RI) is a common complication of diabetes mellitus (DM) in surgical practice. Oxidative stress plays a crucial role in this process. Recombinant human erythropoietin (rhEPO) is usually used to treat anemia resulting from several diseases. However, the functional involvement of rhEPO in diabetic RI/RI remains unclear. The present study was intended to investigate the antioxidant role of rhEPO on RI/RI in DM rats. METHODS: The bilateral renal arteries and veins of streptozotocin-induced diabetic rats were subjected to 45 minutes of ischemia followed by 1, 6, and 24 hours of reperfusion with or without rhEPO pretreatment at the beginning of an I/R procedure. The renal tissue pathomorphology, renal function, oxidative stress, and inflammatory response were evaluated by detection of a series of indices by hematoxylin-eosin staining, commercial kits, enzyme-linked immunosorbent assay, and spectrophotofluorometry, respectively. RESULTS: Compared to the I/R group, renal function was significantly advanced in the erythropoietin group, whose subjects were also subjected to renal tissue injury, oxidative stress, and inflammation. CONCLUSION: These results suggest that rhEPO preconditioning can attenuate diabetic RI/RI through regulating endogenous antioxidant activity.


Assuntos
Diabetes Mellitus Experimental/complicações , Eritropoetina/farmacologia , Rim/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Traumatismo por Reperfusão/etiologia , Animais , Humanos , Masculino , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Traumatismo por Reperfusão/patologia
18.
Life Sci ; 235: 116553, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31185237

RESUMO

AIMS: Dexmedetomidine (Dex) has been noted to have neuroprotective effect against cerebral ischemia-reperfusion (I/R) injury. However, the effect of Dex in diabetic hyperglycemia-exacerbated cerebral I/R injury and its underlying mechanism remain unclear. MAIN METHODS: The infarct volume and brain edema were evaluated by 2,3,5-triphenyltetrazolium chloride staining and standard wet-dry method. Modified neurological severity score was utilized to assess the neurological deficits. The oxidative stress and inflammation were evaluated by detecting reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor (TNF)-α and interleukin (IL)-1ß. Terminal deoxynucleotidyl transferase dUTP nick end labeling assay and cell count kit-8 were applied to measure cell apoptosis and viability. KEY FINDINGS: Dex treatment reduced infarct volume, decreased brain water content and improved neurological deficit in middle cerebral artery occlusion/reperfusion (MCAO/R) mice. Dex treatment reduced the levels of ROS, MDA, TNF-α and IL-1ß in the entire middle cerebral artery territory of diabetic mice subjected to MCAO/R, as well as in primary culture of mouse hippocampal neurons stimulated with 50 mM glucose and oxygen glucose deprivation/reperfusion. Dex treatment inhibited neuronal apoptosis induced by diabetic hyperglycemia-exacerbated cerebral I/R injury. Dex upregulated nuclear factor of activated T-cells 5 (NFAT5) and Sirtuin 1 (SIRT1) expression, induced NF-E2-related factor 2 (Nrf2) translocation from cytoplasm to nucleus and inhibited the acetylation of Nrf2. However, these changes triggered by Dex treatment were abrogated by NFAT5 knockdown. SIGNIFICANCE: Dex protects against diabetic hyperglycemia-exacerbated cerebral I/R injury through attenuation of oxidative stress, inflammation and apoptosis. The underlying mechanism is at least the NFAT5/SIRT1/Nrf2 signaling pathway dependent.


Assuntos
Dexmedetomidina/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Hiperglicemia/complicações , Infarto da Artéria Cerebral Média/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Traumatismo por Reperfusão/prevenção & controle , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Animais , Apoptose/efeitos dos fármacos , Modelos Animais de Doenças , Técnicas In Vitro , Infarto da Artéria Cerebral Média/etiologia , Infarto da Artéria Cerebral Média/patologia , Inflamação/etiologia , Inflamação/patologia , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais
19.
Oxid Med Cell Longev ; 2019: 9549506, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31205591

RESUMO

It has been demonstrated that vagus nerve stimulation (VNS) plays a protective role in ischemia/reperfusion (I/R) injury of various organs. The present study investigates the protective effect of VNS on hepatic I/R injury and the potential mechanisms. Male Sprague-Dawley rats were randomly allocated into three groups: the sham operation group (Sham; n = 6, sham surgery with sham VNS); the I/R group (n = 6, hepatic I/R surgery with sham VNS); and the VNS group (n = 6, hepatic I/R surgery plus VNS). The I/R model was established by 1 hour of 70% hepatic ischemia. Tissue samples and blood samples were collected after 6 hours of reperfusion. The left cervical vagus nerve was separated and stimulated throughout the whole I/R process. The stimulus intensity was standardized to the voltage level that slowed the sinus rate by 10%. VNS significantly reduced the necrotic area and cell death in I/R tissues. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) were also decreased by VNS. In addition, VNS suppressed inflammation, oxidative stress, and apoptosis in I/R tissues. VNS significantly increased the protein levels of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) in the liver. These data indicated that VNS may attenuate hepatic I/R injury by inhibiting inflammation, oxidative stress, and apoptosis possibly via the Nrf2/HO-1 pathway.


Assuntos
Modelos Animais de Doenças , Heme Oxigenase (Desciclizante)/metabolismo , Hepatopatias/prevenção & controle , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Traumatismo por Reperfusão/prevenção & controle , Estimulação do Nervo Vago/métodos , Animais , Apoptose , Heme Oxigenase (Desciclizante)/genética , Hepatopatias/etiologia , Hepatopatias/patologia , Masculino , Fator 2 Relacionado a NF-E2/genética , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia
20.
Scand Cardiovasc J ; 53(4): 192-196, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31169413

RESUMO

Objectives. The hypothermic circulatory arrest (HCA) is still of paramount importance in aortic arch surgery, but the safe period of the arrest is limited. Remote ischaemic preconditioning (RIPC) prepares the cerebral tissue for ischaemic insult. Prolongation of the permissible period of HCA with RIPC may have a major impact on the outcome of aortic operations requiring cessation of blood flow by decreasing the rate of neurological deficits. Design. Twenty pigs were randomised into the RIPC group (n = 10) and the control group (n = 10). The RIPC group underwent four cycles of transient hind limb ischaemia. Both groups underwent cooling with cardiopulmonary bypass to 11 °C followed by a 45-minute HCA and re-warming to 36 °C. Cerebral blood flow was measured with a transit time ultrasonic flowmeter from the right common carotid artery, and the arteriovenous oxygen difference was calculated from sagittal sinus and arterial blood samples. Measurements were taken at several time points during cooling and warming. Temperature coefficient (Q10) was calculated to determine estimated permissible periods of HCA. Results. The Q10 was 2.27 (1.98-2.58) for the RIPC group and 1.87 (1.61-2.25) for the control group. The permissible period of HCA at 18 °C was 26 minutes (20-33) in the RIPC group and 17 minutes (13-25) in the control group (p = .063)(Data expressed in medians and interquartile ranges). Conclusions. RIPC tends to suppress cerebral metabolism during cooling with cardiopulmonary bypass and may prolong estimated permissible period of HCA.


Assuntos
Encéfalo/irrigação sanguínea , Parada Circulatória Induzida por Hipotermia Profunda , Membro Posterior/irrigação sanguínea , Hipóxia Encefálica/prevenção & controle , Precondicionamento Isquêmico/métodos , Traumatismo por Reperfusão/prevenção & controle , Animais , Velocidade do Fluxo Sanguíneo , Encéfalo/metabolismo , Circulação Cerebrovascular , Parada Circulatória Induzida por Hipotermia Profunda/efeitos adversos , Metabolismo Energético , Feminino , Hipóxia Encefálica/etiologia , Hipóxia Encefálica/metabolismo , Hipóxia Encefálica/fisiopatologia , Precondicionamento Isquêmico/efeitos adversos , Duração da Cirurgia , Fluxo Sanguíneo Regional , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Fatores de Risco , Sus scrofa , Fatores de Tempo
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