RESUMEN
Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) has proven to be a valuable tool in the initial diagnosis, staging, and restaging of a variety of cancers. The potential use of FDG-PET in the evaluation and management of hepatocellular carcinoma (HCC) continues to evolve. The purpose of this study was to investigate the effectiveness of FDG-PET for the detection and staging of HCC. In addition, we also assessed the correlation between FDG-PET positivity, tumor size, a-fetal protein level (AFP), and histologic grade. All patients on the hepatobiliary and liver transplant service with biopsy proven HCC that underwent FDG-PET between January 2000 and December 2004 were selected for a retrospective review. Results of the FDG-PET scan were compared with other imaging studies [computed tomography (CT), magnetic resonance imaging (MRI), ultrasonography], intraoperative findings, tumor size, AFP levels, and histologic grade. Of the 20 patients who underwent 18F-FDG PET, increased FDG uptake was noted in 14 scans (70%). These 20 patients fell into 2 groups: 1 for detecting HCC (Group A) and 1 for staging HCC (Group B). There were 7 patients in Group A; only 2 scans (28.6%) showed increased uptake. There were 13 patients in Group B; 12 scans (92.3%) showed increased uptake. In Group B, 11 of the 13 scans (84.6%) provided an accurate representation of the disease process. Two scans failed to accurately portray the disease; one scan failed to show any increase in uptake, and the other scan failed to detect positive nodes that were found during surgery. FDG-PET detected only 2 of 8 tumors (25%) < or = 5 cm in size. All 12 PET scans (100%) in tumors > or = 5 cm and/or multiple in number were detected by FDG-PET. FDG-PET scans with AFP levels < 100 ng/ml were positive in 5 of 9 patients (55.6%). In patients with levels > 100 ng/ml, 6 of 7 patients (85.7%) had positive scans. Histologically, there were 6 well-differentiated, 6 moderately differentiated, and 2 poorly differentiated HCCs. FDG-PET detected 4 of 6 for both well- and moderately differentiated HCCs. Both poorly differentiated HCCs were detected. The intensity was evenly distributed between the different histologic grades. There was a strong correlation of FDG uptake with tumor size. There were 5 HCCs with primary tumors >10 cm in size; 4 showed intense uptake on the scan. In contrast, of the 8 tumors < or = 5 cm in size, 6 were negative for uptake. The sensitivity of FDG-PET in detecting HCC < or = 5 cm in size is low and therefore may not be helpful in detecting all of these tumors. For larger tumors, there is a strong correlation of sensitivity and uptake intensity with tumor size and elevated AFP levels. FDG-PET sensitivity and uptake intensity did not correlate with histologic grade. In the setting of extrahepatic disease, FDG-PET seems to be an effective accurate method for HCC staging; however, whether PET offers any benefit over traditional imaging has yet to be determined.
Asunto(s)
Carcinoma Hepatocelular/diagnóstico por imagen , Carcinoma Hepatocelular/patología , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/patología , Tomografía de Emisión de Positrones , Biomarcadores de Tumor/análisis , Carcinoma Hepatocelular/sangre , Diferenciación Celular , Fluorodesoxiglucosa F18 , Humanos , Neoplasias Hepáticas/sangre , Estadificación de Neoplasias , Radiofármacos , Estudios Retrospectivos , Sensibilidad y Especificidad , alfa-Fetoproteínas/análisisRESUMEN
This study examines the relationship between hypovolemia and remote organ injury following intestinal reperfusion. Sprague-Dawley rats underwent intestinal ischemia (120 min) and reperfusion (90 min, IIR) or sham operation (CTL). The animals received normal saline (NS) at 0, 30, or 40 ml/kg/h intravenously. Lung and intestinal injury was quantitated using an edema index, and liver injury was assessed by measuring bile flow rates. The infusion of 40 ml/kg/h of NS attenuated the intestinal edema index of IIR animals nearly 50% (p < .05). Despite this improvement, this parameter remained nearly 10-fold greater than that of CTL (p < .05). The lung edema index was 70% greater in IIR animals receiving 30 and 40 ml/kg/h of NS than those not receiving NS. The infusion of 40 ml/kg/h of NS restored bile flow rates in IIR animals to that of CTL. These data suggest that hypovolemia may contribute to the intestinal and hepatic injury in this model. The lung injury is independent of hypovolemia.
Asunto(s)
Volumen Sanguíneo , Intestinos/patología , Isquemia/fisiopatología , Traumatismo Múltiple/fisiopatología , Daño por Reperfusión/fisiopatología , Animales , Intestinos/irrigación sanguínea , Hígado/patología , Pulmón/patología , Edema Pulmonar/fisiopatología , Ratas , Ratas Sprague-DawleyRESUMEN
This study examines the hypothesis that hydroxyl radical (OH.) generation during intestinal reperfusion activates the complement system forming the potent chemotaxin C5a. Anesthetized Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IIR). Complement (C) activation was assessed by measuring total plasma C activity and C5a-related chemotaxis and leukoaggregation. Dimethylthiourea and the iron chelator deferoxamine were utilized to assess the role of the OH. in the activation of C in this model. Sham-operated animals served as controls. Total plasma C activity of animals sustaining IIR was 64% of controls (p < .05). Plasma of animals sustaining IIR induced greater chemotaxis and leukoaggregation than plasma from sham-operated groups (p < .05). Treatment of IIR plasma with anti-C5a antibody ameliorated the enhanced leukoaggregation characteristic of IIR plasma. Pretreatment with dimethylthiorea and deferoxamine prevented reperfusion-induced activation of complement and inhibited the chemotactic activity of plasma from IIR animals. These data are consistent with the hypothesis that IIR activates complement and that the OH. generated during reperfusion may be one mechanism by which C is activated in this injury model.
Asunto(s)
Activación de Complemento/fisiología , Radical Hidroxilo/metabolismo , Intestinos/lesiones , Daño por Reperfusión/inmunología , Animales , Factores Quimiotácticos/biosíntesis , Activación de Complemento/efectos de los fármacos , Complemento C5a/antagonistas & inhibidores , Complemento C5a/biosíntesis , Deferoxamina/farmacología , Modelos Animales de Enfermedad , Intestinos/irrigación sanguínea , Masculino , Neutrófilos/fisiología , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/fisiopatología , Tiourea/análogos & derivados , Tiourea/farmacologíaRESUMEN
This study examines the hypothesis that neutrophils isolated from animals sustaining intestinal reperfusion (IIR) induce pulmonary microvascular dysfunction. Lungs were isolated from normal Sprague-Dawley rats and perfused with a physiologic buffer in vitro. Neutrophils (2 x 10(6)) isolated from animals sustaining IIR (n = 5) or sham operation (SHAM; n = 6) were infused into the isolated lung model. A third group of lungs underwent in vitro perfusion without exposure to neutrophils (n = 5). Lung injury was assessed by measuring wet to dry weight ratios and pulmonary artery pressure (PAP). Pulmonary ultrastructure was assessed by electron microscopy. The wet:dry ratio of lungs from animals sustaining IIR was greater than that of lungs exposed to SHAM neutrophils (p = .03) or perfusate alone (p = .02). The PAP of lungs exposed to IIR neutrophils was nearly 10 times greater than that of lungs exposed to SHAM neutrophils (p = .003) or buffer alone (p = .006). Ultrastructural examination of lungs exposed to IIR neutrophils demonstrated interstitial edema with occasional focal disruptions in the alveolar capillary endothelial cell membrane whereas lungs exposed to SHAM neutrophils were normal. These experiments provide important in vitro correlation of prior in vivo studies suggesting that neutrophils are important pathogenic mediators of IIR-induced lung injury.
Asunto(s)
Intestinos/irrigación sanguínea , Lesión Pulmonar , Neutrófilos/fisiología , Daño por Reperfusión , Animales , Técnicas In Vitro , Pulmón/ultraestructura , Masculino , Microcirculación/fisiología , Neutrófilos/metabolismo , Perfusión , Ratas , Ratas Sprague-Dawley , Superóxidos/sangreRESUMEN
Normal rat splanchnic blood flow and eicosanoid synthesis were compared to sham (Sham) and hemorrhage/reperfusion (SK + R) animals treated with 5 days of total parenteral nutrition (TPN). After in vivo measurement of superior mesenteric artery (SMA) blood flow, the splanchnic bed was perfused in vitro and venous effluent assayed for eicosanoid release by EIA. Aortic, SMA, ileal muscularis/serosa, and mucosa homogenates were analyzed for cyclooxygenase (COX) and prostacyclin synthase (PS) content by Western blot and for COX activity by radiochromatography. SK + R + TPN decreased SMA blood flow 33% and increased splanchnic PGI2 release twofold (p < .05) compared with the Sham +TPN and normal groups. groups SK + R + TPN did not alter COX activity in any of the tissues but Western blot analysis showed a twofold increase in COX and PS content in ileum muscularis/serosa (p < .05). These data show that SK + R + TPN induced a decrease in SMA blood flow and a compensatory increase in release of splanchnic PGI2. The mechanism for increased splanchnic PGI2 release after SK + R + TPN was an increase in PS and COX content (not activity) in the ileal muscularis/serosa.
Asunto(s)
Sistema Enzimático del Citocromo P-450/biosíntesis , Epoprostenol/metabolismo , Intestinos/irrigación sanguínea , Oxidorreductasas Intramoleculares , Isomerasas/biosíntesis , Daño por Reperfusión/metabolismo , Animales , Mucosa Intestinal/metabolismo , Masculino , Arterias Mesentéricas/fisiopatología , Nutrición Parenteral , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo RegionalRESUMEN
Intestinal reperfusion (IR)-induced pulmonary edema has been related to endogenous pulmonary thromboxane A2 (TxA2) release. This study examines the hypothesis that alveolar macrophages (aMphis) activated during IR are an important cellular source of TxA2 in this model. Anesthetized Sprague Dawley rats underwent 120 min of intestinal ischemia and 60 min of reperfusion (IR) or sham operation (Sham). aMphis were isolated by bronchoalveolar lavage and incubated in Krebs buffer for 30 min, after which the supernatant was analyzed for TxB2 (metabolite of TxA2) and prostaglandin E2. Other parameters of aMphi activation measured included lysosomal enzyme release (beta-glucuronidase), superoxide (O2-) release, and procoagulant activity. aMphis from animals sustaining IR generated more than twice as much TxA2 and prostaglandin E2 as did those isolated from controls (p < .05). Other evidence of aMphi activation included a nearly 100-fold increase in procoagulant activity, a 7-fold increase in beta-glucuronidase release, and a 2.5-fold increase in O2- release over that of controls (p < .05). These data suggest that TxA2 is a major eicosanoid product of aMphis during IR and that aMphis may be an important cellular participant in IR-induced pulmonary microvascular injury, either directly by releasing O2-, lysosomal enzymes, and pro-coagulant factors, or indirectly by generating TxA2.
Asunto(s)
Dinoprostona/biosíntesis , Intestinos/irrigación sanguínea , Activación de Macrófagos/fisiología , Macrófagos Alveolares/fisiología , Daño por Reperfusión/inmunología , Tromboxano B2/biosíntesis , Animales , Coagulación Sanguínea , Células Cultivadas , Glucuronidasa/biosíntesis , Isquemia/inmunología , Isquemia/fisiopatología , Lisosomas/enzimología , Macrófagos Alveolares/inmunología , Masculino , Arterias Mesentéricas/fisiología , Edema Pulmonar/etiología , Edema Pulmonar/inmunología , Ratas , Ratas Sprague-Dawley , Superóxidos/metabolismoRESUMEN
BACKGROUND: This study examines the hypothesis that pulmonary inducible nitric oxide synthase (iNOS) activity is up-regulated during intestinal reperfusion and that inhibition of NO generation exacerbates pulmonary microvascular dysfunction. METHODS: Sprague-Dawley rats underwent intestinal ischemia and reperfusion (IIR) or sham operation (SHAM). Pulmonary iNOS activity was measured by quantitating the conversion of L-arginine (L-Arg) to L-citrulline. Another set of animals undergoing IIR or SHAM received an inhibitor of NOS (NG-nitro-L-arginine methylester; L-NAME; 20 mg/kg intravenously), substrate for NO generation (L-Arg; 300 mg/kg intravenously), or vehicle (normal saline solution; 3 ml). Pulmonary microvascular dysfunction was then quantitated by measuring the extravasation of Evans blue dye (EBD) into the lung. RESULTS: Inducible NOS activity was six times greater in the lungs of animals sustaining IIR when compared with SHAM (p = 0.0005). The concentration of EBD within the lungs of animals sustaining IIR was 30% greater than SHAM (p < 0.05). Inhibiting NOS with L-NAME significantly increased pulmonary EBD concentration of both IIR and SHAM groups when compared with normal saline solution-treated animals (p < 0.0001). Treatment with L-Arg prevented this IIR-induced increase in pulmonary dye extravasation. CONCLUSIONS: These data suggest that pulmonary iNOS activity is up-regulated in animals sustaining IIR and that this may serve as a compensatory protective response to remote organ injury.
Asunto(s)
Aminoácido Oxidorreductasas/metabolismo , Intestinos/irrigación sanguínea , Isquemia/enzimología , Pulmón/enzimología , Reperfusión , Animales , Arginina/análogos & derivados , Arginina/farmacología , Permeabilidad Capilar/efectos de los fármacos , Azul de Evans , Masculino , Microcirculación/efectos de los fármacos , NG-Nitroarginina Metil Éster , Óxido Nítrico/antagonistas & inhibidores , Óxido Nítrico Sintasa , Circulación Pulmonar/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
BACKGROUND: This study examined the hypothesis that exposure of an endothelial cell (EC) monolayer to tumor necrosis factor-alpha (TNF-alpha) and that burn-activated neutrophils alter EC actin cytoskeleton and enhance the permeability of the monolayer. METHODS: Neutrophils were harvested from rats that had undergone a 45% surface area burn (BURN-neutrophil) or uninjured control rats. ECs were grown on polyester filters or fibronectin-coated glass slides and exposed for 4 hours to media, TNF-alpha (100 ng/mL), or TNF-alpha plus BURN-neutrophil or uninjured control rats (10(7) cells). Monolayer permeability was assessed by measuring the flux of albumin across the cells. EC surface area and microfilament number and length were determined by the staining of actin microfilaments with rhodamine phalloidin followed by fluorescent microscopy. RESULTS: The amount of albumin that moved across the monolayer in response to TNF-alpha plus BURN-neutrophil was twice that of media alone (P <.05) or TNF-alpha alone (P <.05). The number and length of actin microfilaments in ECs exposed to TNF-alpha plus BURN-neutrophil were significantly less than that of cells exposed to media alone or TNF-alpha alone. CONCLUSIONS: These data are consistent with a hypothesis that TNF-alpha plus BURN-neutrophil affect endothelial monolayer permeability by altering EC actin cytoskeletal organization.
Asunto(s)
Actinas/fisiología , Quemaduras/sangre , Citoesqueleto/fisiología , Endotelio Vascular/fisiología , Activación Neutrófila , Neutrófilos/fisiología , Factor de Necrosis Tumoral alfa/farmacología , Actinas/efectos de los fármacos , Animales , Quemaduras/fisiopatología , Permeabilidad de la Membrana Celular/efectos de los fármacos , Permeabilidad de la Membrana Celular/fisiología , Células Cultivadas , Citoesqueleto/efectos de los fármacos , Endotelio Vascular/citología , Endotelio Vascular/efectos de los fármacos , Humanos , Técnicas In Vitro , Masculino , Ratas , Ratas Sprague-Dawley , Venas UmbilicalesRESUMEN
The Nissen fundoplication (NFP) for the management of severe gastroesophageal reflux (GER) in infants and children has become one of the most frequently performed operations in pediatric surgical centers in the United States. Short-term outcome, morbidity, and mortality are consistently favorable in several large series. The long-term success of this procedure is presumed but has not been established objectively. To examine the late results of this operation, 46 infants and children were carefully evaluated more than 5 years after NFP (mean, 6.7 years). Evaluation included parental interview, physical examination, upper gastrointestinal series, and esophageal pH monitoring. The mean age at the time of operation was 4.13 years. Fifty-seven percent of the patients had significant neurologic impairment, and 80% had at least one serious additional medical problem. Twenty-four percent of the children died during the period of follow-up--all but one death related to serious underlying medical problems. Of the 35 survivors, 26 (74.3%) have no symptoms; five (14.3%) have mild symptoms potentially referable to GER that necessitate little if any treatment; four (11.5%) have had symptomatic recurrence of GER necessitating repeat fundoplication. Three of these patients now have no symptoms. Forty-five percent of the patients had at least one postoperative complication. NFP provides efficacious, long-term treatment of GER in infants and children, with acceptable morbidity. Mortality in this group of children is related primarily to associated diseases rather than to GER.
Asunto(s)
Reflujo Gastroesofágico/cirugía , Adolescente , Niño , Preescolar , Estudios de Evaluación como Asunto , Femenino , Reflujo Gastroesofágico/diagnóstico , Humanos , Lactante , Complicaciones Intraoperatorias , Masculino , Complicaciones Posoperatorias/mortalidad , RecurrenciaRESUMEN
BACKGROUND: Intestinal ischemia-reperfusion injury (IIR) induces hepatic and pulmonary dysfunction and thus has been used as a model of multiple organ failure syndrome. This study examines the hypothesis that hepatic blood flow is markedly reduced in this injury model. METHODS: Sprague-Dawley rats underwent 120 minutes of intestinal ischemia and 60 minutes of reperfusion (IIR). Hepatic blood flow was measured with radiolabeled microspheres and Doppler flow probes. Hepatic dysfunction was quantitated by measuring bile flow and serum alanine aminotransferase and hepatic tissue adenosine triphosphate levels. Sham-operated animals served as controls. RESULTS: Intestinal ischemia reduced portal flow by 66% when compared with sham-operated animals (p = 0.0001) but had no effect on hepatic arterial flow. In contrast, reperfusion reduced hepatic artery flow by 80% when compared with controls (p = 0.002) with most of this change occurring within 5 minutes of reperfusion. IIR induced a 63% reduction in bile flow (p < 0.05), a fivefold rise in serum alanine aminotransferase level (p < 0.0002), and a 33% reduction in hepatic adenosine triphosphate level (p < 0.05). CONCLUSIONS: These data suggest that IIR induces profound hepatic hypoperfusion, which is temporally related to acute hepatic dysfunction. This observation suggests that hepatic ischemia may contribute to IIR-induced liver injury.
Asunto(s)
Arteria Hepática/fisiopatología , Intestinos/irrigación sanguínea , Isquemia/fisiopatología , Hígado/irrigación sanguínea , Vena Porta/fisiopatología , Reperfusión , Alanina Transaminasa/sangre , Análisis de Varianza , Animales , Radioisótopos de Cesio , Arteria Hepática/fisiología , Masculino , Microesferas , Músculo Liso Vascular/fisiología , Músculo Liso Vascular/fisiopatología , Vena Porta/fisiología , Ratas , Ratas Sprague-Dawley , Valores de Referencia , Flujo Sanguíneo Regional , Radioisótopos de RutenioRESUMEN
BACKGROUND: This study examines the hypothesis that specific inhibition of the inducible isoform of nitric oxide synthase (iNOS) will attenuate intestinal reperfusion-induced pulmonary microvascular dysfunction. METHODS: Sprague-Dawley rats underwent intestinal ischemia-reperfusion (IR) or sham operation (SHAM). Before injury, the animals received a selective inhibitor of iNOS (S-methylisothiourea sulfate, SMT: L-N6-[1-iminoethyl] lysine L-NIL), a nonselective inhibitor of NOS (NG-nitro-L-arginine methylester, L-NAME) or vehicle (0.9% saline). IR-induced changes in pulmonary microvascular permeability were assessed by quantitating the extravasation of Evans blue dye (EBD)-bound protein into the lung. Pulmonary iNOS activity and content were assessed by radiochemical analysis and Western blot, respectively. RESULTS: There was 60% more EBD within the lungs of animals sustaining IR when compared with controls (P < .05). Pretreatment with SMT or L-NIL totally prevented the increase in EBD extravasation associated with IR. In contrast, pretreatment with L-NAME resulted in a 10% increase in dye extravasation in those animals sustaining IR when compared with similarly injured animals receiving saline (P > .05). There was significantly greater iNOS activity and enzyme content within the lungs of animals sustaining IR compared with controls. CONCLUSIONS: These data are consistent with the hypothesis that the release of nanomolar quantities of nitric oxide generated by iNOS contributes to IR-induced pulmonary microvascular dysfunction.
Asunto(s)
Intestinos/irrigación sanguínea , Óxido Nítrico Sintasa/metabolismo , Edema Pulmonar/metabolismo , Daño por Reperfusión/metabolismo , Animales , Capilares/enzimología , Modelos Animales de Enfermedad , Pulmón/irrigación sanguínea , Pulmón/enzimología , Masculino , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa de Tipo II , Circulación Pulmonar/fisiología , Edema Pulmonar/etiología , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/complicaciones , Organismos Libres de Patógenos EspecíficosRESUMEN
BACKGROUND: This study was performed to determine whether there is a significant association between abdominal aortic aneurysms (AAAs) and malignancy and to determine the impact of malignancy on late survival in patients with AAA. METHODS: We studied 126 men undergoing AAA repair and compared them with 99 men undergoing aortofemoral bypass (AFB) for occlusive disease and with 100 men undergoing herniorrhaphy during the same period. RESULTS: Fifty-one (40%) patients with AAA, 23 (23%) patients undergoing AFB, and 21 (21%) patients undergoing herniorrhaphy were diagnosed with cancer (p = 0.002). By life table analysis the proportion of subjects remaining cancer free at 5 years was 0.60 +/- 0.05 for AAA, 0.83 +/- 0.04 for AFB, and 0.81 +/- 0.04 for herniorrhaphy (p = 0.004). Multivariate analysis selected four independent risk factors for cancer: presence of AAA (p = 0.003, odds ratio 1.4, confidence interval [CI] 1.2 to 1.7), age (p = 0.001, odds ratio per year 1.1, CI 1.0 to 1.1), smoking (p = 0.04, odds ratio 1.5, CI 1.0 to 2.2), and hypertension (p = 0.04, odds ratio 0.73, CI 0.5 to 1.0). Cancer deaths accounted for 32% of late deaths in patients with AAA, which was not different compared with 26% of late deaths in patients undergoing AFB and 36% of late deaths in patients undergoing herniorrhaphy. Five-year cancer-free survival was 0.44 +/- 0.05 for patients with AAA, 0.64 +/- 0.05 for patients undergoing AFB, and 0.70 +/- 0.05 for patients undergoing herniorrhaphy (p < 0.001, AAA versus herniorrhaphy only). CONCLUSIONS: Cancer is more prevalent in men with AAA than in men undergoing AFB or herniorrhaphy. The presence of AAA appears to be an independent risk factor for cancer. Despite the higher cancer prevalence in patients with AAA, cardiovascular disease accounted for the largest number of late deaths in this series, minimizing differences in cancer-free survival between patients with AAA and patients undergoing AFB.
Asunto(s)
Aneurisma de la Aorta/complicaciones , Neoplasias/complicaciones , Anciano , Anastomosis Quirúrgica , Aorta/cirugía , Aorta Abdominal , Aneurisma de la Aorta/mortalidad , Arteriopatías Oclusivas/complicaciones , Arteriopatías Oclusivas/mortalidad , Arteriopatías Oclusivas/cirugía , Arteria Femoral/cirugía , Hernia Inguinal/complicaciones , Hernia Inguinal/mortalidad , Hernia Inguinal/cirugía , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/mortalidad , Análisis de Supervivencia , Procedimientos Quirúrgicos VascularesRESUMEN
This study examines the hypothesis that intestinal reperfusion (IR)-induced pulmonary thromboxane A2 (TxA2) release increases local microvascular permeability and induces pulmonary vasoconstriction. Sprague-Dawley rats underwent 120 min of intestinal ischemia and 60 min of IR. Sham-operated animals (Sham) served as controls. After IR or Sham, the pulmonary vessels were cannulated, and the lungs were perfused in vitro with Krebs buffer. Microvascular permeability was quantitated by determining the filtration coefficient (Kf), and pulmonary arterial (Ppa), venous (Ppv), and capillary (Ppc) pressures were measured to calculate vascular resistance (Rt). After baseline measurements, imidazole (TxA2 synthase inhibitor) or SQ-29,548 (TxA2-receptor antagonist) was added to the perfusate; then Kf, Ppa, Ppv, and Ppc were again measured. The Kf of lungs from IR animals was four times greater than that of Sham (P = 0.001), and Rt was 63% greater in the injured group (P = 0.01). Pc of IR lungs was twice that of controls (5.4 +/- 1.0 vs. 2.83 +/- 0.3 mmHg. IR vs. Sham, respectively; P < 0.05). Imidazole or SQ-29,548 returned Kf to baseline measurements (P < 0.05) and reduced Rt by 23 and 17%, respectively (P < 0.05). IR-induced increases in Pc were only slightly reduced by 500 micrograms/ml imidazole (14%; P = 0.05) but unaffected by lower doses of imidazole (5 or 50 micrograms/ml) or SQ-29,548. These data suggest that IR-induced pulmonary edema is caused by both increased microvascular permeability and increased hydrostatic pressure and that these changes are due, at least in part, to the ongoing release of TxA2.
Asunto(s)
Intestinos/efectos de los fármacos , Circulación Pulmonar/efectos de los fármacos , Tromboxano A2/farmacología , Animales , Masculino , Permeabilidad , Ratas , Ratas Sprague-DawleyRESUMEN
This study examines the hypothesis that intestinal ischemia-reperfusion (I/R) injury contributes to renal dysfunction by altered renal eicosanoid release. Anesthetized Sprague-Dawley rats underwent 60 min of sham or superior mesenteric artery (SMA) occlusion with 60 min of reperfusion. The I/R groups received either allopurinol, pentoxifylline, 1-benzylimidazole, or carrier before SMA occlusion. In vivo renal artery blood flow was measured by Transonic flow probes, the kidneys were then perfused in vitro for 30 min, and the effluent was analyzed for eicosanoid release and renal function. Intestinal I/R caused a twofold increase in the ratio of renal release of thromboxane B2 to prostaglandin E2 and to 6-ketoprostaglandin F1alpha compared with the sham level, with a corresponding 25% decrease in renal sodium and inulin clearance and renal blood flow. Pentoxifylline or allopurinol pretreatment restored renal eicosanoid release and renal sodium and inulin clearance to the sham level but did not alter renal blood flow. Pretreatment with 1-benzylimidazole restored renal function, eicosanoid release, and renal blood flow to sham levels. These data suggest that severe intestinal I/R contributes to the downregulation of renal function. The decrease in renal function is due in part to toxic oxygen metabolites, which occur in the milieu of altered renal eicosanoid release, reflecting a decrease in vasodilator and an increase in vasoconstrictor eicosanoids.
Asunto(s)
Eicosanoides/metabolismo , Isquemia/fisiopatología , Riñón/fisiopatología , Daño por Reperfusión/fisiopatología , Circulación Esplácnica , Alopurinol/farmacología , Animales , Presión Sanguínea/efectos de los fármacos , Imidazoles/farmacología , Técnicas In Vitro , Inulina/metabolismo , Isquemia/metabolismo , Masculino , Pentoxifilina/farmacología , Ratas , Ratas Sprague-Dawley , Circulación Renal/efectos de los fármacos , Daño por Reperfusión/metabolismo , Sodio/metabolismoRESUMEN
The induction of cyclooxygenase is an important event in the pathophysiology of acute lung injury. The purpose of this study was to examine the synergistic effects of various cyclooxygenase products (PGE(2), PGI(2), PGF(2alpha)) on thromboxane A(2) (TxA(2))-mediated pulmonary microvascular dysfunction. The lungs of Sprague-Dawley rats were perfused ex vivo with Krebs-Henseleit buffer containing indomethacin and PGE(2) (5 x 10(-8) to 1 x 10(-7) M), PGF(2alpha) (7 x 10(-9) to 5 x 10(-6) M), or PGI(2) (5 x 10(-8) to 2 x 10(-5) M). The TxA(2)-receptor agonist U-46619 (7 x 10(-8) M) was then added to the perfusate, and then the capillary filtration coefficient (K(f)), pulmonary arterial pressure (Ppa), and total pulmonary vascular resistance (RT) were determined. The K(f) of lungs perfused with U-46619 was twice that of lungs perfused with buffer alone (P = 0.05). The presence of PGE(2), PGF(2alpha), and PGI(2) within the perfusate of lungs exposed to U-46619 caused 118, 65, and 68% increases in K(f), respectively, over that of lungs perfused with U-46619 alone (P < 0.03). The RT of lungs perfused with PGE(2) + U-46619 was approximately 30% greater than that of lungs exposed to either U-46619 (P < 0.02) or PGE(2) (P < 0.01) alone. When paired measurements of RT taken before and then 15 min after the addition of U-46619 were compared, PGI(2) was found to attenuate U-46619-induced increases in RT (P < 0.01). These data suggest that PGE(2), PGI(2), and PGF(2alpha) potentiate the effects of TxA(2)-receptor activation on pulmonary microvascular permeability.
Asunto(s)
Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico/farmacología , Microcirculación/efectos de los fármacos , Prostaglandinas/farmacología , Arteria Pulmonar/fisiología , Circulación Pulmonar/efectos de los fármacos , Análisis de Varianza , Animales , Presión Sanguínea/efectos de los fármacos , Dinoprost/farmacología , Dinoprostona/farmacología , Epoprostenol/farmacología , Técnicas In Vitro , Indometacina/farmacología , Microcirculación/fisiología , Perfusión , Arteria Pulmonar/efectos de los fármacos , Circulación Pulmonar/fisiología , Ratas , Ratas Sprague-Dawley , Resistencia Vascular/efectos de los fármacosRESUMEN
OBJECTIVE: To examine the effects of diabetes mellitus on lipopolysaccharide (LPS)-induced pulmonary edema and alveolar neutrophil recruitment and activation. HYPOTHESIS: Zucker diabetic fatty rats are resistant to the effects of intratracheal LPS on the extravasation of plasma proteins into the lungs. DESIGN: Zucker diabetic fatty (ZDF) rats (genotype fa/fa) were used as a model of diabetes mellitus, while their normoglycemic heterozygous littermates served as controls. Lipopolysaccharide (Escherichia coli 0111: B4; 100-200 microg) or vehicle (0.25 mL of isotonic sodium chloride solution) was instilled into the airways of ZDF and control rats. Four hours later, pulmonary microvascular dysfunction was assessed by measuring the extravasation of Evans blue dye into the lung. Lipopolysaccharide-induced neutrophil recruitment was assessed by counting the number of neutrophils within the bronchoalveolar lavage fluid and measuring their expression of CD11b/CD18 by fluorescence-activated cell analysis sorting. RESULTS: The LPS (200 microg) induced a 32% increase in Evans blue dye extravasation into the lungs of controls (P = .008) but had no such effect in diabetic animals. Pulmonary extravasation of Evans blue dye in controls was greater than that of ZDF rats both at baseline (P = .002) and in response to 200 microg of LPS (P<.001). The LPS upregulated neutrophil CD11b/CD18 expression in diabetic and nondiabetic groups and induced a greater than 50-fold increase in the number of neutrophils within the airways of both control and diabetic groups (P<.001). CONCLUSION: Despite the recruitment of a large number of neutrophils into the lung, the LPS-induced change in pulmonary microvascular permeability in diabetic animals is substantially less than that of nondiabetic controls.
Asunto(s)
Diabetes Mellitus Experimental/inmunología , Lipopolisacáridos/inmunología , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Animales , Permeabilidad Capilar/inmunología , Agua Pulmonar Extravascular/metabolismo , Pulmón/irrigación sanguínea , Masculino , Infiltración Neutrófila/inmunología , Alveolos Pulmonares/inmunología , Ratas , Ratas ZuckerRESUMEN
OBJECTIVES: To examine whether the lung releases nitric oxide (NO) in response to thromboxane A2 and to examine the local release of NO as a protective compensatory mechanism by which the lung responds to the proinflammatory and vasoactive effects of thromboxane A2. DESIGN: The lungs of anesthetized Sprague-Dawley rats were perfused in vitro with Krebs-Henseleit buffer that contained an inhibitor of NO synthase (nitroglycerinenitro-L-arginine methyl ester [L-NAME]) (10(-4) mol/L), an NO donor (sodium nitroprusside) (10(-8) mol/L), or perfusate alone. Following equilibration, the thromboxane A2 receptor agonist 9,11-dideoxy-11alpha, 9alpha-epoxymethanoprostaglandin F2alpha(U-46619) (7.1 X 10(-8) mol/L) was added to the perfusate. Fifteen minutes later, the capillary filtration coefficient, pulmonary arterial pressure, and vascular resistance were measured. Pulmonary NO release was assessed by quantitating the release of cyclic guanosine monophosphate into the perfusate. RESULTS: The capillary filtration coefficient of lungs exposed to U-46619 was 3.5 times greater than that of lungs perfused with buffer alone (P<.05). The addition of sodium nitroprusside reduced the increase in capillary filtration coefficient associated with U-46619 by 50% (P<.05) whereas L-NAME had no effect. The addition of U-46619 to the perfused lung caused a 3.0+/-0.4 mm Hg increase in pulmonary artery pressure (P<.01) with a corresponding rise in total vascular resistance (P<.05). This effect was exacerbated by L-NAME (P<.05) and inhibited by sodium nitroprusside (P<.05). Exposure of the isolated lungs to U-46619 caused a 4-fold increase in cyclic guanosine monophosphate levels within the perfusate. CONCLUSION: These data are consistent with the hypothesis that NO release may be an important protective mechanism by which the lung responds to thromboxane A2.
Asunto(s)
Permeabilidad Capilar , Pulmón/fisiopatología , Óxido Nítrico/fisiología , Tromboxano A2/fisiología , Animales , Ratas , Ratas Sprague-Dawley , Resistencia VascularRESUMEN
This study examines the hypothesis that long-term resuscitation with hyperalimentation (TPN) following acute hemorrhage/reperfusion (H/R) injury stimulates renal release of PGE2. Male Sprague-Dawley rats were anesthetized and subjected to sham or hemorrhage to 30 mmHg for 30 min followed by reperfusion. All rats were placed on TPN for 5 days, then underwent laparotomy for in vivo renal artery and aortic blood flow for 60 min. The kidney was perfused in vitro with Krebs-Henseleit buffer at 3 ml/min (pH 7.4, 37 degrees C) and venous effluent was collected for analysis of PGE2, 6-keto-PGF1 alpha and thromboxane B2 by EIA. Hemorrhage/reperfusion followed by TPN for 5 days increased renal PGE2 2-fold and decreased in vivo renal artery blood flow by 50% compared to the sham group. Hemorrhage/reperfusion followed by TPN did not alter release of the other eicosanoids measured. These data suggest that the kidney has a limited capacity to maintain renal blood flow by increasing release of PGE2 when the animal is subjected to long-term resuscitation with TPN following mild hemorrhage/reperfusion injury.
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Dinoprostona/metabolismo , Hemorragia/metabolismo , Riñón/metabolismo , Daño por Reperfusión/metabolismo , Resucitación/métodos , Animales , Eicosanoides/metabolismo , Riñón/irrigación sanguínea , Masculino , Modelos Biológicos , Nutrición Parenteral Total , Ratas , Ratas Sprague-Dawley , Circulación Renal , Tromboxano B2/metabolismo , Factores de Tiempo , Vasodilatadores/metabolismoRESUMEN
Estrogen has been proposed as a negative risk factor for development of peripheral vascular disease yet mechanisms of this protection are not known. This study examines the hypothesis that estrogen stimulates rat aortic endothelial cell (RAEC) release of PGI2. Male Sprague-Dawley rat abdominal aortic 1-mm rings were placed on 35 mm matrigel plates, and incubated for 1 week. The cells were transferred to a Primaria 60-mm dish and maintained from passage 3 in RAEC complete media and experiments performed between passages 4-10. Cells were incubated with Krebs-Henseleit buffer (pH 7.4) containing carrier or increasing concentrations of beta-estradiol or testosterone for 60 min. The effluent was analyzed for eicosanoid release of 6-keto-PGF1 alpha (6-keto, PGI2 metabolite), PGE2 and thromboxane B2 (TXB2) by EIA (hormone stimulated-basal). Cells were analyzed for total protein by the Bradford method and for cyclooxygenase-1 (COX-1) and prostacyclin synthase (PS) content by Western blot analysis and densitometry. Testosterone did not alter RAEC 6-keto-PGF1 alpha release, whereas estrogen increased RAEC 6-keto-PGF1 alpha release in a dose-related manner. Estrogen preincubation (10 ng/ml) decreased COX-1 and PS content by 40% suggesting that the estrogen-induced increase in male RAEC PGI2 release was not due to increased synthesis of COX-1 or PS. These data support the hypothesis that estrogen stimulation can increase endogenous male RAEC release of PGI2.
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Endotelio Vascular/metabolismo , Epoprostenol/metabolismo , Estrógenos/farmacología , Oxidorreductasas Intramoleculares , 6-Cetoprostaglandina F1 alfa/metabolismo , Animales , Aorta , Western Blotting , Ciclooxigenasa 1 , Sistema Enzimático del Citocromo P-450/metabolismo , Dinoprostona/metabolismo , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/enzimología , Estradiol/sangre , Concentración de Iones de Hidrógeno , Técnicas para Inmunoenzimas , Isoenzimas/metabolismo , Isomerasas/metabolismo , Masculino , Proteínas de la Membrana , Prostaglandina-Endoperóxido Sintasas/metabolismo , Ratas , Ratas Sprague-Dawley , Testosterona/sangre , Testosterona/farmacología , Tromboxano B2/metabolismoRESUMEN
BACKGROUND: The role of mammography in the evaluation of male patients presenting with breast disease is controversial. This controversy is a function of the lack of specific data concerning the diagnostic accuracy of mammography when used in this clinical setting. The purpose of this study was to define the diagnostic accuracy of mammography in the evaluation of male breast disease. METHODS: One hundred and four prebiopsy mammograms from 100 patients with tissue diagnoses were read blindly by two independent radiologists, and placed into one of five predetermined categories: definitely malignant, possibly malignant, gynecomastia, benign mass, and normal. Radiologic/pathologic correlation was performed and the sensitivity (Sn), specificity (Sp), positive (Ppv) and negative predictive value (Npv), and accuracy (Ac) for each of the mammographic diagnostic category determined. RESULTS: The pathologic diagnoses were 12 cancers, including 1 patient with bilateral breast cancer, 70 cases of gynecomastia, 16 benign masses, and 6 normals. The accuracy data for the mammographic diagnostic categories are as follows: malignant (combined definitely and possibly malignant), Sn 92%, Sp 90%, Ppv 55%, Npv 99%, Ac 90%; and overall benignity (combined gynecomastia, benign mass, and normal), Sn 90%, Sp 92%, Ppv 99%, Npv 55%, Ac 90%. Six cancers (50%) coexisted with gynecomastia. CONCLUSIONS: Mammography can accurately distinguish between malignant and benign male breast disease. Although not a replacement for clinical examination, its routine use could substantially reduce the need for biopsy in patients whose mammograms and clinical examination suggest benign disease.