RESUMEN
The aim of this study was carried out to analyse the liver and plasma proteins response to dexamethasone in adult (6-8 months) and old (24 months) rats in order to ascertain the involvement of glucocorticoids in the aging process. The animals received dexamethasone (Dex) for 5 or 6 days. As Dex decreased food intake, all groups were pair fed to dexamethasone-treated old rats. The synthesis of mixed plasma and liver proteins (assessed by a flooding dose of [13C] valine) was similarly greatly improved in adult and old rats after Dex treatment. However, the level of mixed plasma proteins was only slightly increased. When specific plasma proteins were assessed, a similar increase in the concentration of albumin and alpha1 acid glycoprotein was observed in adult and old rats. By contrast, fibrinogen decreased to a greater extend in old rats and alpha2 macroglobulin became undetectable in old animals. It was concluded that the response of plasma and liver proteins to Dex was altered in old rats and may contribute to the pathogenesis of several diseases which occur during aging.
Asunto(s)
Envejecimiento/sangre , Dexametasona/farmacología , Glucocorticoides/farmacología , Hígado/metabolismo , Proteínas/metabolismo , Envejecimiento/efectos de los fármacos , Envejecimiento/metabolismo , Albúminas/metabolismo , Animales , Biomarcadores , Fibrinógeno/metabolismo , Hígado/efectos de los fármacos , Masculino , Orosomucoide/metabolismo , Ratas , Ratas Sprague-Dawley , alfa-Macroglobulinas/metabolismoRESUMEN
Plasma albumin is well known to decrease in response to inflammation. The rate of albumin synthesis from both liver and plasma was measured in vivo by use of a large dose of L-[(2)H(3)-(14)C]valine in rats injected intravenously with live Escherichia coli and in pair-fed control rats during the acute-phase period (2 days postinfection). The plasma albumin concentration was reduced by 50% in infected rats compared with pair-fed animals. Infection induced a fall in both liver albumin mRNA levels and albumin synthesis relative to total liver protein synthesis. However, absolute liver albumin synthesis rate (ASR) was not affected by infection. In plasma, albumin fractional synthesis rate was increased by 50% in infected animals compared with pair-fed animals. The albumin ASR estimated in the plasma was similar in the two groups. These results suggest that hypoalbuminemia is not due to reduced albumin synthesis during sepsis. Moreover, liver and plasma albumin ASR were similar. Therefore, albumin synthesis measured in the plasma is a good indicator of liver albumin synthesis.
Asunto(s)
Infecciones por Escherichia coli/metabolismo , Hígado/metabolismo , ARN Mensajero/metabolismo , Sepsis/metabolismo , Albúmina Sérica/biosíntesis , Proteínas de Fase Aguda/metabolismo , Reacción de Fase Aguda/sangre , Reacción de Fase Aguda/metabolismo , Animales , Peso Corporal , Radioisótopos de Carbono , Deuterio , Infecciones por Escherichia coli/sangre , Fibrinógeno/metabolismo , Alimentos Formulados , Hígado/química , Masculino , Tamaño de los Órganos , Orosomucoide/metabolismo , Proteínas/análisis , Ratas , Sepsis/sangre , Albúmina Sérica/genética , Valina/metabolismo , Valina/farmacocinética , alfa-Macroglobulinas/metabolismoRESUMEN
To explore the regulation of the acute phase response in vivo, the effects of pentoxifylline (PX) treatment (100 mg/kg ip 1 h before infection) were investigated in infected and pair-fed rats 2 and 6 days after an intravenous injection of live bacteria (Escherichia coli). PX treatment prevented the increase in plasma tumor necrosis factor (TNF)-alpha (peak 1.5 h after the infection) and resulted in an 84 and 61% inhibition of plasma interleukin (IL)-1beta and IL-6, respectively (peaks at 3 h). Plasma corticosterone kinetics were not modified by the treatment. Infection increased alpha1-acid glycoprotein (AGP), alpha2-macroglobulin (A2M), and fibrinogen plasma concentrations and decreased albumin levels. PX significantly reduced AGP plasma concentration as early as day 2 in infected animals but reduced A2M and fibrinogen plasma levels only at day 6. The treatment had no effect on the albumin plasma concentration. Hepatic AGP and fibrinogen mRNA levels increased in infected rats, whereas those of A2M were unchanged and those of albumin were decreased. Two days after infection, AGP and fibrinogen mRNA levels were reduced in treated infected animals. PX was ineffective in modifying those of A2M and albumin. These data demonstrate, in vivo, that different acute phase proteins are individually regulated in sepsis. The in vivo effects of PX treatment support the hypothesis that TNF-alpha plays an important role in the regulation of AGP production, whereas other factors seem to be involved in the regulation of A2M, fibrinogen, and albumin expression.
Asunto(s)
Proteínas de Fase Aguda/metabolismo , Infecciones por Escherichia coli/prevención & control , Depuradores de Radicales Libres/farmacología , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Pentoxifilina/farmacología , Sepsis/prevención & control , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas de Fase Aguda/inmunología , Animales , Infecciones por Escherichia coli/sangre , Infecciones por Escherichia coli/inmunología , Masculino , Ratas , Ratas Sprague-Dawley , Sepsis/sangre , Sepsis/inmunologíaRESUMEN
1. Sepsis was induced in rats by an intravenous injection of live bacteria. Infected and pair-fed animals were studied before the infection, in an acute septic phase (day 2 post-infection), in a chronic septic phase (day 6) and in a late septic phase (day 10). Protein synthesis rates were measured in vivo after administration of a flooding dose of L[1-13C]valine. 2. During the acute phase, muscle protein loss associated with infection resulted from both a decrease in protein synthesis and an increase in proteolysis. During the chronic phase and the late phase, the increase of proteolysis in infected rats as compared with pair-fed animals persisted, worsening muscle atrophy. Skin protein synthesis rates were not significantly modified by infection. However, skin protein content decreased 6 and 10 days after infection, suggesting an increased proteolysis in response to sepsis. 3. Protein synthesis in liver of infected rats was twice that of pair-fed animals. Liver protein synthesis remained elevated in infected rats compared with pair-fed animals until day 10. Hypoalbuminaemia and high plasma concentrations of fibrinogen were evident at all periods studied. alpha 2-Macroglobulin and alpha 1-acid glycoprotein reached peak concentrations during the acute phase (concentrations increased 50 times in infected rats). On day 10, the levels of these proteins were still about 12-fold higher. 4. Protein synthesis rates were significantly increased in the digestive tract and lung of infected rats compared with pair-fed groups on days 2 and 6, but were similar in the two groups on day 10 post-infection. The fractional protein synthesis rate was increased 3-fold over the entire experimental period in the spleen. 5. The results show that sepsis stimulates protein synthesis in various tissues over a long time, and that skin, like muscle, can provide amino acids to the rest of the body.
Asunto(s)
Músculo Esquelético/metabolismo , Proteínas/metabolismo , Sepsis/metabolismo , Piel/metabolismo , Enfermedad Aguda , Análisis de Varianza , Animales , Enfermedad Crónica , Mucosa Intestinal/metabolismo , Hígado/metabolismo , Pulmón/metabolismo , Masculino , Proteínas Musculares/metabolismo , Biosíntesis de Proteínas , Ratas , Ratas Sprague-Dawley , Bazo/metabolismoRESUMEN
The influence of the protein content of the meal on protein turnover was investigated in the splanchnic bed and in the remaining parts of the body in humans. Two groups of five subjects consumed every 20 min a liquid formula providing either 1.5 g protein x kg(-1) x day(-1) (P) or no protein (PF). L-[1-(13)C]leucine and L-[5,5,5-(2)H3]leucine were administered by vein and gut, respectively. An open two-pool model was developed to calculate leucine kinetics in both compartments, with the assumption that the enrichment of the tracers incorporated into very low density lipoprotein apolipoprotein B100 at isotopic steady state could reflect the leucine labeling in the splanchnic region. Nonsplanchnic uptake and release of leucine were not significantly different in the two groups. Within the splanchnic area, leucine uptake was 2.1 times higher in the P than in the PF group (P < 0.01), whereas leucine release was reduced but not significantly (-19%) in the P group compared with the PF group. Moreover, data derived from this model showed that protein intake induced an increase in whole body protein synthesis and no change in whole body protein breakdown. Albumin synthesis, as well as its contribution to whole body protein synthesis, was significantly enhanced by protein intake.
Asunto(s)
Proteínas en la Dieta/farmacología , Leucina/farmacocinética , Vísceras/metabolismo , Isótopos de Carbono , Humanos , Cinética , Modelos Biológicos , Albúmina Sérica/metabolismo , TritioRESUMEN
1. The ability of diphtheria-tetanus-poliomyelitis-typhoid vaccination to induce modifications in protein metabolism was investigated in post-absorptive healthy humans. 2. Seven subjects were studied before and 2 days after vaccination. They underwent an intravenous primed constant infusion of L-[1-13C]leucine for 4h. Plasma protein concentrations, whole-body amino acid fluxes and acute-phase protein synthesis were determined. 3. Plasma concentrations of fibrinogen, alpha 1-acid glycoprotein, haptoglobin and alpha 1-antitrypsin were significantly elevated 2 days after vaccination (P < 0.05). Leucine oxidation was unaffected but whole-body protein synthesis and breakdown were both increased (P < 0.05), by 25 and 16% respectively, in subjects who had an elevated body temperature (n = 5). Albumin synthesis was unchanged, but hepatic synthesis of fibrinogen was 56% higher after vaccination. 4. The present investigation indicates that diphtheria-tetanus-poliomyelitis-typhoid vaccination could induce a sustained acute-phase reaction. Moreover, protein metabolism appeared to be extremely sensitive to a mild stress since leucine kinetics and fibrinogen synthesis were affected. Therefore, diphtheria-tetanus-poliomyelitis-typhoid vaccination might represent an attractive model for studying the inflammatory process in humans.