RESUMEN
Mitogen-activated protein kinases (MAPKs) have been the focus of a number of studies, as these compounds are involved in a number of important inflammatory cell signaling mechanisms. Recent studies have further elucidated the role of MAPKs in the inflammatory response, as a result of trauma and/or ischemia-reperfusion (I/R) injury. There are three major classes of MAPKs that may be involved in the inflammatory response: extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs)/c-Jun NH(2)-terminal kinases (JNKs), and p38 MAPKs (p38). This is clinically relevant, because these pathways may be a possible target for anti-inflammatory drug intervention. This review studies the role of MAPKs in trauma and/or I/R.
Asunto(s)
Proteínas Quinasas Activadas por Mitógenos/metabolismo , Daño por Reperfusión/metabolismo , Heridas y Lesiones/metabolismo , Animales , HumanosRESUMEN
Ischemia and reperfusion (I/R) is an important pathologic phenomenon that has not been completely defined from the perspective of the molecular signaling pathways developed immediately at its inception to minutes and hours thereafter. From the practical point of view, we have divided I/R into 3 phases: phase I, which occurs seconds to minutes after the injury and is associated with changes dependent on the activation of phospholipases, intracellular calcium, eicosanoids, other lipid molecules, protein kinases, inducible nitric oxide synthase, and the expression of preformed adhesion molecules like P-selectin; phase II, which occurs minutes to hours after I/R injury and is associated with the active transcription of protein synthesis of molecules like inflammatory cytokines (mainly tumor necrosis factor-alpha and interleukin 1) starting their signaling downstream from the membrane into the cytoplasm where kinases will be activated and send signals to the nucleus for the activation of transcription factors and further continuing with the inflammatory event; and phase III, which occurs several hours to days after I/R and is associated with the appearance of molecular chronic mechanisms of protection like the presence of anti-inflammatory cytokines of the IL-10 type, late adhesion molecules, and other growth factors such as TGF-beta. This completes the whole molecular event related to I/R injury.
Asunto(s)
Daño por Reperfusión/metabolismo , Transducción de Señal , Animales , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , FN-kappa B/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Since the early 20th Century when Emerich Ullman transplanted a pig kidney into the arm of a woman (1902), Princeteau implanted portions of a rabbit kidney into the kidney of a child who was dying of renal insufficiency (1905), Jaboulay transplanted two kidneys from a pig and a goat as donor sources (1906), and Unger implanted a monkey kidney into a human (1910), xenotranplantation has made some strides, mostly related to advanced surgical techniques, improved knowledge of immunological principles, and to steps associated with the development of the most effective immunosuppressive therapy. Innovative surgical techniques were introduced by Alexis Carrel in the first decade of the 1900s, so that vascular anastomoses could be realized without a considerable amount of thrombotic/embolic problems, long before heparin times. Inasmuch as these advances were soundly characterized, it became evident that the results were far from expected and that the time was not ripe for xenotranplantation. It took 50 years (1963) before Keith Reemtsma transplanted 13 kidneys from chimpanzees into patients with kidney failure. Remarkably, one patient survived for 9 months before dying from electrolyte imbalance. In the ensuing years, Starzl (1964), Hardy (1964), Cooley (1968), Ross (1968), Barnard (1977), Bailey (1984) and a few others entered this new field with less than satisfactory accomplishments. The unsolvable barrier of hyperacute rejection required persistence and ingenuity. The recognition of xenoantibodies and their requirement for full depletion, through ex vivo porcine perfusion, plasmapheresis, immunoabsorption and complement inhibition, facilitated important advances in this field. The introduction of accommodation and molecular chimerism has further improved the knowledge of this newly conceived field. Advanced molecular engineering techniques have recently permitted the creation of the clonal Gal-deficient pig by eliminating the alpha-1, 3 galactosyltransferase gene. These discoveries together with better immunosuppression raise hope for the yet unrealized promise of xenotranplantation.
Asunto(s)
Trasplante de Órganos/tendencias , Trasplante Heterólogo/tendencias , Animales , HumanosRESUMEN
Blockade of NO production is followed by an increase in leukocyte rolling and adhesion resulting in some deleterious effects of ischemia. Preischemic administration of NO protects vascular integrity after reperfusion. Exogenous NO causes a direct reduction in leukocyte adhesion. This work was performed to test the hypothesis that exogenous NO administered during the preischemic period to the kidney alone, without coming into contact with the leukocytes, could also reduce leukocyte-endothelium adhesion. Adult rats were subjected to in situ isolation of the left kidney. Solutions were infused through the renal artery and drained through an incision in the renal vein, thus avoiding the systemic circulation. Group IC rats served as an ischemic control, and received 0.9% saline. Group NP received Na nitroprusside. Group S was a nonischemic control. Groups IC and NP were subjected to 75 min of renal ischemia. After this period, vascular structures were repaired and reperfusion allowed. A right nephrectomy was performed. Serum urea and creatinine, myeloperoxidase activity, and histopathological studies were carried out at different intervals after reperfusion. Survival at 15 days was 46%, 80%, and 100% in groups IC, NP, and S, respectively. Differences between groups for serum urea and creatinine were significant only during the first seven days. Myeloperoxidase values were significantly higher in group IC. All rats from group IC and only 20% from group NP showed histological evidence of necrosis. Thus, exogenous NO is protective and acts selectively upon the kidney, modulating its interactions with polymorphonuclear cells after ischemia/reperfusion.
Asunto(s)
Isquemia/patología , Riñón/irrigación sanguínea , Óxido Nítrico/farmacología , Daño por Reperfusión/prevención & control , Animales , Adhesión Celular/efectos de los fármacos , Creatinina/sangre , Endotelio Vascular/citología , Isquemia/metabolismo , Riñón/patología , Pruebas de Función Renal , Masculino , Neutrófilos/efectos de los fármacos , Neutrófilos/fisiología , Ratas , Urea/sangreAsunto(s)
Trasplante de Riñón/economía , Trasplante de Riñón/fisiología , Adolescente , Adulto , Niño , Costos y Análisis de Costo , Eficiencia Organizacional , Femenino , Asignación de Recursos para la Atención de Salud , Humanos , Fallo Renal Crónico/cirugía , Fallo Renal Crónico/terapia , Tiempo de Internación/economía , Donadores Vivos , Masculino , México , Persona de Mediana Edad , Nefrectomía , Diálisis Peritoneal Ambulatoria Continua/economía , Diálisis Renal/economía , Donantes de Tejidos , Recolección de Tejidos y Órganos/economía , Obtención de Tejidos y Órganos/economía , Obtención de Tejidos y Órganos/organización & administraciónAsunto(s)
Trasplante de Riñón/métodos , Trasplante de Riñón/estadística & datos numéricos , Adolescente , Adulto , Niño , Costos y Análisis de Costo , Femenino , Humanos , Trasplante de Riñón/economía , Masculino , México , Persona de Mediana Edad , Práctica Privada/economía , Estudios RetrospectivosAsunto(s)
Trasplante de Riñón/métodos , Nefrectomía/métodos , Adulto , Femenino , Humanos , Trasplante de Riñón/mortalidad , Trasplante de Riñón/fisiología , Tiempo de Internación , Donadores Vivos , Masculino , México , Persona de Mediana Edad , Complicaciones Posoperatorias/epidemiología , Análisis de Supervivencia , Recolección de Tejidos y Órganos/métodosAsunto(s)
Trasplante de Riñón , Necrosis Tubular Aguda/prevención & control , Vasodilatadores/uso terapéutico , Verapamilo/uso terapéutico , Adolescente , Adulto , Cadáver , Niño , Humanos , Inyecciones Intraarteriales , Periodo Intraoperatorio , Riñón , Donadores Vivos , Persona de Mediana Edad , Preservación de Órganos/métodos , Complicaciones Posoperatorias/prevención & control , Arteria Renal , Reperfusión , Estudios Retrospectivos , Donantes de Tejidos , Vasodilatadores/administración & dosificación , Verapamilo/administración & dosificaciónRESUMEN
21-Aminosteroids are antioxidant compounds that prevent iron-dependent lipid peroxidation and improve cell viability. In this work we attempt to define the role of 21-aminosteroids in liver ischemia and reperfusion and assess their possible mode of action, specifically their effect on neutrophil infiltration and nitrite/nitrate levels. Total liver ischemia for 90 min was produced in the rat with the use of a portosystemic shunt. Three groups of animals were studied. One group received the 21-aminosteroid U-74389G (10 mg/ kg) divided into two equal doses 10 min prior to ischemia (7 mg/kg) and 10 min before reperfusion (3 mg/ kg). The two other groups included the sham and the control animals. We studied survival at 7 days and serum liver enzymes, liver myeloperoxidase, plasma nitrites, nitrates, and liver histology at 6 hr postreperfusion. Animal survival improved from 13% in the ischemic control to 52% in the lazaroid treated group (P < 0.05). We observed significant improvements in liver function tests, liver myeloperoxidase levels, as well as in the liver histology (P < 0.05). We could not find statistical difference in plasma nitrite/nitrate (P > 0.1). The 21-aminosteroids significantly improved animal survival after total liver ischemia, through a mechanism that includes blocking neutrophil infiltration which is independent from nitrite/nitrate levels.
Asunto(s)
Antioxidantes/farmacología , Hígado/irrigación sanguínea , Neutrófilos/efectos de los fármacos , Nitratos/sangre , Nitritos/sangre , Pregnatrienos/farmacología , Daño por Reperfusión/prevención & control , Animales , Hígado/efectos de los fármacos , Masculino , Peroxidasa/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
In this study, we tested if the mechanism of protection of a calcium channel blocker, Verapamil (VER), was due to modulation of neutrophil infiltration after ischemia/reperfusion injury, in a rat renal ischemic model. Forty-four Sprague-Dawley rats were subjected to 75 min of warm ischemia and immediate contralateral nephrectomy. The animals were divided into two groups: the ischemic control (IC) group, which received normal saline, and the experimental group that received VER 1.25 mg/kg. The drug was administrated intravenously after ligation of the renal pedicle, before reperfusion. Survival was followed for 7 days. Laboratory tests included renal function tests, with serum creatinine (SCr) and blood urea nitrogen (BUN), light histology and neutrophil infiltration, measured by the myeloperoxidase test in renal tissue. Better survival rate was observed in the VER group (85% at 7 days vs control 50%) (P = 0.08). SCr and BUN at 48 and 72 hr showed a statistical significant difference between the two groups (VER lower than IC P < 0.05). Histological damage was significantly less in the VER group (P < 0.05). Neutrophil infiltration was significantly decreased in the VER group when compared to the IC group (P < 0.05). We concluded then, that VER had a downregulating effect on neutrophil infiltration and this might be an important mechanism of protection during the development of renal ischemic damage.
Asunto(s)
Bloqueadores de los Canales de Calcio/uso terapéutico , Isquemia/tratamiento farmacológico , Isquemia/patología , Riñón/irrigación sanguínea , Neutrófilos/efectos de los fármacos , Verapamilo/uso terapéutico , Animales , Masculino , Ratas , Ratas Sprague-Dawley , Verapamilo/farmacologíaRESUMEN
BACKGROUND: Neutrophil adhesion and migration is associated with hepatic ischemia and reperfusion. The role of a Sialyl Lewis(x) (SLe)(x) oligosaccharide, a ligand for selections, was studied in hepatic ischemia and reperfusion injury. STUDY DESIGN: Total hepatic ischemia was produced in rats for 90 minutes using an extracorporeal portosystemic shunt. To assess the role of SLe(x) in hepatic ischemia and reperfusion injury, 25 mg/kg of an SLe(x) analog, CY-1503, was given five minutes before reperfusion or at reperfusion. Biochemical tests of hepatic injury, myeloperoxidase activity in hepatic tissue, and histologic studies, including neutrophil infiltration determined by the naphthol esterase technique, were analyzed six hours after reperfusion. RESULTS: Significantly improved protection in biochemical hepatic injury tests (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase) was noted between the ischemic and the SLe(x) treated groups. Myeloperoxidase activity and polymorphonuclear cell infiltration in hepatic tissue were decreased in the SLe(x) groups. Histologic protection from hepatic damage was observed in the treated groups. CONCLUSIONS: The SLe(x) oligosaccharide analog, CY-1503, had an important protective role in hepatic ischemia and reperfusion injury. Modulation of SLe(x) in the neutrophil decreased the adhesion of polymorphonuclear cells and their subsequent migration after hepatic ischemia and reperfusion.
Asunto(s)
Isquemia/metabolismo , Antígenos del Grupo Sanguíneo de Lewis , Hígado/irrigación sanguínea , Oligosacáridos/metabolismo , Daño por Reperfusión/metabolismo , Animales , Evaluación Preclínica de Medicamentos , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Isquemia/tratamiento farmacológico , Isquemia/patología , Ligandos , Hígado/enzimología , Hígado/patología , Masculino , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Oligosacáridos/farmacología , Oligosacáridos/uso terapéutico , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patología , Selectinas/metabolismo , Antígeno Sialil Lewis XRESUMEN
The aim of this study was to determine the ideal time of administration of Na-nitroprusside to prevent neutrophil infiltration in ischemically damaged kidneys. Sprague-Dawley rats were subjected to 75 min of renal warm ischemia and contralateral nephrectomy. The animals were divided into 7 groups: the ischemic control (IC), which received normal saline, the sham group without warm ischemia and the experimental groups, which received intravenous Na-nitroprusside (NP) (5 mg/kg) at 75, 30, 15, and 5 min prior to reperfusion. Another experimental group was given verapamil (V) (5 mg/kg) as a NO-independent vasodilator 5 min prior to reperfusion. The final evaluation included survival at seven days, serum creatinine (SCr) and blood urea nitrogen (BUN) daily for 3 days, and neutrophil infiltration determined by the presence of myeloperoxidase (MPO) in renal tissue at 2 hr after reperfusion. Histological damage was assessed at 24 hr. There were significant improvements in all parameters when the Na-NP was administered at 75, 30, and 15 min prior to reperfusion when compared with the control group (p < 0.05). There were no differences either in survival or renal function when the 5 min group was compared with the IC or V groups. It is concluded then, that Na-NP can be administered as late as 15 min before reperfusion and still have a protective effect. It appears that the mechanism of protection of Na-NP is due to blocking of one of the steps of the interaction between leukocytes and endothelium--migration. Furthermore, the verapamil (a NO-independent vasodilator) and Na-NP5 (a NO-dependent vasodilator) groups did not show a beneficial effect in these severely ischemically damaged kidneys, which might be one more reason to believe that Na-NP could be interacting at the level of leukocyte-endothelial cell interaction.
Asunto(s)
Movimiento Celular/efectos de los fármacos , Isquemia/patología , Riñón/irrigación sanguínea , Neutrófilos/patología , Nitroprusiato/administración & dosificación , Animales , Riñón/patología , Masculino , Neutrófilos/efectos de los fármacos , Óxido Nítrico/administración & dosificación , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
BACKGROUND: Ischemia and reperfusion of the liver are associated with changes in the interaction of leukocyte-endothelium cells. The role of an adhesion molecule, P-selectin, is studied in ischemia and reperfusion injury of the liver. STUDY DESIGN: Total hepatic ischemia was produced in the rat for 90 minutes, using a portosystemic shunt. To determine the role of P-selectin in ischemia and reperfusion, a murine IgG1 monoclonal antibody to P-selectin (1 mg/kg) was used at different times (30 minutes before and at reperfusion and five minutes and 24 hours after reperfusion). Rats survived for seven days, and tests showing hepatic injury, myeloperoxidase in hepatic tissue, and histologic studies were analyzed at four hours postreperfusion. RESULTS: Survival improved from 15 percent for the rats in the ischemia control group to 55 percent for those in the group receiving anti-P-selectin antibody given 30 minutes before reperfusion (p < 0.05). We observed an improved statistically significant difference in tests demonstrating hepatic injury, myeloperoxidase in hepatic tissue, and histologic studies in the treated and ischemia control groups. The other groups did not show consistent significant differences. CONCLUSIONS: P-selectin has a significant role in ischemia and reperfusion injury of the liver. Early modulation of the interaction between P-selectin and its ligand decreased neutrophil adhesion and migration and consequently diminished damage to the liver.
Asunto(s)
Isquemia/fisiopatología , Hígado/irrigación sanguínea , Selectina-P/fisiología , Daño por Reperfusión/fisiopatología , Análisis de Varianza , Animales , Anticuerpos Monoclonales/uso terapéutico , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Inmunoglobulina G/inmunología , Isquemia/enzimología , Isquemia/mortalidad , Isquemia/patología , Isquemia/terapia , Hígado/enzimología , Hígado/patología , Masculino , Ratones , Selectina-P/inmunología , Peroxidasa/análisis , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/enzimología , Daño por Reperfusión/mortalidad , Daño por Reperfusión/patología , Daño por Reperfusión/terapia , Estadísticas no Paramétricas , Factores de TiempoAsunto(s)
Isquemia/fisiopatología , Riñón/irrigación sanguínea , Neutrófilos/fisiología , Nitroprusiato/farmacología , Animales , Nitrógeno de la Urea Sanguínea , Creatinina/sangre , Isquemia/sangre , Isquemia/patología , Riñón/efectos de los fármacos , Riñón/patología , Masculino , Malondialdehído/metabolismo , Peroxidasa/sangre , Ratas , Ratas Sprague-Dawley , ReperfusiónRESUMEN
Nitric oxide is an important element that has been found in multiple biological systems, including the gastrointestinal tract. The nitric oxide function is reviewed, and its possible clinical use is commented.
Asunto(s)
Fenómenos Fisiológicos del Sistema Digestivo , Procedimientos Quirúrgicos del Sistema Digestivo , Óxido Nítrico/fisiología , Enfermedades Gastrointestinales/fisiopatología , Enfermedades Gastrointestinales/cirugía , HumanosRESUMEN
This study investigates the role of verapamil, a calcium channel blocker, combined with allopurinol, a xanthine-oxidase inhibitor, when given at reperfusion after severe renal ischemia injury in the rat. Male Sprague-Dawley rats were subjected to 60 minutes of warm ischemia by cross clamping the whole left renal pedicle (artery and vein). At the end of ischemia, the clamps were removed and a contralateral nephrectomy was performed. The animals (n = 40 per group) were divided into five groups; Group 1, ischemic control (IC) receiving lactated Ringer's; Group 2, allopurinol (A) 100 mg/kg; Group 3, verapamil (V) 1.25 mg/kg; Group 4, receiving a combination of A + V at the same concentrations; and Group 5, sham group. Each drug was given intravenously at the end of the ischemic period at reperfusion. Survival was evaluated at 7 days. Renal damage was assessed by kidney function tests (serum creatinine and blood urea nitrogen, or BUN), light histology. Lipid peroxidation was measured in renal tissue using the TBA (thiobarbituric acid) assay. The best survival rate was seen in the combination group of A + V (70% at 7 days; p < .01 vs. control). Single drugs were not as effective as the combination when compared to the IC. Serum creatinine at 24 and 48 hours showed a significant difference between the IC and treatment groups. At 72 hours there were no differences among the treated groups. Histological damage was more pronounced in the IC (Grade 4.0) than in the allopurinol (3.4 +/- 0.8), verapamil (3.0), or A + V (2.2 +/- 0.04).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Alopurinol/administración & dosificación , Isquemia/tratamiento farmacológico , Riñón/irrigación sanguínea , Verapamilo/administración & dosificación , Animales , Quimioterapia Combinada , Isquemia/fisiopatología , Riñón/patología , Riñón/fisiopatología , Peroxidación de Lípido , Masculino , Ratas , Ratas Sprague-Dawley , ReperfusiónRESUMEN
This work studies the role that nitric oxide (NO) plays in ischemia/reperfusion (I/R) of the rat kidney. Sprague-Dawley rats, weighing 250-300 g, were subjected to 75 min of warm ischemia and contralateral nephrectomy. The animals were divided into six groups (n = 12 per group): ischemic control (IC) with normal saline, L-NG-mono-methyl-arginine (L-NMMA) 50 mg/kg, L-arginine (L-Arg) 300 mg/kg, Na-nitroprusside (Na-NP) 2.5 mg/kg, the combination of L-NMMA+Na-NP at the doses used before, and the sham group. All animals received the drug intravenously 60 min prior to ischemia. Survival was evaluated at seven days. Renal damage was assessed by kidney function tests (serum creatinine and blood urea nitrogen) and light histology. Lipid peroxidation was measured in renal tissue using the thiobarbituric acid assay. Significantly better survival was seen in the Na-NP group, as compared to the rest of the study. Serum creatinine at 24 and 48 hr showed a significant difference between the Na-NP group and the other groups. Histological damage was minimal in the Na-NP group. Clearly, the Na-NP had the most beneficial effect in survival and histological structure. Lipid peroxidation was significantly different, with the lower levels seen in the L-NMMA group and the higher levels in the Na-NP group. In base to these results, we conclude that exogenous NO has a beneficial and protective effect of the ischemically damaged rat kidney. This protection is independent of lipid peroxidation. Endogenous NO production does not play a role in I/R injury in our model.
Asunto(s)
Riñón/irrigación sanguínea , Óxido Nítrico/metabolismo , Daño por Reperfusión/prevención & control , Aminoácido Oxidorreductasas/farmacología , Animales , Arginina/análogos & derivados , Arginina/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Peroxidación de Lípido , Masculino , Óxido Nítrico Sintasa , Nitroprusiato/farmacología , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Tasa de Supervivencia , omega-N-MetilargininaRESUMEN
A case of malakoplakia of the colon in a 55-year-old female patient with a massive hemorrhage of the rectum is reported. A barium enema showed polypoid lesions (pseudopolyps). Colonoscopy revealed white-yellowish nodules simulating small pustulae all along the colon at 2 cm from the anal verge. A laparatomy disclosed lobulated intraluminal masses and yellowish lesions in the form of transcolonic plates infiltrating the duodenal wall as well as a fair amount of lymph nodes in the mesentery. We performed a proctocolectomy. The histologic study showed massive infiltrate of histiocytes and numerous Michaelis-Gutmann bodies. This disease is usually found in the urinary tract and rarely found in the colon. The importance of proper histologic examination in order to arrive at a correct diagnosis is emphasized.
Asunto(s)
Enfermedades del Colon/complicaciones , Hemorragia Gastrointestinal/etiología , Malacoplasia/complicaciones , Colon/patología , Enfermedades del Colon/patología , Enfermedades del Colon/cirugía , Urgencias Médicas , Resultado Fatal , Femenino , Hemorragia Gastrointestinal/patología , Hemorragia Gastrointestinal/cirugía , Humanos , Malacoplasia/patología , Malacoplasia/cirugía , Persona de Mediana Edad , Úlcera/complicaciones , Úlcera/patología , Úlcera/cirugíaRESUMEN
An effective and ultrarapid technique for kidney transplantation in the rat is introduced. In this manner, physiological and immunological parameters could be tested without difficulty in small animals such as the rat. Shorter periods of warm ischemia were achieved by rapid harvesting and anastomotic times using a combination of the sleeve technique for the artery, a cuff technique for the vein, and the over-a-stem technique for the ureter. In 20 rats, total vascular (artery and vein) anastomotic times were 5.35 +/- 0.59 min, of which the artery was 4.30 +/- 0.40 minutes and the vein was 1.05 +/- 0.20 min. The ureter anastomotic time was 1.0 +/- 0.1 min. The surgical complications were three ureteral stenoses. The 15 day survival was 100%. Plasma creatinine and histological findings at 24 and 30 days after transplantation were within normal limits with no evidence of ischemic damage. The advantage of this technique is its effectivity and simplicity that allows for reduced times of warm ischemia. This is the fastest technique published so far in the literature. We propose this technique to be employed in all studies of kidney transplantation and preservation in the rat.