Interleukin-1 (IL-1) is a prototypic multifunctional cytokine. IL-1 family include interleukin-1 a (IL-1 a), interleukin-1b (IL-1 b) and interleukin-1 receptor antagonist (IL-1 Ra). IL-1 b is the archetypeal pleiotropic cytokine which have been produced by many cells and exerting its biological effects on almost all cell types. IL-1 b is the most potent of known agents that are gastric cytoprotective, antiulcer, antisecretory and an inhibitor of gastric emptying. IL-1 Ra competes with IL-1 b for cell surface receptor occupancy. Host genetic factors that affect interleukin-1 (IL-1) have been reported to influence the susceptibility of Caucasians to gastric cancer. Whether Asians have the same genetic susceptibility remains unclear. In this study, the genetic associations of IL-1B and IL-1RN polymorphisms with gastric cancer and duodenal ulcer in Taiwan were evaluated. Genomic DNA from 140 unrelated Taiwanese patients with gastric adenocarcinoma, 94 with duodenal ulcer and 165 ethically matched healthy controls was typed for polymorphisms at positions ¡V31, -511, and +3954 in the IL-1B gene, and the variable number of tandem repeats polymorphisms in intron 2 of the IL-1RN gene. The allele frequencies of IL-1RN 2R in gastric cancer cases were much higher than those in healthy controls (9% vs. 3%, p = 0.781). The allele frequencies of IL-1B ¡V31, IL-1B ¡V511 and IL-1B +3954 did not differ. An increased risk of the development of intestinal type gastric carcinoma was found in IL-1RN 2R carriers with an odds ratio (OR) of 4.06 (95% confidence interval [CI]: 1.68 ¡V 9.79, p-value=0.085). And another increased risk of the development of diffuse type gastric carcinoma was found in IL-1RN 2R carriers with an odds ratio (OR) of 3.15 (95% confidence interval [CI]: 1.16 ¡V 8.56, p-value=0.061). A significant association was found in IL-1RN 2R/4R genotype and the risk of the development of duodenal ulcer, with an odds ratio (OR) of 2.57 (95% CI: 1.03 ¡V 6.38, p = 0.292). No significant relationship was noted in duodenal ulcer patients with IL-1B genotype examed in this study. Additionally, a synergistic interaction between blood type A and IL-1 RN 2R carriers existed in gastric cancer patients (OR= 4.51; 95% CI: 1.20 ¡V 16.88, p-value=0.516). The synergistic interaction was even stronger between blood type O and IL-1 RN 2R carriers of duodenal ulcer patients (OR= 10.3; 95% CI: 2.10 ¡V 50.61, p-value=0.160). In conclusion, the genetic polymorphisms of IL-1RN 2R and blood type A are associated with the development of gastric cancer. The genetic polymorphisms of IL-1RN 2R and blood type O are associated with the development of duodenal ulcer.

Made available in DSpace on 2014-06-11T19:33:28Z (GMT). No. of bitstreams: 0 Previous issue date: 2005-03-26Bitstream added on 2014-06-13T20:45:02Z : No. of bitstreams: 1 vergani_sa_dr_arafo.pdf: 639289 bytes, checksum: 6483b0519cf455414c9e0881668e277f (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O objetivo do presente estudo foi o de avaliar os efeitos do controle de placa supragengival, em pacientes com doença periodontal crônica generalizada, por meio dos parâmetros clínicos microbiológicos e imunológicos. Foram selecionados 30 pacientes, com idade entre 32 e 59 anos, apresentando 4 bolsas entre 3 e 5mm e 4 bolsas entre 6 e 10mm e sem envolvimento sistêmico. Após o exame inicial, os pacientes foram submetidos a raspagem supragengival e receberam instruções de higiene oral, sendo acompanhados semanalmente por um período de 30 dias. Os parâmetros clínicos avaliados foram profundidade de sondagem, recessão gengival, índice de placa, índice gengival e sangramento à sondagem. Amostras de fluido crevicular das bolsas foram coletadas para análise da concentração dos mediadores de inflamação interleucina-1b e prostaglandina E2 e identificação pela reação de polimerase em cadeia dos microrganismos Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Bacteroides forsythus, Prevotella intermedia e Prevotella nigrescens. Os resultados demonstraram a ocorrência de melhoras evidenciadas pelos parâmetros clínicos avaliados. Observou-se ainda uma redução significante no número de Porphyromonas gingivalis, Bacteroides forsythus, Prevotella intermedia e Prevotella nigrescens. O microrganismo A. actinomycetemcomitans não apresentou diferença significante. Para o exame imunológico não foram encontradas diferenças nos níveis de interleucina-1b, sendo constatado ainda um aumento nas concentrações de prostaglandina E2 nas bolsas de 6 a 10mm que apresentavam sangramento no final do tratamento. Concluiu-se que decisão da necessidade de tratamento periodontal em sítios profundos, após a realização do controle de placa supragengival, baseada somente na ausência de sangramento à sondagem pode subestimar... . / The aim of the present study was to evaluate the effect of supragingival plaque control, in patients with generalized chronic periodontal disease using clinical, microbiological and immunological parameters. 30 patients were selected, aged 32 to 59 years, presenting 4 periodontal pockets between 3 and 5mm and 4 pockets between 6 and 10mm. After initial exam patients received supragingival scaling and oral hygiene instructions, which were reinforced once a week for 30 days. Clinical parameters were probing depth, gingival resection, plaque index, gingival index and bleeding upon probing. Samples of crevicular fluid were taken for analyses of interleukin-1b and prostaglandin E2 and for identification by polymerase chain reaction of Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Bacteroides forsythus, Prevotella intermedia and Prevotella nigrescens. The results demonstrated an improvement of the clinical parameters. The microbiological findings indicate reduction of Porphyromonas gingivalis, Bacteroides forsythus, Prevotella intermedia, and Prevotella nigrescens. A. actinomycetemcomitans did not show significant difference. In regard to the immunological exam, no differences were observed in interleukin-1b concentration. Prostaglandin E2 concentrations were elevated in pockets between 6 and 10mm with persistent bleeding upon probing after treatment. In conclusion the decision for treatment needs after supragingival plaque control only based on the absence of bleeding upon probing might underestimate the periodontal disease activity.

Resumo: O objetivo do presente estudo foi o de avaliar os efeitos do controle de placa supragengival, em pacientes com doença periodontal crônica generalizada, por meio dos parâmetros clínicos microbiológicos e imunológicos. Foram selecionados 30 pacientes, com idade entre 32 e 59 anos, apresentando 4 bolsas entre 3 e 5mm e 4 bolsas entre 6 e 10mm e sem envolvimento sistêmico. Após o exame inicial, os pacientes foram submetidos a raspagem supragengival e receberam instruções de higiene oral, sendo acompanhados semanalmente por um período de 30 dias. Os parâmetros clínicos avaliados foram profundidade de sondagem, recessão gengival, índice de placa, índice gengival e sangramento à sondagem. Amostras de fluido crevicular das bolsas foram coletadas para análise da concentração dos mediadores de inflamação interleucina-1b e prostaglandina E2 e identificação pela reação de polimerase em cadeia dos microrganismos Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Bacteroides forsythus, Prevotella intermedia e Prevotella nigrescens. Os resultados demonstraram a ocorrência de melhoras evidenciadas pelos parâmetros clínicos avaliados. Observou-se ainda uma redução significante no número de Porphyromonas gingivalis, Bacteroides forsythus, Prevotella intermedia e Prevotella nigrescens. O microrganismo A. actinomycetemcomitans não apresentou diferença significante. Para o exame imunológico não foram encontradas diferenças nos níveis de interleucina-1b, sendo constatado ainda um aumento nas concentrações de prostaglandina E2 nas bolsas de 6 a 10mm que apresentavam sangramento no final do tratamento. Concluiu-se que decisão da necessidade de tratamento periodontal em sítios profundos, após a realização do controle de placa supragengival, baseada somente na ausência de sangramento à sondagem pode subestimar... (Resumo completo, clicar acesso eletrônico abaixo). / Abstract: The aim of the present study was to evaluate the effect of supragingival plaque control, in patients with generalized chronic periodontal disease using clinical, microbiological and immunological parameters. 30 patients were selected, aged 32 to 59 years, presenting 4 periodontal pockets between 3 and 5mm and 4 pockets between 6 and 10mm. After initial exam patients received supragingival scaling and oral hygiene instructions, which were reinforced once a week for 30 days. Clinical parameters were probing depth, gingival resection, plaque index, gingival index and bleeding upon probing. Samples of crevicular fluid were taken for analyses of interleukin-1b and prostaglandin E2 and for identification by polymerase chain reaction of Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Bacteroides forsythus, Prevotella intermedia and Prevotella nigrescens. The results demonstrated an improvement of the clinical parameters. The microbiological findings indicate reduction of Porphyromonas gingivalis, Bacteroides forsythus, Prevotella intermedia, and Prevotella nigrescens. A. actinomycetemcomitans did not show significant difference. In regard to the immunological exam, no differences were observed in interleukin-1b concentration. Prostaglandin E2 concentrations were elevated in pockets between 6 and 10mm with persistent bleeding upon probing after treatment. In conclusion the decision for treatment needs after supragingival plaque control only based on the absence of bleeding upon probing might underestimate the periodontal disease activity. / Orientador: Rosemary Adriana Chiérici Marcantonio / Coorientador: Iracilda Zepponi Carlos / Banca: Carlos Rossa Júnior / Banca: Márcio Fernando de Moraes Grisi / Banca: Luciene Cristina de Figueiredo / Banca: Magda Feres / Doutor

Made available in DSpace on 2014-06-11T19:28:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2004-02-19Bitstream added on 2014-06-13T18:57:07Z : No. of bitstreams: 1 lopes_bmv_me_arafo.pdf: 548412 bytes, checksum: f64e2cc01adfefa526323f3f10303b99 (MD5) / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O objetivo do presente estudo foi comparar o efeito do laser de Er:YAG, associado ou não, à raspagem e alisamento radicular no tratamento periodontal não cirúrgico. Foram selecionados 21 pacientes saudáveis, com doença periodontal crônica, apresentando 4 bolsas periodontais entre 5 e 9mm, em sítios não vizinhos. Os pacientes foram tratados sob efeito de anestesia local e os sítios foram divididos aleatoriamente em quatro grupos, sendo: Grupo Raspagem+Laser: associação da raspagem e alisamento radicular com instrumentos manuais com o laser Er:YAG; Grupo Laser: laser Er:YAG sozinho; Grupo Raspagem: somente raspagem e alisamento radicular com instrumentos manuais; Grupo Controle: não foi feito tratamento algum. Os parâmetros utilizados para o laser de Er:YAG foram 100mJ/pulso em uma freqüência de 10Hz (12,9J/cm2). Os parâmetros clínicos índice de placa (IP), índice gengival (IG), sangramento à sondagem (SS), profundidade de sondagem (PS), recessão gengival (RG) e nível de inserção clínico relativo (NICR) foram avaliados antes, 30 e 90 dias após o tratamento. Amostras de fluido crevicular das bolsas foram coletadas junto com IP, IG e SS para análise da concentração do mediador de inflamação Interleucina-1Beta (IL-1b). Os resultados, após 90 dias, demonstraram para IP melhora significante para somente para o grupo Raspagem (p<0,01), enquanto o IG apresentou melhoras significantes para os grupos Raspagem+Laser e Raspagem (p<0,05), sendo que o grupo Raspagem+Laser obteve uma melhora significantemente maior que o grupo Controle, após 30 e 90 dias (p<0,05). O valor do sangramento à sondagem diminuiu significantemente para os grupos Raspagem+Laser, Laser e Raspagem após 30 dias (p<0,01) e também, com diferença significante quando comparados ao grupo Controle (p<0,05); após 90 dias diferença significante ocorreu para todos os grupos (p<0,01)... . / The aim of the present study was to compare the effectiveness of an Er:YAG laser, with a combination or not, to that of scaling and root planning (SRP) with hand instruments for non-surgical periodontal treatment. Twenty-one healthy patients with chronic periodontal disease were selected presenting 4 periodontal pockets between 5 and 9mm, in sites non-neighbors. The patients were treated under local anesthesia and the sites were divided randomly in four groups, being: Group Scaling+Laser (Group 1): combination of SRP with manual instruments and an Er:YAG laser; Group Laser (Group 2): an Er:YAG laser alone; Group Sacaling (Group 3): only SRP with hand instruments; Group Control (Group 4): it was not made any treatment. The parameters used for the Er:YAG laser were 100mJ/pulso and 10Hz (12,9J/cm2). Clinical assessments plaque index (PI), gingival index (GI), bleeding on probing (BOP), probing depth (PD), gingival resection (GR), and clinical attachment level (CAL) were made prior to and at 30 and 90 days after the treatment. Gingival crevicular fluid samples were taken for analyses concentration of the mediator of inflammation interleukin-1b in the same day that IP, IG and SS. The results, after 90 days, demonstrated for PI a significant reduction only for the group 3 (p<0,01), while GI presented significant improvements for groups 1 and 3 (p<0,05), and the group 1 showed an improvement was significantly higher than the group 4, after 30 and 90 days (p<0,05). The reduction of BOP was significant to groups 1, 2 and 3 after 30 days (p<0,01) and also, with significant difference when compared to the group 4 (p<0,05); after 90 days significant difference occurred for all the groups (p<0,01). The mean value of the PD, after 30 days (p<0,001) and after 90 days (p<0,001), decreased in all groups, except in group 4; and still, after... (Complete abstract, click electronic address below).

Resumo: O objetivo do presente estudo foi comparar o efeito do laser de Er:YAG, associado ou não, à raspagem e alisamento radicular no tratamento periodontal não cirúrgico. Foram selecionados 21 pacientes saudáveis, com doença periodontal crônica, apresentando 4 bolsas periodontais entre 5 e 9mm, em sítios não vizinhos. Os pacientes foram tratados sob efeito de anestesia local e os sítios foram divididos aleatoriamente em quatro grupos, sendo: Grupo Raspagem+Laser: associação da raspagem e alisamento radicular com instrumentos manuais com o laser Er:YAG; Grupo Laser: laser Er:YAG sozinho; Grupo Raspagem: somente raspagem e alisamento radicular com instrumentos manuais; Grupo Controle: não foi feito tratamento algum. Os parâmetros utilizados para o laser de Er:YAG foram 100mJ/pulso em uma freqüência de 10Hz (12,9J/cm2). Os parâmetros clínicos índice de placa (IP), índice gengival (IG), sangramento à sondagem (SS), profundidade de sondagem (PS), recessão gengival (RG) e nível de inserção clínico relativo (NICR) foram avaliados antes, 30 e 90 dias após o tratamento. Amostras de fluido crevicular das bolsas foram coletadas junto com IP, IG e SS para análise da concentração do mediador de inflamação Interleucina-1Beta (IL-1b). Os resultados, após 90 dias, demonstraram para IP melhora significante para somente para o grupo Raspagem (p<0,01), enquanto o IG apresentou melhoras significantes para os grupos Raspagem+Laser e Raspagem (p<0,05), sendo que o grupo Raspagem+Laser obteve uma melhora significantemente maior que o grupo Controle, após 30 e 90 dias (p<0,05). O valor do sangramento à sondagem diminuiu significantemente para os grupos Raspagem+Laser, Laser e Raspagem após 30 dias (p<0,01) e também, com diferença significante quando comparados ao grupo Controle (p<0,05); após 90 dias diferença significante ocorreu para todos os grupos (p<0,01)... (Resumo completo, clicar acesso eletrônico abaixo). / Abstract: The aim of the present study was to compare the effectiveness of an Er:YAG laser, with a combination or not, to that of scaling and root planning (SRP) with hand instruments for non-surgical periodontal treatment. Twenty-one healthy patients with chronic periodontal disease were selected presenting 4 periodontal pockets between 5 and 9mm, in sites non-neighbors. The patients were treated under local anesthesia and the sites were divided randomly in four groups, being: Group Scaling+Laser (Group 1): combination of SRP with manual instruments and an Er:YAG laser; Group Laser (Group 2): an Er:YAG laser alone; Group Sacaling (Group 3): only SRP with hand instruments; Group Control (Group 4): it was not made any treatment. The parameters used for the Er:YAG laser were 100mJ/pulso and 10Hz (12,9J/cm2). Clinical assessments plaque index (PI), gingival index (GI), bleeding on probing (BOP), probing depth (PD), gingival resection (GR), and clinical attachment level (CAL) were made prior to and at 30 and 90 days after the treatment. Gingival crevicular fluid samples were taken for analyses concentration of the mediator of inflammation interleukin-1b in the same day that IP, IG and SS. The results, after 90 days, demonstrated for PI a significant reduction only for the group 3 (p<0,01), while GI presented significant improvements for groups 1 and 3 (p<0,05), and the group 1 showed an improvement was significantly higher than the group 4, after 30 and 90 days (p<0,05). The reduction of BOP was significant to groups 1, 2 and 3 after 30 days (p<0,01) and also, with significant difference when compared to the group 4 (p<0,05); after 90 days significant difference occurred for all the groups (p<0,01). The mean value of the PD, after 30 days (p<0,001) and after 90 days (p<0,001), decreased in all groups, except in group 4; and still, after... (Complete abstract, click electronic address below). / Orientador: Rosemary Adriana Chiérici Marcantonio / Coorientador: Letícia Helena Theodoro / Banca: Denise Madalena Palomari Spolidorio / Banca: Silvia Rosana Soares Carneiro / Mestre

A técnica de laserterapia é um método não-invasivo que demonstra clinicamente ser eficaz na redução da sensibilidade à dor. O presente estudo visou examinar os efeitos da aplicação do LASER sobre a sensibilidade dolorosa induzida pela constrição crônica do nervo isquiático (CCI) de ratos. Os animais foram submetidos a ensaios comportamentais e a dez sessões de laserterapia. Observamos melhora para os testes comportamentais o que corrobora com os ensaios de imunoblotting no gânglio da raiz dorsal, onde observamos uma diminuição de Substância P no grupo de animais tratados com LASER. Com relação aos ensaios imunoenzimático de ELISA, observamos diminuição de citocinas pró-inflamatória e uma tendência ao aumento de citocina anti-inflamatória. Não observamos diferença estatística na análise dos receptores opióides MOR , DOR e KOR . Podemos concluir que o LASER é eficaz e age na modulação da dor neuropática. / The technique of laser therapy is a not invasive method that demonstrates clinically to be effective in reducing sensitivity to pain. This study aimed to examine the effects of application of LASER on pain sensitivity induced by chronic constriction of the sciatic nerve (CCI) in rats. The animals were subjected to behavioral tests and the ten sessions of laser therapy. We observed and improvement for behavioral tests which corroborates with immunoblotting assays in the dorsal root ganglion, where we observes a decrease of substance P in the group of animals treated with LASER. Regarding immunoenzymatic ELISA assay, we observed a decrease of pro-inflammatory cytokines and a possible increase in anti-inflammatory cytokine. No statistical difference in the analysis of opioid receptor MOR, DOR and KOR.

A técnica de laserterapia é um método não-invasivo que demonstra clinicamente ser eficaz na redução da sensibilidade à dor. O presente estudo visou examinar os efeitos da aplicação do LASER sobre a sensibilidade dolorosa induzida pela constrição crônica do nervo isquiático (CCI) de ratos. Os animais foram submetidos a ensaios comportamentais e a dez sessões de laserterapia. Observamos melhora para os testes comportamentais o que corrobora com os ensaios de imunoblotting no gânglio da raiz dorsal, onde observamos uma diminuição de Substância P no grupo de animais tratados com LASER. Com relação aos ensaios imunoenzimático de ELISA, observamos diminuição de citocinas pró-inflamatória e uma tendência ao aumento de citocina anti-inflamatória. Não observamos diferença estatística na análise dos receptores opióides MOR , DOR e KOR . Podemos concluir que o LASER é eficaz e age na modulação da dor neuropática. / The technique of laser therapy is a not invasive method that demonstrates clinically to be effective in reducing sensitivity to pain. This study aimed to examine the effects of application of LASER on pain sensitivity induced by chronic constriction of the sciatic nerve (CCI) in rats. The animals were subjected to behavioral tests and the ten sessions of laser therapy. We observed and improvement for behavioral tests which corroborates with immunoblotting assays in the dorsal root ganglion, where we observes a decrease of substance P in the group of animals treated with LASER. Regarding immunoenzymatic ELISA assay, we observed a decrease of pro-inflammatory cytokines and a possible increase in anti-inflammatory cytokine. No statistical difference in the analysis of opioid receptor MOR, DOR and KOR.

CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / This work as main objective to evaluate the eletrogenic effect in preparations of Ãleum of rabbit fixes in chambers of Ãssing, in presence of supernatant of macrophages (S.MfS), stimulated with microcistin-LR (MCLR), of Microcystis aeruginosa. S.MfS estimulated with MCLR (3,2.10-7M; 9,6.10-7M e 3,2.10-6M), produces effect secretion, of the form dose-dependent; being that short circuit current (Isc), the secular chain variation (t) can be described for an equation of the type Isc = a . ekt for a correlation coefficient r = 0,9988 and Iscmaximo = 128,16  14,54 ÂA . cm-2. Later, was observed that the metabolic processes associatesâ geneses of the FSI, from stimulated macrophages, require the participation of a protein G, sensible pertussis active toxin. It was also verified that inhibing of protÃic synthesis, proteases, phosfolipase A2, ciclooxigenases, lipoxigenases, synthesis TNF-a, and antagonists of the PAF, they had reduced the FSI synthesis. With the application of monoclonal antibodies, it was verified that interleukin-b (IL-1b), was the main FSI; as also, that macrophages stimulated with MCLR, in the concentrations above, produced IL-1b and TNF-a, of form dose-dependent. The pay-treatment of the ileum mucosal with bumetanide, indomethacin, tetrodotoxin and HOE, disclosed that the secretory effect, by means of stimulated action of the S.MfS with MCLR is dependent of the secretion of ions chloride, with the participation of PAF, prostaglandins and mediators of the enteric nervous system. With this effect, it associates reduction of the transepitelial resistance (Rte), also mediated for prostaglandins, TNF-a, and indirectly IL-1b. The analysis of the coefficient of Hurst, disclosed that these effect had not occurred of random form, but had involved significant alterations in the kinetic parameters of the eletrogÃnic effect, to the level of the ileum mucosal. Macrophages stimulated for MCLR, produces and liberate more TNF-a of that IL-1b, to the Constant taxes, being this a linked characteristic to the type of employed stimulation. It is concluded, therefore, that MCLR stimulates macrophages to produce substances that can act as intestinal secretion factor, to the level of the ileum mucosal, involving chloride canals, reduction of the Rte, requesting for this, the participation of pro-inflammatory mediators and the enteric nervous system. / Este trabalho teve-se como principal objetivo, avaliar os efeitos eletrogÃnicos em preparaÃÃes de Ãleo de coelho fixadas em cÃmaras de Ãssing, em presenÃa de sobrenadante de macrÃfagos (S.MfS) estimulados com microcistina-LR MCLR de Microcystis aeruginosa. S.MfS estimulados com MCLR (3,2.10-7M; 9,6.10-7M e 3,2.10-6M), produz, de forma dose-dependente; sendo que a variaÃÃo temporal (t) da corrente de curto-circuito (Isc), pode ser descrita por uma equaÃÃo do tipo Isc = a . ekt; para um coeficiente de correlaÃÃo r = 0,9988 e Iscmaximo = 128,16  14,54 ÂÂcm-2. Posteriormente, observou-se que os processos metabÃlicos associados à gÃnese do fator deâ secreÃÃo intestinalâ (FSI), a partir de macrÃfagos estimulados, requer a participaÃÃo de uma proteÃna G sensÃvel à toxina pertusis ativa. Verificou-se tambÃm que inibidores de sÃntese protÃica, proteases, fosfolipase A2, cicloxigenases, lipoxigenases,; sÃntese de TNF-a e antagonista do PAF, reduziram a sÃntese de FSI. Com o emprego de anticorpos monoclonais, verificou-se que IL-1b era o principal FSI; como tambÃm, que macrÃfagos estimulados com MCLR, nas concentraÃÃes acima, reduziu IL-1b e TNF-a, de forma dose-dependente. O prÃ-tratamento da mucosa ileal com bumetanida, indometacina, tetrodotoxina e HOE, revelou que o efeito secretÃrio mediante aÃÃo do S.MfS estimulados com MCLR, à dependente da secreÃÃo de Ãons cloreto, com a participaÃÃo de PAF, prostaglandinas e mediadores do sistema nervoso entÃrico. A este efeito associa-se a diminuiÃÃo da resistÃncia transepitelial (Rte), tambÃm mediada por, prostaglandinas, PAF, TNF-a e, indiretamente, IL-1b. A anÃlise do coeficiente de Hurst (H), revelou que estes efeitos nÃo ocorreram ao acaso, mas envolveram alteraÃÃes significativas nos parÃmetros cinÃticos dos efeitos eletrogÃnicos, ao nÃvel da mucosa ileal. MacrÃfagos estimulados com MCLR produz e libera mais TNFa do que IL-1b, à taxas constantes ; sendo esta uma caracterÃstica atrelada ao tipo de estÃmulo empregado. Conclui-se, portanto, que MCLR estimula macrÃfagos a produzir substÃncias que podem atuar como fator de âsecreÃÃo intestinalâ ao nÃvel da mucosa ileal, envolvendo canais de cloreto, diminuiÃÃo de Rte; requisitando para isto, a participaÃÃo de mediadores prÃ-inflamatÃrios e do sistema nervoso entÃrico.

Les rétinopathies ischémiques (RI) sont la cause majeure de cécité chez les personnes âgées de moins de 65 ans. Il existe deux types de RIs soit la rétinopathie du prématuré (ROP) ainsi que la rétinopathie diabétique (RD). Les RIs sont décrites en deux phases soit la phase de vasooblitération, marquée par une perte importante de vaisseaux sanguins, et une phase de néovascularisation secondaire à lʼischémie menant à une croissance pathologique de vaisseaux. Cette seconde phase peut générer des complications cliniques telles quʼun oedème dans lʼhumeur vitré ainsi que le détachement de la rétine chez les patients déjà atteints dʼune RI. Les traitements approuvés pour les RIs visent à réduire la formation des vaisseaux pathologiques ou lʼoedème; mais ceux-ci malheureusement ne règlent pas les problèmes sous-jacents tels que la perte vasculaire et lʼischémie. La rétine est un tissu hautement vascularisé qui contribue à lʼirrigation et à lʼhoméostasie des neurones. Lʼinteraction neurovasculaire, comprenant de neurones, vaisseaux et cellules gliales, contribue au maintien de cette homéostasie. Durant le développement, les neurones et les cellules gliales jouent un rôle important dans la vascularisation de la rétine en sécrétant des facteurs qui stimulent l'angiogenèse. Cependant, nos connaissances sur lʼinteraction neurovasculaire dans les RIs sont limitées. En identifiant les interactions importantes entre les cellules composant cette unité neurovasculaire dans la rétine, nous pourrons viser des cibles qui engendreront une revascularisation seine afin de diminuer les signes pathologiques chez les patients atteints dʼune RI. Les travaux présentés dans cette thèse visent à mieux expliquer cette interaction neurovasculaire en soulignant des concepts importants propres aux RIs. En utilisant un modèle de rétinopathie induite par lʼoxygène chez la souris, qui reproduit les caractéristiques importantes de la ROP (et en certaines instances, la RD), nous identifions quelques molécules clés jouant un rôle significatif dans les RIs soit la sémaphorine 3A (sema3A), lʼIL-1β, ainsi que le récepteur PAR2. Nos résultats démontrent que Sema3A, sécrétée par les cellules ganglionnaires rétiniennes (CGRs) durant une ischémie, empêche la revascularisation normale et que cette expression est induite par lʼIL-1β provenant des microglies activées. En bloquant Sema3A directement ou via lʼinhibition de lʼIL- 1β, nous remarquons une revascularisation seine ainsi quʼune diminution importante des vaisseaux pathologiques. Cela nous indique que Sema3A est impliquée dans la guidance vasculaire et quʼelle contribue à la pathogenèse des RIs. Lʼactivation de façon exogène de PAR2, identifié aussi comme régulateur du récepteur de lʼIL-1β (IL- 1RI) sur les CGRs, se traduit par une diminution séquentielle de lʼIL-1RI et de Sema3A ce qui mène également à une revascularisation seine. En conclusion, ces travaux soulignent lʼimportance de lʼinteraction neurovasculaire ainsi que la guidance vasculaire dans les RIs. Ils renforcent lʼimportance de la communication entre neurone, vaisseau et microglie dans la pathogenèse des RIs. Finalement, nous identifions quelques molécules clés qui pourront servir comme cibles afin de lutter contre lʼischémie qui cause des problèmes vasculaires chez les patients atteints dʼune RI. / Ischemic retinopathies (IRs), namely, retinopathy of prematurity (ROP) and diabetic retinopathy (DR), are the major cause of blindness in persons under the age of 65. IRs are biphasic disorders described by an initial vasoobliterative phase marked by a persistent microvascular degeneration, which leads to ischemia. Retinal ischemia, secondary to vessel loss, incites a second neovascularization phase represented by an aberrant, misdirected neovessel formation into the vitreous, which can cause adverse clinical complications including vitreous hemorrhaging and tractional retinal detachment. While current treatments aim at reducing vitreous/retinal hemorrhaging and/or pathological pre-retinal neovascularization, these regimens fail to address the underlying problem; that is, microvascular decay and retinal ischemia. The retina is a highly metabolic tissue that requires a significant amount of nutrients and oxygen. This is supplied by an intricate and highly regulated vascular network required to maintain homeostasis and proper function. The intricate cellular interactions in the neurovascular unit – the consortium of vessel, neurons and support glia – are required for regulating and maintaining homeostasis under normal conditions. However, the understanding of how this unit functions under ischemic stress, that which is seen in patients suffering from IRs, is not well defined. The present work underlines several important concepts of neurovascular coupling in IRs in efforts to identify potential therapeutic agents that may help curb retinal ischemia by stimulating normal revascularization. Using a mouse model of oxygen-induced retinopathy (OIR), which reproduces the salient features of ROP (and in some instances DR), we identified key players involved in generating the pathophysiological signatures associated with IRs; namely, semaphorin3A (Sema3A), interleukin-1β (IL-1β) and protease-activated receptor 2 (PAR2). Our results show that neuronal-derived Sema3A, secreted by ischemic retinal ganglion cells (RGCs), acts as a potent vaso-repulsive molecules that impedes normal revascularization. Activated microglia contribute to this process by secreting IL-1β, which induces paracrine release of Sema3A expression contributing to microvascular decay as well as pathological pre-retinal neovascularization. Inhibition of Sema3A or IL-1β translates to rapid revascularization and, as a result, a significant reduction in pathological neovessel formation. These results demonstrate that Sema3A is directly involved in vascular guidance and precipitates the pathophysiological features associated with IRs. PAR2, found on RGCs, was also identified as a key regulatory mechanism involved in dampening IL-1β induced Sema3A mediated vascular decay by reducing IL-1 receptor (IL-1RI). Exogenous activation of neuronal PAR2 translates to a sequential reduction of both IL-1RI and Sema3A resulting in accelerated revascularization and consequentially pre-retinal neovascularization. In conclusion, these studies highlight the importance of neurovascular coupling associated with IRs. Herein, we demonstrate the consorted interaction between neuron, vessel and glia and its impact on shaping the retinal vasculature during disease. Moreover, we underscore the significant impact of neuronal guidance cues in manifesting the salient vascular features of IRs. Finally, we identify key players that may serve as potential therapeutic avenues in curbing retinal ischemia in efforts to reduce vascular complications associated with IRs.