Allopurinol and xanthine oxidase inhibition in liver ischemia reperfusion.

INTRODUCTION: Allopurinol was first introduced, in 1963, as a xanthine oxidase inhibitor when it was investigated for concomitant use with cancer chemotherapy drugs. Today it is used in gout and hyperuricemia. Due to its additive benefit in preventing oxidative damage, attention has shifted towards the use of allopurinol in organ ischemia and reperfusion. CURRENT STATUS: Currently, the mechanism by which allopurinol exerts a protective benefit in ischemia reperfusion related events is not fully understood. There are various theories: it may act by inhibiting the irreversible breakdown of purine substrates, and/or by inhibiting the formation of reactive oxygen species, and/or by protecting against damage to the mitochondrial membrane. AIM: This work focuses on liver ischemia and reperfusion injury in an effort to better understand the mechanisms associated with allopurinol and with this pathological entity. REVIEW OF LITERATURE: The current research, mainly in animal models, points to allopurinol having a protective benefit, particularly if used pre-ischemically in liver ischemia reperfusion injury. Furthermore, after reviewing allopurinol dosing and administration, it was found that 50 mg/kg is statistically the most effective dose in attenuating liver ischemia reperfusion injury. Owing to the limited number of samples, the time of administration did not show statistical difference, but allopurinol was often beneficial when given around 1 h before ischemia. CONCLUSION: In conclusion, allopurinol, through its known xanthine oxidase inhibitory effect, as only one of the potential mechanisms, has demonstrated its potential application in protecting the liver during ischemia and reperfusion.

Effects of dantrolene on ischemia-reperfusion injury in animal models: a review of outcomes in heart, brain, liver, and kidney.

BACKGROUND/OBJECTIVES: Ischemia-reperfusion (IR) is the restoration of blood flow to a tissue that was formerly deficient of blood flow. Tissue damage after IR is considered an IR injury (IRI). During IR, there is an increased level of cytosolic calcium ([Ca(2+)]i) due to the release of calcium from mitochondrial, sarcoendoplasmic reticulum, and nuclear organelles. Dantrolene sodium (dantrolene) is a 1-[[[5-(4-nitrophenol)-2-furanyl]methylene]amino]-2, 4-imidazolidinedione sodium salt with a nonspecific mechanism, inhibiting organelle release of Ca(2+) into the cytosol. This work reviews the outcomes of administering dantrolene in brain, heart, liver, and kidney animal models of IRI. METHODS: An extensive PubMed, MEDLINE, and MEDLAR literature review during the last 30 years on the effect of dantrolene in IRI in animal models was analyzed to determine the clinical implications of this important study. Particular attention was given to dantrolene in heart, brain, liver, and kidney IRI. RESULTS: Heart: Nine studies of heart IRI were reviewed and include an in vivo dog model (n = 1), in vivo rabbit model (n = 1), isolated dog myocardial fibers (n = 1), and isolated rat hearts (n = 6). Four studies showed decreased infarct size and increased cardiac function after IRI. One in vivo rabbit study found no difference in infarct size or cardiac function after IRI versus controls. Dantrolene may be protective or inductive of post-IRI arrhythmias depending on preestablished myocyte cycling times. Brain: Nine studies of brain IRI were reviewed and include an in vivo dog model (n = 1), in vivo gerbil model (n = 2), and in vivo rat models (n = 6). Dantrolene shows protective decreases in apoptotic markers in 6 studies, but it shows no effect on the necrotic core and mixed effects on reduction of infarct volume. One study found increased mortality in the dantrolene group. Liver: One study of in vivo rat liver IRI found that dantrolene decreased liver function tests, tissue necrosis factor α, tissue necrosis, and increased interleukin 10. Kidney: One study of in vivo rat kidney IRI showed that dantrolene had no effect. CONCLUSIONS: Dantrolene shows protective effects in animal models of heart, brain, and potentially liver IRI, reinforcing the importance of calcium homeostasis during IRI. Variations of dose, timing of administration, route of administration, and outcomes between studies make definitive conclusions difficult. The nonspecific mechanism of action of dantrolene may also account for the variation among studies. Lack of studies in the liver and kidney makes any consensus in these organs premature, and thus, emphasis for this review was put on studies of the heart and brain.

Inflammatory mediators of liver ischemia-reperfusion injury.

Liver ischemia and reperfusion--which cause liver damage that is significant in a variety of diseases, injuries, and procedures (including but not limited to trauma and transplant)--have been the focus of many investigations in recent years. Although the mechanisms of ischemia-reperfusion injury are numerous and complex, many advances in treatment have been made. The following review considers recent advances in the understanding of hepatic ischemia-reperfusion injury and focuses on inflammatory mediators of significance. To provide a unique analysis and evaluation, we emphasized the most recent pertinent investigations of the last decade. Specific topics addressed include reactive oxygen species, nitric oxide, toll-like receptors, ischemic preconditioning, T cells, heme oxygenase-1, heat shock proteins, erythropoietin, selectins, protein kinases, matrix metalloproteinases, and cytokines.

Nitric oxide mechanism of protection in ischemia and reperfusion injury.

In 1992 nitric oxide (NO) was declared molecule of the year by Science magazine, and ever since research on this molecule continues to increase. Following this award, NO was shown to be a mediator/protector of ischemia and reperfusion injury in many organs, such as the heart, liver, lungs, and kidneys. Controversy has existed concerning the actual protective effects of NO. However, literature from the past 15 years seems to reinforce the consensus that NO is indeed protective. Some of the protective actions of NO in ischemia and reperfusion are due to its potential as an antioxidant and anti-inflammatory agent, along with its beneficial effects on cell signaling and inhibition of nuclear proteins, such as NF-kappa B and AP-1. New therapeutic potentials for this drug are also continuously emerging. Exogenous NO and endogenous NO may both play protective roles during ischemia and reperfusion injury. Sodium nitroprusside and nitroglycerin have been used clinically with much success; though only recently have they been tested and proven effective in attenuating some of the injuries associated with ischemia and reperfusion. NO inhalation has, in the past, mostly been used for its pulmonary effects, but has also recently been shown to be protective in other organs. The potential of NO in the treatment of ischemic disease is only just being realized. Elucidation of the mechanism by which NO exerts its protective effects needs further investigation. Therefore, this paper will focus on the mechanistic actions of NO in ischemia and reperfusion injury, along with the compound's potential therapeutic benefits.

Protein kinases in organ ischemia and reperfusion.

There is ample evidence of the role that protein kinases play in the signaling pathways secondary to ischemia and reperfusion (I/R). The protein kinases initiate several interconnected downstream cascades regulated by phosphorylation and dephosphorylation reactions. The signaling transduction pathways ultimately initiate the nuclear transcription of the inflammatory and anti-inflammatory genes to repair and assist in the recovery of damaged cells. Although some of the I/R mechanisms are well identified, there is still a lack of general application of this knowledge in clinical practice and particularly in the role that their induction or inhibition can play in disease treatment or improving illness management. This is a review of the current understanding of the role that protein kinases play in the phosphoregulatory mechanisms, which mediate the complex processes of signal transduction secondary to organ I/R injury. Under ischemic conditions, diverse families of protein kinases, including tyrosine kinases, receptor serine kinases, and mitogen-activated protein (MAP) kinases, catalyze the phosphorylation of several proteins that initiate the cascade of events regulated by phosphorylation reactions and subsequent inflammatory gene expression. This phosphorylation catalyzed by protein kinases can nevertheless be reversed by a second group of enzymes, called protein phosphatases, which remove the phosphate and in that way modulate the activity of the protein kinases. The potential role that protein kinase inhibitors play is discussed on the basis of a new understanding of the mechanisms modulating phosphoregulated pathways.

Evaluation of a novel cold storage solution (HBs) in a rat kidney transplant model.

We developed an improved solution for hypothermic storage (0-4 degrees C) of kidneys. The cold storage solution (HBS) was composed of macromolecules, high-energy cellular substrates, and a mixture of antiproteolytic amino acids, antioxidants, and anti-inflammatory compounds. The objectives in developing this solution were to achieve superior metabolic support of the kidney during cold storage and to protect against ischemic injury. Inbred Brown Norway rats, weighing 225-250 g, were subjected to orthotopic ultrarapid technique for kidney isotransplantation to minimize warm ischemia and to test the preservation process. The kidney was transplanted after 12 h of preservation. The animals were divided into three groups based upon the preservation solution utilized: HBS solution, HTK solution (Custodiol), and UW solution (UWS)(ViaSpan). Among the recipients, each group had two subsets. The first subset of animals was used to assess survival at 7 days as well as the reperfusion damage index (RDI) based on the macroscopic physical characteristics of the kidney at the time of transplantation. The second subset in each group was utilized to measure serum creatinine and blood urea nitrogen at 4 and 7 days, and histology at death or sacrifice. Mean +/- standard deviation (M +/- SD) was used for all parameters studied. The HBS solution showed significantly better protection at 12 h when compared to HTK and UW solutions. The reperfusion damage index (RDI) showed excellent preservation in the HBS (14 +/- 1), good preservation in UWS (13 +/- 1.5), and moderate preservation in the HTK (11 +/- 2) group. Histology was in concordance with the RDI, showing better histological findings with HBS and UW solutions than with the HTK group. Serum creatinine was significantly better in the HBS group when compared to HTK and UWS. Survival was statistically different, with 80% survival at 7 days in the HBS group, 20% survival in the HTK group, and 50% survival in the UWS group (p < .05). The HBS solution offered a new alternative for kidney cold storage with significantly better results when compared to the current gold standards of HTK and UW solutions in Brown Norway rats. This solution warrants further testing in other mammals.

Ryanodine receptor antagonism protects the ischemic liver and modulates TNF-alpha and IL-10.

BACKGROUND: Dantrolene is a ryanodine receptor and intracellular calcium antagonist. The ryanodine receptor (RyR) Ca(2+) release channel mobilizes Ca(2+) from internal stores to support a variety of cellular functions, including the inflammatory response after ischemia and reperfusion. The pharmacological mechanism of dantrolene is associated with the inhibition of the release of Ca(2+) from the skeletal muscle sarcoplasmic reticulum (SR). We hypothesized that dantrolene could exert a protective effect in our model of liver ischemia and reperfusion by modulating TNF-alpha and IL-10. MATERIAL AND METHODS: Mice subjected to 90 min of partial (70 to 80%) hepatic ischemia and 3 h of reperfusion were divided into five groups (n = 6/group): sham, ischemic control, and the dantrolene 1 mg/kg group studied at three times of administration: 15 min before reperfusion (DAN-PRE), at the time of reperfusion (DAN-RP), and 15 min after reperfusion (DAN-POS). The parameters measured at 3 h of reperfusion included serum liver function tests alanine aminotransferase (ALT) and aspartate aminotransferase (AST), TNF-alpha, and IL-10 in serum and liver histology. RESULTS: It was demonstrated that the RyR intracellular calcium antagonist dantrolene offered the most significant protection for the ischemic liver when given before reperfusion and at the time of reperfusion. AST significantly differed between the control group and the DAN-PRE and DAN-RP groups (P < 0.05). ALT showed a statistically significant decrease in the DAN-PRE treated group and a decrease, although not significant, in the DAN-RP. Histological examination demonstrated a significant decrease in vacuolization in the same both groups (P < 0.05). Necrosis was significantly diminished when dantrolene was used at the time of reperfusion; congestion decreased in the same groups but without statistical significant difference. The levels of TNF-alpha were significantly decreased in the DAN-RP group. There was a decrease in TNF-alpha in the DAN-PRE group but not statistically significant. IL-10 reflected the protection observed in necrosis and vacuolization in the histopathology with an increment at the time of reperfusion (P < 0.05). DAN-POS did not exert a protective effect in ALT, AST, liver histology, or cytokine response. CONCLUSION: For the first time the ryanodine receptor antagonist dantrolene offered significant functional and structural protection of the ischemic liver when given at the time for reperfusion and partial protection when given prereperfusion. RyR inhibition approach down-regulated the expression of TNF-alpha and induced an increment of the protective cytokine IL-10 when administered at the time of reperfusion. There was no protective effect of dantrolene after reperfusion.

Anti-ischemic effect of selectin blocker through modulation of tumor necrosis factor-alpha and interleukin-10.

BACKGROUND: Preliminary studies in our laboratories indicate that a recently discovered synthetic drug, TBC-1269, acts as a multiple selectin blocker and provides protection against tissue damage in rats that are subjected to severe liver ischemia/reperfusion. Here, we report that this effect is dose and time dependent, with its effects acting through the modulation of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10. MATERIAL AND METHODS: Mice subjected to 90 min of partial (70-80%) hepatic ischemia and 3 h of reperfusion were divided into eight groups (n=6/group): sham, ischemic control (IC), three groups of TBC-1269-treated animals at different concentrations (10, 20, 40, mg/kg) and another three groups of TBC-1269 given at 40 mg/kg at different times of administration: 15 min prereperfusion but after ischemia (no pretreatment), at the time of reperfusion, and at 15 min after reperfusion. The parameters measured at 3 h of reperfusion included liver function tests (alanine aminotransferase and aspartate aminotransferase), histopathology analysis and measurements using enzyme-linked immunosorbent assay in serum of TNF-alpha and IL-10. Statistical analysis included analysis of variance with P values of <0.05 for significance. Results were expressed as mean +/- SD. RESULTS: The liver function tests showed statistically significant differences between the ischemic control group and both the sham group and the group treated with 40 mg/kg at the time of reperfusion (40@RP). These results correlated well with the histopathological analysis in that we found no difference in vacuolization, congestion, and necrosis between the 40@RP group and the sham group. The TNF-alpha and the IL-10 also reflected the protection observed in histopathology, with a decrease in TNF- alpha from the high levels observed in the IC (32 +/- 2.32 pg/mL) to a lower level of 8.5 +/- 4.04 mg observed in the 40@RP group, and an increment in the levels of the protective IL-10 from 2.8 +/- 2.9 pg/mL in the IC group versus 37.9 +/- 11.6 pg/mL in the 40@RP treated group (P<0.05). Lower doses and different times of administration of TBC-1269 did not show a protective effect. The IC group showed no difference in damage by histopathology or liver enzymes compared to the rest of the groups, except the 40@RP group. CONCLUSION: In this work, we demonstrated that the small molecule multiple selectin inhibitor (TBC-1269) offered significant protection for the ischemic liver when given at 40 mg/kg at the time of perfusion. Lower doses and different times of administration did not show the optimal drug effect. The protection observed in the liver function tests (alanine aminotransferase and aspartate aminotransferase) and histopathology in this group was also reflected in the significant decrease in serum TNF-alpha and equally significant increase in serum protective IL-10.

Selectin inhibition modulates NF-kappa B and AP-1 signaling after liver ischemia/reperfusion.

The infiltration of neutrophils after ischemia and reperfusion (I/R) is facilitated by the expression of adhesion molecules on the surface of both leukocytes and endothelial cells. Adhesion molecules of the selectin family are of particular importance at the onset of neutrophil mediated injury, as demonstrated by the occurrence of many cellular interactions with the final extravasation of inflammatory leukocytes at the site of I/R damage. Previous studies demonstrated a prevention of neutrophil extravasation and protection of ischemic damage when a small anti-selectin molecule was used. In this study, we tested a new small anti-selectin compound (OC-229) in a murine model of partial hepatic I/R. The aim of this study was to determine the effect of OC-229 on liver function and histology after I/R and to evaluate its role in the modulation of the inflammatory molecular signaling pathways of NF-kappa B and AP-1 under the same experimental condition. Mice subjected to 90 min of partial (70-80%) hepatic ischemia and 3 h of reperfusion were divided into three groups (n = 9/group): sham, ischemic control, and treated group, which received 25 mg/kg of the anti-selectin small molecule OC-229. These groups were studied when the treatment was given at the time of reperfusion (no pretreatment was given). The parameters measured at 3 h of reperfusion included liver function tests (ALT and AST), liver histology, and liver tissue electrophoretic mobility shift assay (EMSA) for NF-kappa B and AP-1. It was demonstrated that the multiselectin inhibitor OC-229 offered significant protection for the ischemic liver when given at 25 mg/kg at the time of reperfusion. ALT and AST serum levels significantly decreased when the ischemic control and the group receiving OC-229 were compared (p = .01). Treated animals demonstrated better histological findings as well. The EMSA showed dissociation of NF-kappa B and AP-1 activity in the liver nuclear extracts after selectin inhibition treatment. A reduction in the activity of AP-1 and an increment in NF-kappa B activation was seen. In this work, we obtained evidence that the small-molecule selectin inhibitor OC-229 offered functional and histological protection of the ischemic liver when given at 25 mg/kg at the time for reperfusion. There was dissociation in the activation signals of NF-kappa B and AP-1. Increase in NF-kappa B and reduction of the activation of AP-1 were noted at 3 h of reperfusion.

Phosphoregulation of signal transduction pathways in ischemia and reperfusion.

Ischemia/reperfusion (I/R) injury triggered by pathogenic processes, such as organ transplant dysfunction, stroke, myocardial infarction, and shock, stimulate both immune and inflammatory pathways. Inflammatory cell activation and cytotoxic cytokine expression are associated with reperfusion injury. The activation of these inflammatory mediators initiates several interconnected downstream cascades regulated by phosphorylation and dephosphorylation reactions. These complex phosphorylation-dependent signal transduction pathways ultimately initiate nuclear transcription of inflammatory as well as anti-inflammatory genes to repair and assist in the recovery of damaged cells. Radical oxygen species (ROS) production, under ischemic conditions, initiates a cascade of events regulated by phosphorylation/dephosphorylation reactions and inflammatory gene expression. This is a review of the current understanding of the phosphoregulatory mechanisms that mediate the complex processes of signal transduction secondary to I/R injury. The rationale for inhibiting or activating signaling pathways as a promising molecular target for ameliorating reperfusion injury in I/R-related diseases, such as stroke, myocardial infarction, and storage for transplantation, is discussed on the basis of a new understanding of the mechanisms modulating phosphoregulatory pathways. In addition, we present part of our ongoing research in this field with phosphoregulatory signal transduction and its potential application.

Molecular biology of apoptosis in ischemia and reperfusion.

This study reviews the current understanding of the mechanisms that mediate the complex processes involved in apoptosis secondary to ischemia and reperfusion (I/R) and is not intended as a complete literature review of apoptosis. Several biochemical reactions trigger a cascade of events, which activate caspases. These caspases exert their effect through downstream proteolysis until the final effector caspases mediate the nuclear features characteristic of apoptosis, DNA fragmentation and condensation. Within the context of ischemia, the hypoxic environment initiates the expression of several genes involved in inflammation, the immune response, and apoptosis. Many of these same genes are activated during reperfusion injury in response to radical oxygen species generation. It is plausible that inhibition of specific apoptotic pathways via inactivation or downregulation of those genes responsible for the initiation of inflammation, immune response, and apoptosis may provide promising molecular targets for ameliorating reperfusion injury in I/R-related processes. Such inhibitory mechanisms are discussed in this review. Important targets in I/R-related pathologies include the brain during stroke, the heart during myocardial infarction, and the organs during harvesting and/or storage for transplantation. In addition, we present data from our ongoing research of specific signal transduction-related elements and their role in ischemia/reperfusion injury. These data address the potential therapeutic application of anti-inflammatory and anti-ischemic compounds in the prevention of I/R damage.

Reactive oxygen species and molecular biology of ischemia/reperfusion.

Ischemic reperfusion injury is a complex pathophysiological event associated with significant impairment of multiple vascular and cellular responses. Oxidative damage due to the presence of radical oxygen species is the essential step that initiates a wide range of intracellular stress signaling processes that culminate in excessive cytokine and chemokine response, adhesion molecule upregulation and nitric oxide overproduction. As we studied all the various mechanisms of injury, we began deciphering the best means to treat the ischemic insult by modulating those proteins or active mediators that are responsible for the lesion. In this manner, we have utilized free radical scavengers, calcium channel blockers, membrane stabilizers, vasodilators, exogenous nitric oxide and arginine, adhesion molecule blockers and small molecule selectin antagonists, in an effort to improve cell function and survival after ischemia and reperfusion. The continuous investigation of new and old compounds that mitigate the ischemic injury will permit us to advance this important field of medicine.

Selectin inhibition modulates Akt/MAPK signaling and chemokine expression after liver ischemia-reperfusion.

Tissue damage after ischemia and reperfusion (I/R) is largely caused by the sequelae of neutrophil infiltration. This inflammatory process can be initiated as the result of stroke, coronary ischemia, trauma, and other related conditions. The infiltration of neutrophils is facilitated by the expression of adhesion molecules on the surface of endothelial cells. Particularly important are the selectin family of adhesion molecules at the onset of neutrophil-mediated injury. The aim of this study was to determine the role of selectin inhibition in the modulation of chemokine expression and Akt/MAPK signaling after liver I/R. In addition, we evaluated the optimal dose and time of administration of a small molecule selectin inhibitor, TBC-1269. Mice subjected to 90 min of partial (70-80%) hepatic ischemia followed by 3 h of reperfusion were divided into 15 groups (n = 4/group); sham, ischemic control, and 10, 20, and 40 mg/kg dose groups for the antiselectin molecule were studied at 3 times of drug administration: 1 h before reperfusion (but after ischemia), at the time of reperfusion, and at 15 min after reperfusion. The parameters measured after 3 h of reperfusion included liver function tests (ALT and AST), histopathology, and tissue myeloperoxidase (MPO). Chemokine expression (MIP-1alpha, MIP-1beta, MIP-2 and KC), Akt, MAPK (p44/p42), and RSK expressions were also measured in liver tissue by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, respectively. It was demonstrated that the small molecule multi-selectin inhibitor (TBC-1269) offered the most significant protection for the ischemic liver when given at 40 mg/kg at the time ofreperfusion. AST significantly differed between the control group and the group receiving 40 mg/kg at the time of reperfusion (p = .01). MPO levels in the liver tissue of the ischemic controls were significantly increased when compared to the levels of this enzyme in the TBC-1269 group at 40 mg/kg. Histological examination reflected the same results, with a significant difference (p = .02) between these same two groups. The chemokine profile also showed that the same treatment group had a downregulation of MIP-lalpha, MIP-1beta, MIP-2, and KC, as well as a lower expression of Akt, MAPK(p44/42), and RSK when compared to the control group. Thus, we demonstrated that the small molecule selectin inhibitor, TBC-1269, offered significant functional and structural protection of the ischemic liver when given at 40 mg/kg at the time of reperfusion. Lower doses and different times of administration did not show as prominent a drug effect. This selectin inhibition modulated the expression of Akt, MAPK (p44/42), and RSK, as well as MIP-1alpha, MIP-1beta, MIP-2, and KC chemokines. These alterations in cellular signaling and chemokine expression represent potential mechanisms or pathways of inflammatory response in I/R.

Papel del óxido nítrico en isquemia y reperfusión / Role of nitric oxide in ischemia and reperfusion

Objetivo. Analizar y revisar el papel que juega el óxido nítrico en el fenómeno de isquemia/reperfusión en la procuración, preservación y trasplante de órganos. Sede. Centro de Investigación Biomédica de Occidente. IMSS. Diseño. Consulta, revisión y análisis de la literatura, con selección de 58 artículos acerca del tema. Resultado. El papel del óxido nítrico en el fenómeno de isquemia/reperfusión es controversial; los estudios experimentales sugieren que la alteración en ciertos sistemas enzimáticos de las células y tejidos isquémicos, predispone a la formación de intermediarios reactivos del oxígeno como: El anión superóxido (O2), el peróxido de hidrógeno (H2O2), radicales óxidrilos (OH), etcétera. Conjugados con estos elementos existen otros que intervienen en la respuesta inflamatoria post-isquemia, como son los eiconsanoides producidos a partir del ácido araquidónico, y que comprenden a las prostaglandinas, los tromboxanos y los leucotrienos; estos compuestos poseen la capacidad y propiedad de producir daño durante el fenómeno de la isquemia/reperfusión. El gas óxido nítrico es una molécula pequeña, un radical libre muy inestable y reactivo, así como una molécula versátil; se encuentra involucrada en diversas vías metabólicas como son: la transmisión a nivel del sistema nervioso central, la transmisión entre la célula endoterial y la fibra muscular para producir vasodilatación, en sepsis, etcétera. La fuente de nitrógeno para la síntesis de ON es la L-arginina, se produce mediante la acción de una enzima, la ON-sintetaza. Los principales efectos del ON son: inhibe la ribonucleotidil reductasa, inhibe la síntesis celular del DNA, bloque la fosfoorilalción oxidativa y diminuye la síntesis de proteínas. En el fenómeno isquemia/reperfusión el ON produce un efecto dañino debido a su interacción con los radicales libres, empero, algunos autores postulan que posee un efecto protector al disminuir la adhesión plaquetaria al endotelio, la infiltración neutrofílica, la migración leucocitaria post-isquémica de polimorfonucleares, la interacción de los leucocitos con las células endoteliales en las fases de rodamiento y adhesión. Asimismo, bloquea la expresión del factor de necrosis tumoral (FNT). Conclusión. Hasta el momento actual es evidente que el ON interviene en las interacciones leucocitocélula endotelial, pero no es claro si ejerce algún efecto sobre el endotelio

Simposio: enfermedades del páncreas. Apoyo nutricio en pancreatitis aguda grave ¿es útil? / Symposium Diseases of pancreas: nutritional support in severe acute pancreatitis, is it usefull?

Objetivo: Analizar los resultados del apoyo nutricio en pancreatitis aguda grave. Sede: Clínica de hiperalimentación y cirugía, Guadalajara, Jalisco, México. Diseño: Estudio retrospectivo, observacional, sin análisis estadístico ni grupo control. Pacientes y métodos: Se estudiaron 17 pacientes portadores de pancreatitis aguda grave (PAG) que recibieron apoyo nutricio durante un período comprendido entre enero de 1991 a enero de 1995. Los criterios de inclusión fueron los siguientes: cuadro clínico y datos de laboratorio de la enfermedad en estudio, evidencia de necrosis pancreática en la tomografía axial computarizada (TAC), con o sin masa abdominal palpable, con 3 o más criterios de Ranson y que hubieran sido seguidos en su evolución y resultado final por los investigadores. Se analizaron las siguientes variables edad, sexo, etiología de la pancreatitis aguda, días de evoluación y ayuno al momento de la interconsulta, albúmina inicial y final, peso inicial y final, tipo de apoyo nutricio y requerimientos aportados, número de días con apoyo nutricio, días de estancia en cuidados intensivos y en el hospital, apoyo nutricio en el hogar durante la convalecencia; tipo de tratamiento médico o quirúrgico, número de intervencione spractidadas, estratificación por criterios de Ranson, métodos de acceso para el apoyo nutricio y morbilidad hospitalaria. Resultados: Doce pacientes fueron hombres y 5 mujees su promedio de edad fue de 36 años, mínima de 13 y máxima de 60 años. La etiología de la pancreatitis aguda fue por el alcoholismo en 6 pacientes, biliar en 5, postraumática en 3, secundaria a medicamentos en 2 y por hiperlipidemia en uno. Promedio de días de evolución y ayuno al momento de la interconsulta para apoyo nutricio 9; todos presentaron entre 3 y 7 criterios de Ranson, promedio 4. Albúmina inicial promedio de 2.7 g/dl, final de 3.4 g/dl. Quince pacientes requirieron 2 cirugías en promedio y 2 fueron tratados conservadoramente. Doce recibieron nutrición parenteral a través de un catéter venoso central de múltiples vías y 5 recibieron nutrición mixta. El promedio de proteínas administradas fue de 2g/kg/día. Diez pacientes permanecieron, en promedio, 10 días en terapia intensiva y el apoyo nutricio se dio por espacio de 25 días en promedio, con extremos de 10 días mínimo y 45 máximo. Todos los pacientes perdieron, en promedio, 15 por ciento de su peso. La morbilidad fue del 70.5 por ciento, la estancia hospitalaria promedio fue de 25 días con mínimo de 10 a 45 días. Dos pacientes fallecieron por falla orgánica múltiple (FOM) (12 por ciento): Conclusión: La aplicación temprana de nutrición artificial disminuye la morbimortalidad

Hemorragia masiva del aparato digestivo, secundaria a Malacoplaquia colónica ulcerada / Massive hemorrhage of the digestive tract secondary to ulcerated colonic malacoplakia

Reportamos un caso de malacoplaquia del colon que se presentó como hemorragia del tubo digestivo bajo masiva en una paciente femenina de 55 años de edad. Un colon por enema demostró lesiones polipoideas. La colonoscopía reveló nodulaciones pseudo-polipoideas color blanco amarillento, aparentando pequeñas pústulas que se extendían a todo el colon a partir de 2 cm del margen anal. La laparotomía reveló la presencia de masas lobuladas en la luz intestinal y lesiones amarillentas en forma de placas transmulares que infiltraban pared duodenal, así como gran cantidad de ganglios en todo el mesenterio. Realizamos protocolectomía. El estudio microscópico demostró infiltración masiva de histiocitos y numerosos cuerpos de Michaelis-Gutmann. Esta enfermedad se presenta casi exclusivamente en las vías urinarias y es extremadamente rara en el intestino. Enfatizamos en la importancia de un adecuado examen histológico que nos permita un diagnóstico correcto