RESUMEN
AIMS/HYPOTHESIS: Several lines of evidence suggest that incretin-based therapies suppress the development of cardiovascular disease in type 2 diabetes. We investigated the possibility that glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can prevent the development of atherosclerosis in Apoe (-/-) mice. METHODS: Apoe (-/-) mice (17 weeks old) were administered GLP-1(7-36)amide, GLP-1(9-36)amide, GIP(1-42) or GIP(3-42) for 4 weeks. Aortic atherosclerosis, oxidised LDL-induced foam cell formation and related gene expression in exudate peritoneal macrophages were determined. RESULTS: Administration of GLP-1(7-36)amide or GIP(1-42) significantly suppressed atherosclerotic lesions and macrophage infiltration in the aortic wall, compared with vehicle controls. These effects were cancelled by co-infusion with specific antagonists for GLP-1 and GIP receptors, namely exendin(9-39) or Pro(3)(GIP). The anti-atherosclerotic effects of GLP-1(7-36)amide and GIP(1-42) were associated with significant decreases in foam cell formation and downregulation of CD36 and acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) in macrophages. GLP-1 and GIP receptors were both detected in Apoe (-/-) mouse macrophages. Ex vivo incubation of macrophages with GLP-1(7-36)amide or GIP(1-42) for 48 h significantly suppressed foam cell formation. This effect was wholly abolished in macrophages pretreated with exendin(9-39) or (Pro(3))GIP, or with an adenylate cyclase inhibitor, MDL12,330A, and was mimicked by incubation with an adenylate cyclase activator, forskolin. The inactive forms, GLP-1(9-36)amide and GIP(3-42), had no effects on atherosclerosis and macrophage foam cell formation. CONCLUSIONS/INTERPRETATION: Our study is the first to demonstrate that active forms of GLP-1 and GIP exert anti-atherogenic effects by suppressing macrophage foam cell formation via their own receptors, followed by cAMP activation. Molecular mechanisms underlying these effects are associated with the downregulation of CD36 and ACAT-1 by incretins.
Asunto(s)
Apolipoproteínas E/metabolismo , Aterosclerosis/tratamiento farmacológico , Incretinas/farmacología , Acetil-CoA C-Acetiltransferasa/metabolismo , Animales , Apolipoproteínas E/genética , Aterosclerosis/metabolismo , Aterosclerosis/patología , Western Blotting , Antígenos CD36/metabolismo , Línea Celular , Células Cultivadas , Células Espumosas/citología , Células Espumosas/efectos de los fármacos , Polipéptido Inhibidor Gástrico/farmacología , Péptido 1 Similar al Glucagón/análogos & derivados , Péptido 1 Similar al Glucagón/farmacología , Humanos , Masculino , Ratones , Ratones Noqueados , Microscopía Confocal , Fragmentos de Péptidos/farmacología , Péptidos/farmacología , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
The relationship between bronchovascular cuff formation and lung lymph flow in hydrostatic edema was evaluated. After a balloon was inserted into the left atrium to increase left atrial pressure for 5 hrs, peripheral lung tissues were resected for analysis of the wet-dry ratio and cuff formation. The degree of cuff formation was expressed as the cuff ratio (outer diameter of cuff/outer diameter of microvessel or airway) in three size categories: 80-200, 200-400, and 400-750 microm in diameter. The amount of excess lung lymph (Ex LL) for 5 hrs was calculated from the recorded data for the whole lymph flow wave. The wet-dry ratio showed a significant correlation with ALAP and lung lymph flow increased significantly (flow rate, 0.67 +/- 0.46 ml/min (mean +/- SD); Ex LL, 56.4 +/- 47.6 ml). Cuff formation was found at all levels of the bronchovascular tree, with a larger cuff ratio (> 1.3) observed at arteries and veins of 80-200 microm in diameter, but a significant correlation with Ex LL was found only for arteries of 80-200 microm. Fluid accumulation in lung interstitium first occurred at smaller extra-alveolar arteries even under mild hydrostatic pressure elevation with a significant increase in lymph flow.
Asunto(s)
Edema/fisiopatología , Pulmón/fisiopatología , Linfa/fisiología , Análisis de Varianza , Animales , Edema/etiología , Atrios Cardíacos/fisiopatología , Presión , OvinosRESUMEN
AIM: Lung lymph has commonly been studied using a lymph fistula created by tube cannulation into the efferent duct of the caudal mediastinal node in sheep. In this method, the tail region of the caudal mediastinal node is resected and the diaphragm is cauterized to exclude systemic lymph contamination, and cannulation is performed into one of the multiple efferent ducts originating from the caudal mediastinal node. Moreover, the pumping activity of lymphatics might be diminished by cannulation. Therefore, the purpose of the study was to evaluate the flow rate of lung lymph with maintenance of intact lymphatic networks around the caudal mediastinal node to the thoracic duct in sheep. METHODS: An ultrasound transit-time flow meter was used to measure lung lymph flow. The thoracic duct was clamped just above the diaphragm and the flow probe was attached to the thoracic duct just after the last junction with an efferent duct from the caudal mediastinal node. The lung lymph flow rate was measured at baseline and under conditions of lung-oedema formation. RESULTS: The baseline lung lymph flow rate in our model was three- to sixfold greater than values obtained with the cannulation method. With oedema-formation, the lung lymph flow rate was the same as that measured using cannulation. CONCLUSION: The lung lymph flow was unexpectedly large under the conditions of the study, and our data suggest that the drainage effect of lymphatics is significant as a safety factor against pulmonary oedema formation.
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Pulmón/fisiología , Linfa/fisiología , Animales , Presión Sanguínea , Cateterismo/métodos , Cauterización , Diafragma/cirugía , Femenino , Pulmón/diagnóstico por imagen , Linfa/diagnóstico por imagen , Masculino , Edema Pulmonar/etiología , Edema Pulmonar/patología , Edema Pulmonar/fisiopatología , Reproducibilidad de los Resultados , Reología/métodos , Oveja Doméstica , Toracotomía/métodos , UltrasonografíaRESUMEN
We performed a unilateral pulmonary arterial occlusion (UPAO) test for the preoperative evaluation of right ventricular functions as a loading test in patients undergoing a lung resection without cardiac complications preoperatively. We investigated the relationship between changes in right ventricular hemodynamic functions and postoperative cardiac complications, namely right heart failure or arrhythmia. To evaluate the right ventricular hemodynamic function test, we measured the mean pulmonary arterial pressure, cardiac index, right ventricular ejection fraction end-diastolic volume, and stroke volume before and during the UPAO test using the thermodilution method, and calculated the total pulmonary vascular resistance and right ventricular stroke work indexes. The incidence of postoperative cardiac complications was not related to the changes in the total pulmonary vascular resistance index. However, the postoperative cardiac complications were common in patients whose right ventricular end-diastolic volume index was increased by more than 20% during the UPAO test. These results suggest that the changes in the right ventricular end-diastolic volume index during the UPAO test can predict postoperative cardiac complications in patients undergoing a pulmonary resection.
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Arritmias Cardíacas/diagnóstico , Insuficiencia Cardíaca/diagnóstico , Pruebas de Función Cardíaca/métodos , Neumonectomía , Complicaciones Posoperatorias/diagnóstico , Volumen Sistólico , Sístole , Resistencia Vascular , Función Ventricular Derecha , Predicción , Humanos , Arteria Pulmonar , TermodiluciónRESUMEN
We investigated the short-term effects of a phosphodiesterase III inhibitor (Olprinone) on hemodynamics and thoracic duct lymph flow in anesthetized open-chest sheep with heart failure induced by endothelin-1 (cardiogenic shock). Ultrasound transit-time flow probes were attached to the thoracic duct, the ascending aorta and the renal artery. Arterial, pulmonary and central venous pressures were monitored. Endothelin-1 was infused intravenously at a dosage that reduced cardiac output to 50% or more of baseline (n=11). The effects of Olprinone were examined (n=5) by intravenous infusion after endothelin-1 administration. Other sheep (n=6) were used as controls. Olprinone significantly increased cardiac output that had been decreased by endothelin-1 and further increased thoracic duct flow that had been increased by endothelin-1. Increased arterial and pulmonary pressures induced by endothelin-1 administration were rapidly decreased by Olprinone. Renal arterial flow and central venous pressure were, however, unchanged by Olprinone. Overall, Olprinone acutely improved experimental cardiogenic shock (heart failure) induced by endothelin-1, and maintained thoracic duct lymph flow at a high level after endothelin-1 administration.
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Endotelina-1/efectos adversos , Inhibidores Enzimáticos/uso terapéutico , Insuficiencia Cardíaca/inducido químicamente , Insuficiencia Cardíaca/tratamiento farmacológico , Imidazoles/farmacología , Piridonas/farmacología , 3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Animales , Gasto Cardíaco/efectos de los fármacos , Presión Venosa Central/efectos de los fármacos , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3 , Modelos Animales de Enfermedad , Endotelina-1/administración & dosificación , Femenino , Pulmón/química , Pulmón/efectos de los fármacos , Masculino , Modelos Cardiovasculares , Circulación Renal/efectos de los fármacos , Ovinos , Choque Cardiogénico/inducido químicamente , Choque Cardiogénico/tratamiento farmacológico , Conducto Torácico/efectos de los fármacos , Factores de Tiempo , Resultado del Tratamiento , Resistencia Vascular/efectos de los fármacosRESUMEN
We created anexperimental model of pulmonary metastasis based on subcutaneously implanted Lewis lung cancer in mice and observed in vivo the microcirculation of spontaneously metastasized tumors in the lung. The mice lung was held by a small handmade suction ring to stop cardiac and respiratory movement. Using fluorescent microscopy, tumor microcirculation and normal lung microcirculation in the same lung lobe were compared by measuring microvessel diameter and blood flow velocity [red blood cell (rbc) velocity]. In normal microcirculation, the mean values of microvessel diameter and rbc velocity were 10.4 +/- 2.7 microm and 188 +/- 63 microm/s, respectively. In tumor microcirculation, the mean values of the same were 10.6 +/- 3.3 microm and 105 +/- 40 microm/s. The rbc velocity in normal microcirculation was significantly higher (P < 0.001) than that in tumor microcirculation. The calculated shear rates of normal microcirculation and tumor microcirculation were 73.4 +/- 23.4 (/s) and 41.2 +/- 16.1 (/s), respectively. The shear rate of the tumor microcirculation was significantly slower (P < 0.001) than that of the normal microcirculation. We demonstrated a feasibility of observation and measurement of tumor microcirculation in the lung and confirmed that the physiologic data were compatible to those in the brain or in the liver reported by others. This model might be useful for studying metastatic tumor pathophysiology in the lung microcirculation.
Asunto(s)
Carcinoma Pulmonar de Lewis/secundario , Neoplasias Pulmonares/secundario , Circulación Pulmonar , Animales , Carcinoma Pulmonar de Lewis/irrigación sanguínea , Dextranos/farmacocinética , Estudios de Factibilidad , Fluoresceína-5-Isotiocianato/análogos & derivados , Fluoresceína-5-Isotiocianato/farmacocinética , Colorantes Fluorescentes/farmacocinética , Hemorreología , Inyecciones Subcutáneas , Neoplasias Pulmonares/irrigación sanguínea , Ratones , Ratones Endogámicos C57BL , Microcirculación , Trasplante de NeoplasiasRESUMEN
Because we experienced each 1 operative case of diffuse malignant mesothelioma of the pleura and pseudomesotheliomatous carcinoma of the lung discovered with pleural effusion, clinical comparison investigated both. The first case was suspected diffuse malignant mesothelioma of the pleura before operation, and we performed pleuropneumonectomy. But the pathologic diagnosis was adenocarcinoma of the lung, what is so called pseudomesotheliomatous carcinoma. The second case had inhaled asbestos and his pleural effusion revealed high concentrations of hyaluronic acid. Thoracoscopic biopsy showed malignant mesothelioma, and we performed pleuropneumonectomy. The pathologic final diagnosis was diffuse malignant mesothelioma of the pleura. In clinical differential diagnosis of diffuse malignant mesothelioma of the pleura and pseudomesotheliomatous carcinoma of the lung, history of inhalation of asbestos and concentrations of hyaluronic acid in pleural effusion are helpful. And thoracoscopic biopsy is necessary in established diagnosis.