RESUMO
Mycophenolate mofetil (MMF) is a purine synthesis inhibitor commonly used as immunosupresive agent in transplantation. Kidney grafts undergo more or less prolonged cold ischemia after harvesting which results in variable degrees of ischemia reperfusion injury. To determine whether the inhibition of early events of cellular infiltration may influence the severity of damage induced by ischemic acute renal failure, 45 Sprague Dawley rats were given MMF at a dose of 20mg/kg/day (MMF-rats) by gavage 2 days before (pre-MMF group, n=15) or after (post-MMF group, n=15) clamping the left renal artery for 40 minutes followed by rigt-sided nephrectomy. (control group, n=15) received vehicle. Serum Creatinine (Screat) was measured daily in all groups. On the 2nd post-ischemic day Screat was significantly lower (p=0.001) in pre-MMF group compared with post-MMF group and control group (4 +/- 2mg/dl post-MMF group vs 1.7 +/- 1.2 mg/dl pre-MMF group, control group 5+/-2, p< 0.05). Kidney biopsies shown that the histologic damage was 54 +/- 28% in post-MMF group vs 34+/- 22% in pre-MMF group and 61 +/- 25% in control group (pre-MMF vs post-MMF, p NS). On the 5th day post-ischemic, MMF-rats showed more severe tubulointerstitial necrosis (pre-MMF group: 17 +/- 20 %, post-MMF group: 33 +/- 27%) than controls (4 +/- 5%). The severity of ATN was significantly higher in post-MMF group compared with controls (p=0.01). Tubulointersticial T-lymphocyte (T CD 5) and monocyte (ED 1) infiltration evaluated on the 2nd post-ischemic day was less intense in group I (T CD5: 3 +/- 3, ED 1: 10 +/- 9, cel/mm2) compared to post-MMF group (T CD 5: 10 +/- 4, ED 1: 55 +/- 40) and to control group (T CD 5: 10+/- 4, ED 1: 64 +/- 46). However, on the 5th post-ischemia day, ED 1 infiltration was significantly higher in post-MMF group (24 +/- 18%) compared to pre-MMF group (5 +/- 5, p NS) and also in pre-MMF group vs control group (31 +/- 33, p< 0.05). Our results suggest that MMF given before a renal ischemic insult may reduce the severity of histologic damage resulting from ischemia reperfusion injury.
Assuntos
Injúria Renal Aguda/imunologia , Injúria Renal Aguda/patologia , Imunossupressores/farmacologia , Isquemia/imunologia , Isquemia/patologia , Rim/irrigação sanguínea , Ácido Micofenólico/análogos & derivados , Animais , Masculino , Ácido Micofenólico/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
We found that substance P (SP) and calcitonin gene-related peptide (CGRP) (0.3-1 microM) increased, in a concentration-dependent manner, the basal secretion of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF alpha) from cultured lymphocyte-enriched mononuclear cells isolated from human peripheral blood. SP and CGRP (0.1 microM) synergistically increased basal TNF alpha secretion. Dynorphin A((1-17)) (0.1-1 microM) did not modify basal cytokine secretion. Lipopolysaccharide (10 ng/ml)-induced cytokine secretion and [(3)H]thymidine uptake were not altered by any neuropeptide (at 0.1 microM). Thus, SP and CGRP stimulate the production of pro-inflammatory cytokines from lymphocytes only at high concentrations, similar to those reached during tissue damage.
Assuntos
Peptídeo Relacionado com Gene de Calcitonina/farmacologia , Interleucina-1/metabolismo , Interleucina-6/metabolismo , Leucócitos Mononucleares/efeitos dos fármacos , Substância P/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Dinorfinas/farmacologia , Humanos , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Fito-Hemaglutininas/farmacologia , Acetato de Tetradecanoilforbol/farmacologiaRESUMO
To determine whether treatment with melatonin (MLT) improves the efficiency of immunization against Venezuelan equine encephalomyelitis (VEE) virus, mice were vaccinated with TC-83 VEE virus and treated daily with MLT (1 or 5 mg/kg) starting 3 days before immunization, until 10 days after. IgM antibody titers were determined at days 7, 14, and 21 post-immunization. IL-10 levels were assayed at day 14 postvaccination. Treatment with MLT increased antibody titers 14 days after the immunization. IL-10 levels also increased with MLT treatment (1 and 5 mg/kg). Mice were challenged with live VEE virus at day 21 postimmunization, and viral titers were plaque assayed in chicken embryo fibroblasts 4 days after the infection. Following this challenge brain virus levels were significantly reduced. The results suggest that MLT treatment enhances the efficiency of mice immunization against VEE virus.
Assuntos
Adjuvantes Imunológicos/farmacologia , Vírus da Encefalite Equina Venezuelana/imunologia , Encefalomielite Equina Venezuelana/prevenção & controle , Imunização , Melatonina/farmacologia , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/análise , Encéfalo/virologia , Vírus da Encefalite Equina Venezuelana/isolamento & purificação , Encefalomielite Equina Venezuelana/virologia , CamundongosRESUMO
BACKGROUND: Interstitial mononuclear cell infiltration is a feature of experimental models of salt-sensitive hypertension (SSHTN). Since several products of these cells are capable of modifying local vascular reactivity and sodium reabsorption, we investigated whether mycophenolate mofetil (MMF), a drug known to inhibit infiltration and proliferation of immune cells, would modify the SSHTN induced by angiotensin II (Ang II) infusion. METHODS: Sprague-Dawley rats received Ang II for two weeks using subcutaneous minipumps. A high-sodium (4% NaCl) diet was started on the third week and was maintained until the eighth week. MMF (30 mg/kg, N = 15), an immunosuppressive drug, or vehicle (N = 15) was given daily by gastric gavage during the initial three weeks. Sham-operated rats (N = 9) were used as controls. Body weight, blood pressure (tail-cuff plethysmography), and serum creatinine were determined weekly. Urinary malondialdehyde (MDA) excretion, renal histology, and immunohistology, including the presence of Ang II and superoxide-producing cells, were analyzed at the end of Ang II infusion and at eight weeks. RESULTS: MMF treatment did not modify hypertension induced during exogenous Ang II infusion, but prevented the subsequent SSHTN. Tubulointerstitial injury resulting from Ang II infusion was significantly reduced by MMF treatment, as were proliferative activity, T-cell infiltration and activation (interleukin-2 receptor expression), superoxide-producing cells, and urinary MDA excretion. Ang II-producing cells were present in the renal tubulointerstitium of rats with SSHTN (60 +/- 30 Ang II-positive cells/mm(2) at 8 weeks) and were reduced by two thirds in the MMF-treated group. Forty percent of lymphocytes infiltrating the tubulointerstitium stained positive for Ang II. The expression of Ang II receptors in the kidney was unmodified. CONCLUSIONS: SSHTN resulting from Ang II infusion is associated with infiltration and activation of immune cells that produce Ang II. MMF treatment reduces these features and prevents the development of SSHTN.
Assuntos
Angiotensina II/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Hipertensão Renal/tratamento farmacológico , Ácido Micofenólico/farmacologia , Vasoconstritores/farmacologia , Angiotensina II/análise , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal , Divisão Celular/fisiologia , Creatinina/sangue , Modelos Animais de Doenças , Fibronectinas/análise , Hipertensão Renal/induzido quimicamente , Hipertensão Renal/prevenção & controle , Rim/química , Rim/imunologia , Rim/patologia , Leucócitos Mononucleares/imunologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/urina , Ácido Micofenólico/análogos & derivados , Osteopontina , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/análise , Sialoglicoproteínas/análise , Superóxidos/metabolismo , Vasoconstritores/análiseRESUMO
Recent studies have suggested that subtle microvascular and tubulointerstitial injury in the kidney can cause salt-sensitive hypertension. To test this hypothesis, we determined whether the mild renal disease induced by transient blockade of nitric oxide (NO) synthesis would result in salt-sensitive hypertension and whether prevention of the renal injury by coadministration of the immunosuppressive agent mycophenolate mofetil (MMF) would block the development of salt sensitivity. N(omega)-nitro-L-arginine-methyl ester (L-NAME; 70 mg/100 ml in the drinking water) was administered for 3 wk to rats with or without MMF (30 mg x kg(-1) x day(-1) by gastric gavage), followed by a 1-wk "washout" period in which the MMF was continued, which was followed in turn by placement on a high-salt (4% NaCl) diet for an additional 4 wk. Renal histology was examined at 3 and 8 wk, and blood pressure was measured serially. L-NAME treatment resulted in acute hypertension and the development of mild renal injury. During the washout period, blood pressure returned to normal, only to return to the hypertensive range on exposure of the animals to a high-salt diet. MMF treatment prevented the development of hypertension in response to a high-salt diet. This correlated with the ability of MMF to inhibit specific aspects of the renal injury, including the development of segmental glomerulosclerosis, the infiltration of T cells and ANG II-positive cells, and the thickening of afferent arterioles.
Assuntos
Hipertensão/prevenção & controle , Imunossupressores/farmacologia , Ácido Micofenólico/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Animais , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Glomerulosclerose Segmentar e Focal/induzido quimicamente , Glomerulosclerose Segmentar e Focal/patologia , Hipertensão/induzido quimicamente , Rim/metabolismo , Rim/patologia , Linfócitos/imunologia , Macrófagos/imunologia , Masculino , Ácido Micofenólico/análogos & derivados , NG-Nitroarginina Metil Éster , Nefrite Intersticial/induzido quimicamente , Nefrite Intersticial/imunologia , Nefrite Intersticial/patologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina , Receptor Tipo 2 de Angiotensina , Receptores de Angiotensina/análiseRESUMO
Male albino mice immunodepressed after the injection of dexamethasone (DEX) were inoculated intraperitoneally with the Guajira strain of Venezuelan equine encephalomyelitis (VEE) virus. Melatonin (MLT) was administered daily, at a dose of 500 micrograms/kg bodyweight, for 3 days before virus inoculation and 10 days after. Serum levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) were determined in all the experimental groups (control, DEX, DEX + MLT, DEX + VEE, DEX + VEE + MLT, VEE and MLT). At day 6 after the virus inoculation, the survival rate was significantly increased from 0% in group DEX + VEE to 32.5% in the group of immunodepressed infected mice treated with MLT (DEX + VEE + MLT). By day 10 a survival rate of 10% was found in group DEX + VEE + MLT and 0% in group VEE. No alterations in IL-2 serum levels were observed. MLT increased GM-CSF in control and in DEX-treated mice. In the VEE virus-infected mice treated with DEX, serum levels of GM-CSF increased progressively from day 1 to 5 postinoculation. In contrast, the levels of GM-CSF in infected immunodepressed mice treated with MLT decreased significantly from day 1 to 5 postinoculation. At day 5 after viral inoculation, no differences were detected in the cerebral viral titres in groups VEE, DEX + VEE and DEX + MLT + VEE. These results show that MLT does not inhibit VEE viral replication in the brain of immunodepressed mice.
Assuntos
Adjuvantes Imunológicos/uso terapêutico , Encefalomielite Equina Venezuelana/tratamento farmacológico , Terapia de Imunossupressão/efeitos adversos , Melatonina/uso terapêutico , Animais , Dexametasona/imunologia , Encefalomielite Equina Venezuelana/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Interleucina-2/sangue , Masculino , Melatonina/imunologia , Camundongos , Análise de SobrevidaRESUMO
Renal infiltration with macrophages and monocytes is a well-recognized feature of not only immune, but also nonimmune kidney disease. This review focuses on the investigations that have shown accumulation of immunocompetent cells in experimental models of acute and chronic ischemia, protein overload, hypercholesterolemia, renal ablation, obstructive uropathy, polycystic kidney disease, diabetes, aging, murine hypertension, and nephrotoxicity. We examine the mechanisms of infiltration of immunocompetent cells and their participation in the self-perpetuating cycle of activation of the angiotensin system, generation of reactive oxygen species, and further recruitment of monocytes and lymphocytes. We also discuss the possibility of antigen-dependent and antigen-independent mechanisms of immune cell activation in these animal models. Finally, we review the recent studies in which suppression of cellular immunity with mycophenolate mofetil has proven beneficial in attenuating or preventing the progression of renal functional and histologic damage in experimental conditions of nonimmune nature.
Assuntos
Nefropatias/imunologia , Nefropatias/patologia , Animais , Antígenos/metabolismo , Modelos Animais de Doenças , Humanos , Imunocompetência , Imunossupressores/farmacologia , Nefropatias/tratamento farmacológico , Ativação Linfocitária , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos/patologia , Ativação de Macrófagos , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Modelos Biológicos , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/farmacologiaRESUMO
Immunosuppressive therapy has been shown to either improve or, more frequently, enhance the development of atherosclerosis. We tested the effect of mycophenolate mofetil (MMF), an inhibitor of nucleotide synthesis widely used in transplant therapy, in diet-induced atherosclerosis in the rabbit. Two groups (n=10 each) of New Zealand White (NZW) rabbits were fed a 1% cholesterol diet for 12 weeks. One group received MMF (CHOL+MMF group) by gastric gavage (30 mg/kg daily) and the other group (CHOL) received the same volume of saline by the same route. There were no differences in the serum cholesterol (mean values > or =30 mmol/l in both groups after 2 weeks) or in the triglyceride, blood sugar, total protein, and albumin serum levels and weight gain in both groups of animals. The cholesterol-fed untreated rabbits had atherosclerotic plaques covering 43.9.1+/-SD 16.40% of their thoracic aorta and 41.9+/-22. 59% of their abdominal aorta, while the MMF treated group had 18. 5+/-7.17% and 17.7+/-9.71%, respectively (P<0.01). The cholesterol content of the aorta (mg/g) in the cholesterol-fed untreated group was 4.61+/-SD 1.21 in the thoracic aorta and 4.54+/-2.07 in the abdominal aorta, whereas the MMF treated group had and 2.83+/-0.84 and 2.77+/-1.44, respectively (P<0.01). Infiltrating macrophages (RAM 11 positive cells/100 nuclei) in the intimal layer of the aorta were 58.4+/-SD26.16 in the CHOL group and 8.5+/-5.51 in the CHOL+MMF group: (P<0.001). CD18 positive cells/100 nuclei were 27.4+/-17.6 in the CHOL group and 5.3+/-3.82 in the CHOL+MMF group (P<0.01), and the intima/media ratio was 0.66+/-0.11 in the CHOL group and 0. 30+/-0.09 in the MMF treated rabbits (P<0.001). MMF also reduced proliferating smooth muscle cells (HHF35 positive) infiltrating between the macrophages. These results indicate that MMF ameliorates importantly the atherogenic potential of a high cholesterol diet and this effect is associated with a reduction in macrophage and foam cell infiltration and smooth muscle cell proliferation and infiltration. Since chronic treatment with this drug is given routinely in various clinical conditions with relatively minor side effects, consideration may be given to its use as adjuvant therapy in atherosclerotic cardiovascular disease.
Assuntos
Arteriosclerose/tratamento farmacológico , Arteriosclerose/patologia , Inibidores Enzimáticos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Ácido Micofenólico/análogos & derivados , Análise de Variância , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/patologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/patologia , Colesterol/análise , Colesterol/sangue , Dieta Aterogênica , Modelos Animais de Doenças , Imuno-Histoquímica , Masculino , Ácido Micofenólico/farmacologia , Coelhos , Valores de Referência , Estatísticas não ParamétricasRESUMO
We investigated whether the administration of melatonin (MLT) reduces the death rate and evolution of the disease in mice infected with Venezuelan equine encephalomyelitis (VEE) virus. Our results show that, MLT protects mice infected with the virus. The mortality rate was reduced from 100% to 16% merely by increasing the dose from 0 to 1000 micrograms/MLT per kg body weight MLT significantly postponed the onset of the disease and death by several days. In surviving mice very high titres of VEE virus IgM antibodies were found seven weeks after virus inoculation. MLT significantly reduced VEE virus levels in blood and brain of infected mice and increased the survival rate when the length of pretreatment was augmented from 3 to 7 or 10 days before virus inoculation. Serum levels of interleukin-2 were not affected by MLT administration. In control mice receiving MLT as well as in infected mice treated or non-treated with MLT, interferon gamma levels in sera were increased. Interleukin-4 concentrations were found to be elevated in sera of non-infected mice receiving MLT, but did not differ from controls in infected mice treated or non-treated with the hormone. MLT reduced the degree of cell destruction produced by VEE virus in culture plates of chicken embryo fibroblasts. The protective effect of MLT warrants further investigation of the possibility of using this hormone for the treatment of humans and equines infected with VEE virus.