L'arrêt cardiaque (AC), responsable de 50000 morts par an en France, est un problème de santé publique. La majorité des décès survenant chez les patients réanimés avec succès est liée à une défaillance multiviscérale associée à une réponse inflammatoire systémique définissant le syndrome post-AC. L'AC réanimé est un modèle extrême d'ischémie-reperfusion (I/R) globale à l'origine de dysfonctions mitochondriales. L'ouverture du pore de transition de perméabilité mitochondrial (mPTP), inhibée par la ciclosporine A (CsA), joue un rôle déterminant dans les lésions d'I/R focales. Nous avons fait l'hypothèse que des interventions thérapeutiques prévenant l'ouverture du mPTP pourraient limiter le syndrome post-AC. Au cours de ce travail de thèse, nous avons mis au point un modèle d'AC chez le lapin et utilisé des préparations de mitochondries isolées à partir des organes vitaux pour étudier le rôle du mPTP dans la physiopathologie des défaillances d'organes post-AC. Dans un premier travail, nous avons montré que l'administration in vivo de CsA prévenait, en inhibant le mPTP au niveau du myocarde, la dysfonction cardiovasculaire post-AC. Nous avons étendu cette démonstration aux autres organes vitaux et montré ainsi des effets protecteurs mitochondriaux ubiquitaires de la CsA. Par la suite, nos travaux se sont attachés à étudier l'influence de la température corporelle sur les dysfonctions mitochondriales impliquées dans le syndrome post-AC. Nos résultats ouvrent de nouvelles perspectives dans le traitement de l'AC chez l'Homme / Cardiac arrest (CA) is a public health with more than 50,000 sudden deaths annually in France. A majority of immediate survivors die of multiple organ failure combined with systemic inflammatory response known as the post-CA syndrome. Resuscitated CA represents a model of whole body ischemia-reperfusion (I/R) leading to mitochondrial dysfunctions. Opening of the mitochondrial permeability transition pore (mPTP), which can be inhibited by cyclosporine A (CsA), play a key role in reperfusion injury after focal ischemia. We hypothesized that therapeutic intervention targeting the mPTP could prevent the post-CA syndrome. In the present work, we developed a model of CA in rabbits and we used mitochondria preparations from vital organs to study the role of the permeability transition in the pathophysiology of the post-CA syndrome. In our first study, we have determined that CsA, by inhibiting mPTP opening (in heart), prevented CA-induced myocardial dysfunction. We extended this demonstration to the other vital organs and therefore reported a ubiquitous mitochondrial protective effect of CsA. Subsequently, we have focused our research on the influence of temperature on mitochondrial dysfunction involved in the post-CA syndrome. Our experimental findings open up new therapeutic perspectives in the treatment of CA in Humans

Dendritic cells (DC) are potent antigen presenting cells involved in the initiation of the alloimmune response and organ transplant rejection. This thesis, has investigated pharmacological and genetic approaches to manipulate DC in order to generate tolerogenic DC which elicit poor allostimulatory activity as potential cell therapy agents to treat allograft rejection. In the first aspect of this study, human monocyte-derived DC were used to study the influence of Rapamycin (RAPA) on DC phenotype and function. This study showed that RAPA when added to monocytes prior to DC differentiation or after DC maturation generated tolerogenic DC as evidenced by the ability of these cells to induce T cell hyporesponsiveness. However, T cell hyporesponsiveness was associated with downregulation of costimulatory molecules only when added prior to differentiation and surprisingly was not influenced by the induction of CD4 ⁺FoxP3 ⁺ T cells. To assess the effects of RAPA on DC function in the transplant setting an in vivo chimeric model of ovine vascularised skin allograft transplantation was established in immunocompromised NOD/SCID mice as a host. This model was established as a preliminary model to acquire in vivo data prior to testing the effect of pharmacologically modified DC in the preclinical ovine model of renal allograft transplantation, also established in the host laboratory. Firstly, comparison of ovine DC obtained from cannulation of the prefemoral lymphatic vessels in sheep demonstrated that RAPA-modified ovine DC acted as poor stimulators of allogeneic ovine T cells similar to human DC treated with RAPA. Secondly, in NOD/SCID mice engrafted with ovine skin, the infusion of allogeneic ovine T cells together with RAPA-modified ovine DC reduced histological rejection in comparison to control DC. In the second aspect of this study, the effects of genetic manipulation of DC were investigated. In order to investigate the effects of genetic modification of DC, two isoforms of the human HLA-G molecule, HLA-G1 (membrane bound) and HLA-G5 (soluble isoform) were used to generate adenoviral vectors. Unexpectedly, both HLA-G isoforms expressed by human DC transfectants were unable to induce allogeneic T cell hyporesponsiveness in the mixed lymphocyte reaction (MLR). Surprisingly, in the MLR the allogeneic T cells acquired HLA-G1, but not HLA-G5, indicating that direct cell contact and membrane transfer from DC to T cells occurred (Trogocytosis). In addition to HLA-G1, costimulatory molecules (CD40, CD80, CD86 and MHC Class II) were also cotransferred from DC to allogeneic T cells. Accordingly, in secondary proliferation assays T cells immunoselected after co-culture with allogeneic untransfected DC (TUT) demonstrated potent antigen presenting activity when used as stimulators of autologous T cells (analogous to the indirect pathway of antigen presentation). In contrast to TUT, immunoselected T cells that acquired HLA-G1 (THLA-G1) upon co-culture with DCtransfectants showed poor stimulatory capacity. Thus the data reported in this thesis supports the proposed novel concept that HLA-G acquired by T cells through genetically modified DC, functions to autoregulate T cells via T-T cell interaction through the HLA-G receptor ILT2 (negative signalling receptor) expressed on T cells. In conclusion, this thesis has firstly provided supportive evidence that the pharmacological modification of human and ovine DC with RAPA has potential therapeutic effects on allograft rejection. Secondly, the genetic modification of DC to induce expression of HLA-G has specifically allowed the transfer of this molecule to T cells by trogocytosis and the inhibition of alloreactive T cell expansion. / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2009

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Kulak Burun Boğaz Anabilim Dalı, 2007. / Bibliyografya var.

Made available in DSpace on 2015-12-10T14:22:51Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-08-28. Added 1 bitstream(s) on 2015-12-10T14:29:04Z : No. of bitstreams: 1 000854498.pdf: 879979 bytes, checksum: 3dae153d2ccebad6555cca9bb94cdb49 (MD5) / Lesão isquêmica nos rins contribui decisivamente para o aumento da morbimortalidade. Várias estratégias de intervenção na lesão isquemia-reperfusão (LIR) têm sido propostas, dentre estas, a utilização da Ciclosporina A (CsA). A literatura, contudo, apresenta resultados controversos quanto ao seu benefício. O objetivo deste trabalho foi avaliar o efeito da CsA na LIR renal em ratos. Trata-se de um estudo experimental conduzido de março a junho de 2013, no laboratório da Unidade de Pesquisa Experimental (UNIPEX) da UNESP de Botucatu. Variáveis de controle da homeostase: pressões arteriais sistólica (PAS), diastólica (PAD) e média (PAM), peso e temperatura (T) foram incluídas, além das medidas de creatinina, ureia e sódio séricos e classificação de RIFLE (protocolo de diagnóstico e estratificação de risco na lesão renal aguda (LRA)). Avaliação histológica foi realizada ao término do experimento. Os parâmetros PAS, PAD, PAM e T foram aferidos nos tempos T0 (início do experimento, após dissecção da artéria carótida esquerda); T1 (após o desclampeamento da artéria renal esquerda); e T2 (30 minutos após a reperfusão). As dosagens de creatinina, ureia e sódio foram realizadas nos momentos M0, que correspondeu ao tempo T0; M1, correspondente ao tempo T2; e M2, 12 horas após o procedimento cirúrgico inicial. Foram incluídos no estudo 30 ratos Wistar alocados aleatoriamente em três grupos: Sham (S): laparotomia e nefrectomia direita. Controle (C): laparotomia e nefrectomia direita, isquemia-reperfusão em rim esquerdo. Cicloscoprina (CsA): os mesmos procedimentos realizados no grupo anterior e administração de ciclosporina (CsA) em duas doses de 15 mg/kg, 24 horas antes do procedimento cirúrgico inicial e imediatamente antes deste. As avaliações descritivas do RIFLE mostraram que tanto o grupo Controle como CsA apresentaram resultados negativos em relação ao grupo Sham. A avaliação dos valores de... / Kidney ischemic injury contributes decisively to the increase of morbidity and mortality. Various strategies of intervention in Ischemia-Reperfusion Injury (IRI) have been proposed, among them, the use of Cyclosporine A (CsA). However, studies present controversial results in relation to its benefits. The goal of this study was asses the effect of CsA in kidney IRI in rats. This is an experimental study conducted from March to June of 2013 in the laboratory of Unidade de Pesquisa Experimental (UNIPEX) of UNESP in Botucatu. Variables of homeostasis: systolic blood pressure (PAS), diastolic blood pressure (PAD), mean blood pressure (PAM), weight and temperature (T) controls were included, as were the measures of serum creatinine, urea nitrogen, and sodium, and RIFLE classification (protocol of diagnosis and risk stratification in acute renal injury), measured during three moments: PAS, PAD, PAM and T were measured at T0 (after catheterization of the carotid artery); T1 (after the clamping of the left renal artery); T2 (30 minutes after reperfusion). Serum creatinine, urea nitrogen and sodium were collected at M0 (T0); M1 (T2) and M2, 12 hours after the initial surgical procedure. Histological evaluation was performed at the end of the experiment. Thirty rats were included, randomly allocated in three groups: sham group (GS), which had only laparotomy and right nephrectomy; control group (GC) which additionally had ischemia reperfusion maneuver, and cyclosporine A group (GCsA), which besides having the afore mentioned procedures would use CsA intraperitoneal (15 mg/kg), 24 hours before and at the moment of initial surgical procedure. The RIFLE descriptive evaluations showed that the Control group and the CsA group presented negative results in relation to the Sham group. The assessment of the sodium levels did not present a meaningful difference of its numbers in each group during the three moments. About kidney function, the paired ...

Objectif De nombreux travaux ont souligné le rôle de la Cyclosporine A (CsA) dans la prévention des lésions d'ischémie-reperfusion (I/R) mais aucun n'a été effectué sur poumons isolés de grands mammifères. Notre objectif était de mesurer pour la première fois les effets de la CsA sur les lésions d'I/R dans un modèle de poumons porcins reperfusés ex vivo, en évaluant plusieurs doses de CsA pour différents temps d'ischémie. Méthodes L'expérimentation A a été conduite sur 4 groupes de 8 paires de poumons chacune : un groupe contrôle et 3 groupes recevant différentes concentrations de CsA (1, 10 ou 30 μM) au moment de l'ischémie et au début de la reperfusion, après 2 heures d'ischémie. L'expérimentation B a été conduite sur 3 groupes de 5 paires de poumons chacune. Les poumons de chaque paire étaient séparés juste après le début de l'ischémie. Les premiers poumons étaient évalués après une ischémie de 2 heures (jour 0), sans CsA. Les seconds poumons étaient évalués après une ischémie de 24 heures (jour 1), soit sans soit avec CsA (1 ou 5 μM), administrée le cas échéant au début de la reperfusion. Résultats La CsA augmentait le rapport PO2/FiO2 avec un effet dose mais augmentait également la pression artérielle pulmonaire, la pression capillaire et les résistances vasculaires pulmonaires, à 10 et 30 μM mais pas à 1 ni 5 μM. Les poumons qui recevaient 30 μM de CsA affichaient des concentrations élevées en cytokines pro-inflammatoires. La concentration en RAGE (receptor for advanced glycation endproducts) dans le lavage broncho-alvéolaire diminuait avec la CsA à J1 en comparaison à J0. Conclusions Lors de l'I/R pulmonaire, les bénéfices cellulaires des doses élevées de CsA sont contrebalancés par ses effets hémodynamiques sur la microvascularisation. A faibles doses, la CsA semble améliorer la fonction pulmonaire. / Objective Several works highlighted the role of Cyclosporine A (CsA) in the prevention of ischemia reperfusion (I/R) injuries but none on isolated lungs of big mammals. Our objective was to measure for the first time the effects of CsA in I/R injuries in an ex vivo reperfused pig lungs model, by evaluating several doses of CsA for different times of ischemia. Methods Experimentation A was performed on 4 groups of 8 pairs of lungs each: a control group and 3 groups receiving different concentrations of CsA (1, 10 or 30 μM) at the time of ischemia and at the beginning of the reperfusion, after a 2 hours ischemia. Experimentation B was performed on 3 groups of 5 pairs of lungs each. Lungs from each pair were separated just after the beginning of ischemia. The first lungs were evaluated after a 2 hours ischemia (day 0), without CsA. The second lungs were evaluated after a 24 hours ischemia (day 1), either without or with CsA (1 or 5 μM), administered when appropriate at the beginning of the reperfusion. Results CsA improved the PO2/FiO2 ratio with a dose dependent effect but increased pulmonary arterial pressure, capillary pressure, and pulmonary vascular resistances, at 10 and 30 μM but neither at 1 or 5 μM. Lungs receiving 30 μM of CsA displayed elevated concentrations in pro-inflammatory cytokines. Concentrations in RAGE (receptor for advanced glycation endproducts) in broncho-alveolar lavage decreased with CsA at day 1 compared to day 0. Conclusions During pulmonary I/R, the cellular benefits of high doses of CsA are counterbalanced by its hemodynamic effects on microvascularisation. At low doses, CsA seems to improve lung function.

Orientador: Norma Sueli Pinheiro Módolo / Banca: Luiz Antonio Vane / Banca: Angélica de Fátima Assunção Braga / Resumo: Lesão isquêmica nos rins contribui decisivamente para o aumento da morbimortalidade. Várias estratégias de intervenção na lesão isquemia-reperfusão (LIR) têm sido propostas, dentre estas, a utilização da Ciclosporina A (CsA). A literatura, contudo, apresenta resultados controversos quanto ao seu benefício. O objetivo deste trabalho foi avaliar o efeito da CsA na LIR renal em ratos. Trata-se de um estudo experimental conduzido de março a junho de 2013, no laboratório da Unidade de Pesquisa Experimental (UNIPEX) da UNESP de Botucatu. Variáveis de controle da homeostase: pressões arteriais sistólica (PAS), diastólica (PAD) e média (PAM), peso e temperatura (T) foram incluídas, além das medidas de creatinina, ureia e sódio séricos e classificação de RIFLE (protocolo de diagnóstico e estratificação de risco na lesão renal aguda (LRA)). Avaliação histológica foi realizada ao término do experimento. Os parâmetros PAS, PAD, PAM e T foram aferidos nos tempos T0 (início do experimento, após dissecção da artéria carótida esquerda); T1 (após o desclampeamento da artéria renal esquerda); e T2 (30 minutos após a reperfusão). As dosagens de creatinina, ureia e sódio foram realizadas nos momentos M0, que correspondeu ao tempo T0; M1, correspondente ao tempo T2; e M2, 12 horas após o procedimento cirúrgico inicial. Foram incluídos no estudo 30 ratos Wistar alocados aleatoriamente em três grupos: Sham (S): laparotomia e nefrectomia direita. Controle (C): laparotomia e nefrectomia direita, isquemia-reperfusão em rim esquerdo. Cicloscoprina (CsA): os mesmos procedimentos realizados no grupo anterior e administração de ciclosporina (CsA) em duas doses de 15 mg/kg, 24 horas antes do procedimento cirúrgico inicial e imediatamente antes deste. As avaliações descritivas do RIFLE mostraram que tanto o grupo Controle como CsA apresentaram resultados negativos em relação ao grupo Sham. A avaliação dos valores de... / Abstract: Kidney ischemic injury contributes decisively to the increase of morbidity and mortality. Various strategies of intervention in Ischemia-Reperfusion Injury (IRI) have been proposed, among them, the use of Cyclosporine A (CsA). However, studies present controversial results in relation to its benefits. The goal of this study was asses the effect of CsA in kidney IRI in rats. This is an experimental study conducted from March to June of 2013 in the laboratory of "Unidade de Pesquisa Experimental (UNIPEX)" of UNESP in Botucatu. Variables of homeostasis: systolic blood pressure (PAS), diastolic blood pressure (PAD), mean blood pressure (PAM), weight and temperature (T) controls were included, as were the measures of serum creatinine, urea nitrogen, and sodium, and RIFLE classification (protocol of diagnosis and risk stratification in acute renal injury), measured during three moments: PAS, PAD, PAM and T were measured at T0 (after catheterization of the carotid artery); T1 (after the clamping of the left renal artery); T2 (30 minutes after reperfusion). Serum creatinine, urea nitrogen and sodium were collected at M0 (T0); M1 (T2) and M2, 12 hours after the initial surgical procedure. Histological evaluation was performed at the end of the experiment. Thirty rats were included, randomly allocated in three groups: sham group (GS), which had only laparotomy and right nephrectomy; control group (GC) which additionally had ischemia reperfusion maneuver, and cyclosporine A group (GCsA), which besides having the afore mentioned procedures would use CsA intraperitoneal (15 mg/kg), 24 hours before and at the moment of initial surgical procedure. The RIFLE descriptive evaluations showed that the Control group and the CsA group presented negative results in relation to the Sham group. The assessment of the sodium levels did not present a meaningful difference of its numbers in each group during the three moments. About kidney function, the paired ... / Mestre

Orientador: Mary Anne Heidi Dolder, Sergio Luis Pinto da Matta / Dissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia / Made available in DSpace on 2018-08-10T09:43:10Z (GMT). No. of bitstreams: 1 Monteiro_JulianaCastro_M.pdf: 5278625 bytes, checksum: 63e213bed61e034d07b8ef348696a065 (MD5) Previous issue date: 2007 / Resumo: TA ciclosporina A (CsA) possui potentes propriedades imunossupressivas e tem sido amplamente usada na terapia de transplantes de órgãos, aumentando as taxas de sobrevivência dos enxertos, e no tratamento de algumas doenças auto-imunes. Apesar de ser um importante medicamento, diversas reações colaterais são verificadas, entre elas a toxicidade testicular, levando à infertilidade masculina. Heteropterys aphrodisiaca é uma planta com indicações de estimulante e potente afrodisíaco, que aumenta o peso corporal e testicular e o volume das células de Leydig nos testículos de ratos adultos. Assim o efeito da associação dessas drogas foi estudado em ratos Wistar em idade reprodutiva, com avaliação da morfometria, estrutura e ultra-estrutura testicular. Foram utilizados 30 ratos divididos em 5 grupos: I- controle; II- tratamento com CsA; III- concomitante uso de CsA e H. aphrodisiaca; IV- pré-tratamento com H. aphrodisiaca por 30 dias, seguido de CsA por 26 dias; V- tratamento com H. aphrodisiaca. CsA foi administrada na dose de 15 mg/kg/dia e H. aphrodisiaca na dose de 0.5 ml de infusão preparada com 25g de raízes secas/100 ml água fervente. Os tratamentos foram administrados diariamente por gavagem, durante 56 dias. Aumento do peso corporal foi observado em todos os grupos, mas os grupos II e III tiveram menor ganho de peso. O peso dos testículos e dos órgãos sexuais acessórios, assim como a proporção e o volume dos compartimentos tubular e intersticial não alteraram nos grupos tratados. Com a administração de CsA houve aumento na proporção de tecido conjuntivo e redução na proporção de células de Leydig que, além disso, eram menores e com citoplasma mais denso que as células dos animais de outros grupos tratados. Por outro lado, a infusão de H. aphrodisiaca resultou em aumento do volume nuclear das células de Leydig. Os níveis de testosterona plasmáticos, o número de células de Leydig por testículo e por grama de testículo aumentou significativamente nos animais do grupo III. CsA causou degeneração das células germinativas, vacuolização nas células de Sertoli, espermátides arredondadas anormais e atrofia das organelas envolvidas na síntese de esteróides nas células de Leydig. H. aphrodisiaca causou vacuolização nas células de Sertoli, perda do contato e espaçamento entre as células germinativas e aumento de retículo endoplasmático liso e mitocôndrias nas células de Leydig. O tratamento concomitante e sequencial com CsA e H. aphrodisiaca foi efetivo em manter a ultra-estrutura das células de Leydig. Nesses tratamentos, as alterações observadas no epitélio seminífero foram a combinação das modificações observadas em cada tratamento separadamente. Entretanto, H. aphrodisiaca exerceu um efeito protetor no epitélio germinativo, uma vez que as modificações encontradas nesses grupos foram menos severas em relação ao grupo tratado somente com CsA / Abstract: Cyclosporine A (CsA) has potent immunosuppressive properties and it has markedly improved the ability of transplant patients to survive grafts and is also used in some autoimmune diseases. However, the drug has several side effects, including testicular toxicity, leading to male infertility (and temporary impotence?). Stimulant and aphrodisiac properties has been attributed to the plant, Heteropterys aphrodisiaca. Data from other experiments suggests that the root extract can increase body and testicular weight and the volume of Leydig cells in rat testis. Thus, the present work was undertaken to study the association of the drug and the medicinal herb in Wistar rats, evaluating testicular morphometry, structure and ultrastructure. Thirty adult rats were used, divided into five groups: I- control; II¿ CsA; III¿ simultaneous use of CsA and H. aphrodisiaca; IV- H. aphrodisiaca for 30 days and CsA sequentially for another 26 days; V- H. aphrodisiaca. CsA was administered at a dose of 15 mg/kg/day and/or H. aphrodisiaca at a dose of 0.5 ml of the infusion prepared with 25g of roots/100ml boiling water, daily by gavage, during 56 days. Increased body weight was observed for all groups, but the animals that received CsA for 56 days showed the smallest body weight gain. The testis and accessory sex organs weights were unchanged. The volume and volumetric proportion of seminiferous tubules and interstitial compartments did not alter in all treated groups. Morphometry showed increased connective tissue volumetric proportion and decreased Leydig cell volumetric proportion in CsA-treated rats. The Leydig cells of CsA-treated animals were smaller and more dense than other groups. On the other hand, the H. aphrodisiaca infusion resulted in an increase in Leydig cell nuclear volume. The plasma testosterone levels and number of Leydig cells per testis increased significantly in group III. Using transmission electron microscopy, it was possible to ascertain that CsA caused germ cell degeneration, Sertoli cell vacuolization, abnormal round spermatids and atrophy of the organelles involved in steroid synthesis in Leydig cells. H. aphrodisiaca caused Sertoli cell vacuolization, loss of germ cell attachment and expanded intercellular spaces between germ cells and Leydig cells with more mitochondria and smooth endoplasmic reticulum. The simultaneous and sequential treatment with H. aphrodisiaca and CsA was effective in maintaining the Leydig cell ultrastructure. In these treatments, the seminiferous epithelium alterations were a combination of the modifications observed for each isolated treatment. However it can be stated that H. aphrodisiaca had a protective effect on the testicular tissue, since less severe modifications were found for this group in relation to the rats that received only CsA / Mestrado / Biologia Celular / Mestre em Biologia Celular e Estrutural

Orientador: Marilda Mazzali / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-08T15:27:17Z (GMT). No. of bitstreams: 1 Mazali_FernandaCristina_M.pdf: 3384913 bytes, checksum: 0d3a47a884265f3d5949b9aff82161a6 (MD5) Previous issue date: 2006 / Resumo: Objetivo: Hiperuricemia é uma complicação freqüente da terapêutica com ciclosporina (CsA). Estudos anteriores demonstraram que a hiperuricemia exacerba a lesão intersticial e vascular no modelo experimental de nefrotoxicidade por CsA (CsA ntx). O presente estudo tem como hipótese que a normalização da uricemia preveniria o desenvolvimento da nefropatia crônica por CsA. Metodologia: A nefropatia crônica por CsA foi induzida em ratos machos, Sprague Dawley, através da injeção subcutânea diária de CsA (15mg/kg/dia), por um período de 7 semanas, em associação com dieta hipossódica (CSA). O efeito do controle da hiperuricemia foi determinado através do tratamento concomitante com um inibidor de xantina oxidase (alopurinol, 15mg/Kg/dia ? CSA/ALP) ou com um agente uricosúrico (benzbromarona, 15mg/Kg/dia, CSA/BENZ), em bebedouro. O grupo-controle incluiu ratos tratados com veículo (VEH, injeções SC diárias de óleo de oliva). Ao sacrifício foram realizadas análises funcionais e histológicas. Resultados: Os animais do grupo CSA desenvolveram hiperuricemia leve (ácido úrico 4.36 vs 2.49 mg/dl, CSA vs VEH, p<0.05), com hialinose arteriolar, atrofia tubular, fibrose intersticial em faixa, aumento de proliferação celular e redução da expressão de VEGF. O tratamento com alopurinol ou benzbromarona reduziu a lesão renal, assim como os níveis de ácido úrico e creatinina sérica (ácido úrico 2.03 CSA/ALP e 2.93 mg/dl, CSA/BENZ, p<0.05 vs VEH e CSA). Ambos os tratamentos reduziram a fibrose intersticial, a proliferação celular, infiltrado de macrófagos, expressão de osteopontina e hialinose arteriolar, em associação com restauro da expressão de VEGF, com proteção comparável entre as duas drogas. Conclusão: A hiperuricemia exacerba a nefropatia pela CsA em ratos. Tratamento concomitante com alopurinol ou benzbromarone reduz a severidade da lesão. Como ambas as drogas promovem proteção semelhante, concluímos que o efeito protetor é associado ao controle da hiperuricemia, mais importante que o efeito antioxidante do alopurinol / Abstract: Aim: Hyperuricemia frequently complicates cyclosporine (CSA) therapy. Previous studies have shown that hyperuricemia increases the interstitial and vascular lesions in the cyclosporine model. We therefore tested the hypothesis that normalization of uric acid could prevent the development of cyclosporine toxicity. Material and Methods: CSA nephropathy was induced by the administration of CSA (15 mg/kg/day) for 7 weeks to rats on a low salt diet (CSA group). The effect of preventing hyperuricemia on CSA nephropathy was determined by concomitant treatment with the xanthine oxidase inhibitor, allopurinol (CSA-ALP), or with the uricosuric, benzbromarone (CSA-BENZ), in the drinking water. Control groups included rats treated with vehicle (VEH). Histological and functional studies were determined at sacrifice. Results:. CSA treated rats developed mild hyperuricemia with arteriolar hyalinosis, tubular atrophy, striped interstitial fibrosis, increased cell proliferation and decreased VEGF expression. Treatment with either allopurinol (CSA-ALP) or benzbromarone (CSA-BENZ) reduced renal injury. Both treatments reduced interstitial fibrosis, cell proliferation, macrophage infiltration, osteopontin expression and arteriolar hyalinosis in association with restoration of VEGF expression. Both drugs provided comparable protection. Conclusions: An increase in uric acid exacerbates CSA nephropathy in the rat. Concomitant treatment with allopurinol or benzbromarone reduced the severity of renal disease. As both drugs promoted similar protection, we can conclude that the protective effect is associated with lowering uric acid levels, more than the antioxidant effect of allopurinol / Mestrado / Ciencias Basicas / Mestre em Clinica Medica