Efeito protetor da via hemeoxigenase 1/ BILIVERDINA/ CO em modelos de lesÃes gÃstricas em camundongos â papel da guanilato ciclase solÃvel (GCS) e da no sintase (NOS)
Autor(a) principal: | |
---|---|
Data de Publicação: | 2009 |
Tipo de documento: | Tese |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFC |
Texto Completo: | http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=6887 |
Resumo: | Objective: To evaluate the protective effect of the heme-oxygenase 1 (HO-1)/biliverdin/CO pathway in models of gastropathy in mice, evaluating the role of the soluble guanylate cyclase (GCs) and of the constitutive NOS in this event. Methods: Protocol 1: Mice were pre-treated with hemin (HO-1 inducer; 1,3,10 mg/Kg, i.p.), biliverdin (HO-1 product; 1,3 or 10 mg/Kg., i.p.), DMDC (CO donor; 2.5, 7.5, 12.5 or 10 Âmol/Kg, i.p.) or ZnPP IX (HO-1 antagonist; 0,3, 1 or 3 mg/kg. i.p.), one hour before, gastric damage was induced by ethanol 50% (hemin, biliverdin, DMDC) or 25% (ZnPP IX). In another group, the animals were pre-treated with ODQ (12.5 mg/kg, v.o) or L-NAME (3 mg/Kg, v.o), thirty minutes before of the treatments cited previously. After 1h, the mice were sacrificed and the stomachs removed for evaluation of the gastric lesions (Image J). Protocol 2: Mice were pre-treated with hemin (3 mg/Kg, i.p.), biliverdin (3 mg/Kg., i.p.), DMDC (12,5 Âmol/Kg) or ZnPP IX (3,0 mg/kg), one hour before of the administration of INDO 30 mg/Kg (hemin, biliverdin, DMDC) or 10 mg/Kg (ZnPP IX). In another group, the animals were pre-treated with ODQ (12.5 mg/kg, v.o) or L-NAME (3 mg/Kg, v.o), thirty minutes before of the treatments cited previously. Three hours after, the mice were sacrificed and the stomachs removed for evaluation of the gastric lesions, utilizing a digital paquimetry. In all of the experimental groups, fragments of the gastric mucous were collected for determination of the concentration of MDA, GSH or bilirubin. Another samples of tissue was removed for microscopic analyzes and HO-1 expression by immunohistochemistry. The detection of the TNF-α, IL-1β, IL-10 and MPO activity were evaluated only in the INDO gastropathy. Results: Ethanol increased the expression of HO-1 and the levels of bilirrubin in the gastric tissue. Hemin, biliverdin and DMDC reduced gastric damage, MDA levels and GSH consume in ethanol 50%- induced gastropathy. The histological parameters, edema, hemorrhage and loses of epithelial cells, were diminished in the presence of hemin, biliverdin or DMDC. ZnPP IX amplified the ethanol-induced gastric lesion, increased MDA formation and decreased the GSH concentration in gastric mucosa. The histological parameters also were amplified after the handling with ZnPP IX. Bilirubin concentration was elevated during the protection induced by hemin and biliverdin, but not DMDC. INDO increased the HO-1 expression and the bilirrubin levels in the gastric mucosa. Hemin, biliverdin or DMDC reduced the gastric lesion, the MPO activity, and the MDA levels and increased the GSH concentration in the gastropathy INDO- induced. The histological parameters, edema, hemorrhage, loss of epithelial cells and the presence of inflammatory cells, were inhibited by hemin, biliverdin or DMDC. ZnPP IX amplified the effect of the INDO increasing the gastric lesion, the MPO activity, the MDA levels and the GSH consume. The histological parameters also were amplified after the handling with ZnPP IX. Bilirubin was shown elevated during the protection induced by hemin and biliverdin, but not DMDC. Hemin, biliverdin and DMDC diminished the TNF-α and IL-1β concentrations and increased the IL-10. ODQ and L-NAME completely abolished the DMDC protective gastric effect, but not biliverdin in the gastropathy ethanol or INDO- induced. Conclusion: HO-1/biliverdin/CO pathway plays a protective effect against ethanol or INDO-induced gastric damage. In the gastropathy by ethanol, the protection is dependent of the anti-oxidant action by bilirubin and CO. However, in the model of INDO gastropathy, we observe an anti-oxidant and anti-inflammatory action. The mechanism of gastro protective action of the CO, but not of the biliverdin, is dependent of the CO/ NOS/ GMPc pathway. |
id |
UFC_bd55b0cb68ca07dcd7d6ed216b56d683 |
---|---|
oai_identifier_str |
oai:www.teses.ufc.br:4928 |
network_acronym_str |
UFC |
network_name_str |
Biblioteca Digital de Teses e Dissertações da UFC |
spelling |
info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/doctoralThesisEfeito protetor da via hemeoxigenase 1/ BILIVERDINA/ CO em modelos de lesÃes gÃstricas em camundongos â papel da guanilato ciclase solÃvel (GCS) e da no sintase (NOS)2009-11-30Marcellus Henrique Loiola Ponte de Souza51211700330http://lattes.cnpq.br/4001596522263940Gerly Anne de Castro Brito24198846391http://lattes.cnpq.br/8991062042568398Mirna Marques Bezerra87708124468http://lattes.cnpq.br/0614961188016863Thiago Mattar Cunha05032170690http://lattes.cnpq.br/0585283327853481Ricardo Bentes de Azevedo15454746215http://lattes.cnpq.br/907233248435531583851259149http://lattes.cnpq.br/1674590681546363Antoniella Souza GomesUniversidade Federal do CearÃPrograma de PÃs-GraduaÃÃo em FarmacologiaUFCBRLesÃo gÃtrica Hemeoxigenase-1heme-oxygenase 1 gastric lesions FARMACOLOGIAObjective: To evaluate the protective effect of the heme-oxygenase 1 (HO-1)/biliverdin/CO pathway in models of gastropathy in mice, evaluating the role of the soluble guanylate cyclase (GCs) and of the constitutive NOS in this event. Methods: Protocol 1: Mice were pre-treated with hemin (HO-1 inducer; 1,3,10 mg/Kg, i.p.), biliverdin (HO-1 product; 1,3 or 10 mg/Kg., i.p.), DMDC (CO donor; 2.5, 7.5, 12.5 or 10 Âmol/Kg, i.p.) or ZnPP IX (HO-1 antagonist; 0,3, 1 or 3 mg/kg. i.p.), one hour before, gastric damage was induced by ethanol 50% (hemin, biliverdin, DMDC) or 25% (ZnPP IX). In another group, the animals were pre-treated with ODQ (12.5 mg/kg, v.o) or L-NAME (3 mg/Kg, v.o), thirty minutes before of the treatments cited previously. After 1h, the mice were sacrificed and the stomachs removed for evaluation of the gastric lesions (Image J). Protocol 2: Mice were pre-treated with hemin (3 mg/Kg, i.p.), biliverdin (3 mg/Kg., i.p.), DMDC (12,5 Âmol/Kg) or ZnPP IX (3,0 mg/kg), one hour before of the administration of INDO 30 mg/Kg (hemin, biliverdin, DMDC) or 10 mg/Kg (ZnPP IX). In another group, the animals were pre-treated with ODQ (12.5 mg/kg, v.o) or L-NAME (3 mg/Kg, v.o), thirty minutes before of the treatments cited previously. Three hours after, the mice were sacrificed and the stomachs removed for evaluation of the gastric lesions, utilizing a digital paquimetry. In all of the experimental groups, fragments of the gastric mucous were collected for determination of the concentration of MDA, GSH or bilirubin. Another samples of tissue was removed for microscopic analyzes and HO-1 expression by immunohistochemistry. The detection of the TNF-α, IL-1β, IL-10 and MPO activity were evaluated only in the INDO gastropathy. Results: Ethanol increased the expression of HO-1 and the levels of bilirrubin in the gastric tissue. Hemin, biliverdin and DMDC reduced gastric damage, MDA levels and GSH consume in ethanol 50%- induced gastropathy. The histological parameters, edema, hemorrhage and loses of epithelial cells, were diminished in the presence of hemin, biliverdin or DMDC. ZnPP IX amplified the ethanol-induced gastric lesion, increased MDA formation and decreased the GSH concentration in gastric mucosa. The histological parameters also were amplified after the handling with ZnPP IX. Bilirubin concentration was elevated during the protection induced by hemin and biliverdin, but not DMDC. INDO increased the HO-1 expression and the bilirrubin levels in the gastric mucosa. Hemin, biliverdin or DMDC reduced the gastric lesion, the MPO activity, and the MDA levels and increased the GSH concentration in the gastropathy INDO- induced. The histological parameters, edema, hemorrhage, loss of epithelial cells and the presence of inflammatory cells, were inhibited by hemin, biliverdin or DMDC. ZnPP IX amplified the effect of the INDO increasing the gastric lesion, the MPO activity, the MDA levels and the GSH consume. The histological parameters also were amplified after the handling with ZnPP IX. Bilirubin was shown elevated during the protection induced by hemin and biliverdin, but not DMDC. Hemin, biliverdin and DMDC diminished the TNF-α and IL-1β concentrations and increased the IL-10. ODQ and L-NAME completely abolished the DMDC protective gastric effect, but not biliverdin in the gastropathy ethanol or INDO- induced. Conclusion: HO-1/biliverdin/CO pathway plays a protective effect against ethanol or INDO-induced gastric damage. In the gastropathy by ethanol, the protection is dependent of the anti-oxidant action by bilirubin and CO. However, in the model of INDO gastropathy, we observe an anti-oxidant and anti-inflammatory action. The mechanism of gastro protective action of the CO, but not of the biliverdin, is dependent of the CO/ NOS/ GMPc pathway.Objetivo: Avaliar o efeito protetor da via hemeoxigenase 1 (HO-1)/ biliverdina/ CO em modelos de gastropatia em camundongos e o papel da guanilato ciclase solÃvel (GCs) e da NOS constitutiva neste evento. MÃtodos: Protocolo 1: Camundongos foram prÃ-tratados hemina (indutor da HO-1; 1,3 ou 10mg/Kg, i.p.), biliverdina (produto da HO-1; 1,3 ou 10mg/Kg, i.p.), DMDC (doador de CO; 2,5, 7,5, 12,5 ou 25 μmol/Kg, i.p.) ou ZnPP I(inibidor da HO-1; 0,3, 1,0 ou 3,0 mg/kg. i.p.) uma hora antes da administraÃÃo por gavagem de etanol 50% (hemina, biliverdina, DMDC) ou 25% (ZnPP IX). Em outro grupo, os animais foram prÃ-tratados com ODQ (12,5 mg/kg, v.o) ou L-NAME (3 mg/Kg, v.o), trinta minutos antes dos tratamentos citados anteriormente. Depois de 1h, os camundongos foram sacrificados e os estÃmagos removidos para avaliaÃÃo das lesÃes gÃstricas (Image J). Protocolo 2: Camundongos foram prÃ-tratados hemina (3,0 mg/kg), biliverdina (3,0 mg/kg), DMDC (12,5 μmol/Kg) ou ZnPPIX (3,0 mg/Kg) uma hora antes da administraÃÃo de INDO 30 mg/Kg (hemina, biliverdina, DMDC) ou 10 mg/Kg (ZnPP IX). Em outro grupo os animais foram prÃ-tratados com ODQ (12,5 mg/kg, v.o) ou L-NAME (3 mg/Kg, v.o), trinta minutos antes dos tratamentos citados anteriormente. TrÃs horas depois, os camundongos foram sacrificados e os estÃmagos removidos para avaliaÃÃo das lesÃes gÃstrica, utilizando um paquÃmetro digital. Em todos os grupos experimentais, fragmentos da mucosa gÃstrica foram coletados para determinaÃÃo da concentraÃÃo de MDA, GSH e bilirrubina. Outra amostra de tecido foi retirada para analise microscÃpica e imunohistoquÃmica. A detecÃÃo das citocinas TNF-α, IL-1β e IL-10, bem como a atividade de MPO foram avaliados somente na gastropatia por INDO. Resultados: O etanol aumentou a expressÃo de enzima HO-1 e dos nÃveis de bilirrubina no tecido gÃstrico. Hemina, biliverdina ou DMDC reduziram a lesÃo gÃstrica, os nÃveis de MDA e o consumo de GSH induzido por etanol 50%. Os parÃmetros histolÃgicos, edema, hemorragia e perda de cÃlulas epiteliais, foram diminuÃdos na presenÃa de hemina, biliverdina ou DMDC. ZnPP IX amplificou o efeito do etanol 25%, aumentando a lesÃo gÃstrica, os nÃveis de MDA e o consumo de GSH. Os parÃmetros histolÃgicos tambÃm foram amplificados apÃs o tratamento com ZnPP IX. A concentraÃÃo de bilirrubina se mostrou elevada apenas na gastroproteÃÃo induzida por hemina e biliverdina, mas nÃo pelo DMDC. INDO aumentou a expressÃo da HO-1 e os nÃveis de bilirrubina na mucosa gÃstrica. Hemina, biliverdina ou DMDC reduziram a lesÃo gÃstrica, a atividade de MPO, os nÃveis de MDA e aumentaram a concentraÃÃo de GSH na gastropatia por INDO. Os parÃmetros histolÃgicos, edema, hemorragia, perda de cÃlulas epiteliais e a presenÃa de cÃlulas inflamatÃrias, foram inibidas pela hemina, biliverdina ou DMDC. ZnPP IX amplificou o efeito da INDO aumentando a lesÃo gÃstrica, a atividade de MPO, os nÃveis de MDA e o consumo de GSH. Os parÃmetros histolÃgicos tambÃm foram amplificados apÃs o tratamento com ZnPP IX. Bilirrubina se mostrou elevada apenas na gastroproteÃÃo induzida por hemina e biliverdina, mas nÃo pelo DMDC. Hemina, biliverdina e DMDC diminuÃram as concentraÃÃes de TNF-α e IL-1β e aumentaram a IL-10. ODQ e L-NAME reverteram o efeito protetor do DMDC, mas nÃo da biliverdina, na gastropatia induzida por etanol ou INDO. ConclusÃo: A via HO-1/biliverdina/CO participa do processo de defesa da mucosa gÃstrica contra lesÃes induzidas por etanol ou INDO. Na gastropatia por etanol, a proteÃÃo à dependente da aÃÃo antioxidante da bilirrubina e CO. Entretanto, no modelo de gastropatia por INDO, observamos uma aÃÃo antioxidante e antiinflamatÃria. Evidenciamos ainda que o mecanismo de aÃÃo gastroprotetor do CO, mas nÃo da biliverdina à dependente da via CO/GMPc/NOS.Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgicohttp://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=6887application/pdfinfo:eu-repo/semantics/openAccessporreponame:Biblioteca Digital de Teses e Dissertações da UFCinstname:Universidade Federal do Cearáinstacron:UFC2019-01-21T11:19:58Zmail@mail.com - |
dc.title.pt.fl_str_mv |
Efeito protetor da via hemeoxigenase 1/ BILIVERDINA/ CO em modelos de lesÃes gÃstricas em camundongos â papel da guanilato ciclase solÃvel (GCS) e da no sintase (NOS) |
title |
Efeito protetor da via hemeoxigenase 1/ BILIVERDINA/ CO em modelos de lesÃes gÃstricas em camundongos â papel da guanilato ciclase solÃvel (GCS) e da no sintase (NOS) |
spellingShingle |
Efeito protetor da via hemeoxigenase 1/ BILIVERDINA/ CO em modelos de lesÃes gÃstricas em camundongos â papel da guanilato ciclase solÃvel (GCS) e da no sintase (NOS) Antoniella Souza Gomes LesÃo gÃtrica Hemeoxigenase-1 heme-oxygenase 1 gastric lesions FARMACOLOGIA |
title_short |
Efeito protetor da via hemeoxigenase 1/ BILIVERDINA/ CO em modelos de lesÃes gÃstricas em camundongos â papel da guanilato ciclase solÃvel (GCS) e da no sintase (NOS) |
title_full |
Efeito protetor da via hemeoxigenase 1/ BILIVERDINA/ CO em modelos de lesÃes gÃstricas em camundongos â papel da guanilato ciclase solÃvel (GCS) e da no sintase (NOS) |
title_fullStr |
Efeito protetor da via hemeoxigenase 1/ BILIVERDINA/ CO em modelos de lesÃes gÃstricas em camundongos â papel da guanilato ciclase solÃvel (GCS) e da no sintase (NOS) |
title_full_unstemmed |
Efeito protetor da via hemeoxigenase 1/ BILIVERDINA/ CO em modelos de lesÃes gÃstricas em camundongos â papel da guanilato ciclase solÃvel (GCS) e da no sintase (NOS) |
title_sort |
Efeito protetor da via hemeoxigenase 1/ BILIVERDINA/ CO em modelos de lesÃes gÃstricas em camundongos â papel da guanilato ciclase solÃvel (GCS) e da no sintase (NOS) |
author |
Antoniella Souza Gomes |
author_facet |
Antoniella Souza Gomes |
author_role |
author |
dc.contributor.advisor1.fl_str_mv |
Marcellus Henrique Loiola Ponte de Souza |
dc.contributor.advisor1ID.fl_str_mv |
51211700330 |
dc.contributor.advisor1Lattes.fl_str_mv |
http://lattes.cnpq.br/4001596522263940 |
dc.contributor.referee1.fl_str_mv |
Gerly Anne de Castro Brito |
dc.contributor.referee1ID.fl_str_mv |
24198846391 |
dc.contributor.referee1Lattes.fl_str_mv |
http://lattes.cnpq.br/8991062042568398 |
dc.contributor.referee2.fl_str_mv |
Mirna Marques Bezerra |
dc.contributor.referee2ID.fl_str_mv |
87708124468 |
dc.contributor.referee2Lattes.fl_str_mv |
http://lattes.cnpq.br/0614961188016863 |
dc.contributor.referee3.fl_str_mv |
Thiago Mattar Cunha |
dc.contributor.referee3ID.fl_str_mv |
05032170690 |
dc.contributor.referee3Lattes.fl_str_mv |
http://lattes.cnpq.br/0585283327853481 |
dc.contributor.referee4.fl_str_mv |
Ricardo Bentes de Azevedo |
dc.contributor.referee4ID.fl_str_mv |
15454746215 |
dc.contributor.referee4Lattes.fl_str_mv |
http://lattes.cnpq.br/9072332484355315 |
dc.contributor.authorID.fl_str_mv |
83851259149 |
dc.contributor.authorLattes.fl_str_mv |
http://lattes.cnpq.br/1674590681546363 |
dc.contributor.author.fl_str_mv |
Antoniella Souza Gomes |
contributor_str_mv |
Marcellus Henrique Loiola Ponte de Souza Gerly Anne de Castro Brito Mirna Marques Bezerra Thiago Mattar Cunha Ricardo Bentes de Azevedo |
dc.subject.por.fl_str_mv |
LesÃo gÃtrica Hemeoxigenase-1 |
topic |
LesÃo gÃtrica Hemeoxigenase-1 heme-oxygenase 1 gastric lesions FARMACOLOGIA |
dc.subject.eng.fl_str_mv |
heme-oxygenase 1 gastric lesions |
dc.subject.cnpq.fl_str_mv |
FARMACOLOGIA |
dc.description.sponsorship.fl_txt_mv |
Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico |
dc.description.abstract.por.fl_txt_mv |
Objective: To evaluate the protective effect of the heme-oxygenase 1 (HO-1)/biliverdin/CO pathway in models of gastropathy in mice, evaluating the role of the soluble guanylate cyclase (GCs) and of the constitutive NOS in this event. Methods: Protocol 1: Mice were pre-treated with hemin (HO-1 inducer; 1,3,10 mg/Kg, i.p.), biliverdin (HO-1 product; 1,3 or 10 mg/Kg., i.p.), DMDC (CO donor; 2.5, 7.5, 12.5 or 10 Âmol/Kg, i.p.) or ZnPP IX (HO-1 antagonist; 0,3, 1 or 3 mg/kg. i.p.), one hour before, gastric damage was induced by ethanol 50% (hemin, biliverdin, DMDC) or 25% (ZnPP IX). In another group, the animals were pre-treated with ODQ (12.5 mg/kg, v.o) or L-NAME (3 mg/Kg, v.o), thirty minutes before of the treatments cited previously. After 1h, the mice were sacrificed and the stomachs removed for evaluation of the gastric lesions (Image J). Protocol 2: Mice were pre-treated with hemin (3 mg/Kg, i.p.), biliverdin (3 mg/Kg., i.p.), DMDC (12,5 Âmol/Kg) or ZnPP IX (3,0 mg/kg), one hour before of the administration of INDO 30 mg/Kg (hemin, biliverdin, DMDC) or 10 mg/Kg (ZnPP IX). In another group, the animals were pre-treated with ODQ (12.5 mg/kg, v.o) or L-NAME (3 mg/Kg, v.o), thirty minutes before of the treatments cited previously. Three hours after, the mice were sacrificed and the stomachs removed for evaluation of the gastric lesions, utilizing a digital paquimetry. In all of the experimental groups, fragments of the gastric mucous were collected for determination of the concentration of MDA, GSH or bilirubin. Another samples of tissue was removed for microscopic analyzes and HO-1 expression by immunohistochemistry. The detection of the TNF-α, IL-1β, IL-10 and MPO activity were evaluated only in the INDO gastropathy. Results: Ethanol increased the expression of HO-1 and the levels of bilirrubin in the gastric tissue. Hemin, biliverdin and DMDC reduced gastric damage, MDA levels and GSH consume in ethanol 50%- induced gastropathy. The histological parameters, edema, hemorrhage and loses of epithelial cells, were diminished in the presence of hemin, biliverdin or DMDC. ZnPP IX amplified the ethanol-induced gastric lesion, increased MDA formation and decreased the GSH concentration in gastric mucosa. The histological parameters also were amplified after the handling with ZnPP IX. Bilirubin concentration was elevated during the protection induced by hemin and biliverdin, but not DMDC. INDO increased the HO-1 expression and the bilirrubin levels in the gastric mucosa. Hemin, biliverdin or DMDC reduced the gastric lesion, the MPO activity, and the MDA levels and increased the GSH concentration in the gastropathy INDO- induced. The histological parameters, edema, hemorrhage, loss of epithelial cells and the presence of inflammatory cells, were inhibited by hemin, biliverdin or DMDC. ZnPP IX amplified the effect of the INDO increasing the gastric lesion, the MPO activity, the MDA levels and the GSH consume. The histological parameters also were amplified after the handling with ZnPP IX. Bilirubin was shown elevated during the protection induced by hemin and biliverdin, but not DMDC. Hemin, biliverdin and DMDC diminished the TNF-α and IL-1β concentrations and increased the IL-10. ODQ and L-NAME completely abolished the DMDC protective gastric effect, but not biliverdin in the gastropathy ethanol or INDO- induced. Conclusion: HO-1/biliverdin/CO pathway plays a protective effect against ethanol or INDO-induced gastric damage. In the gastropathy by ethanol, the protection is dependent of the anti-oxidant action by bilirubin and CO. However, in the model of INDO gastropathy, we observe an anti-oxidant and anti-inflammatory action. The mechanism of gastro protective action of the CO, but not of the biliverdin, is dependent of the CO/ NOS/ GMPc pathway. Objetivo: Avaliar o efeito protetor da via hemeoxigenase 1 (HO-1)/ biliverdina/ CO em modelos de gastropatia em camundongos e o papel da guanilato ciclase solÃvel (GCs) e da NOS constitutiva neste evento. MÃtodos: Protocolo 1: Camundongos foram prÃ-tratados hemina (indutor da HO-1; 1,3 ou 10mg/Kg, i.p.), biliverdina (produto da HO-1; 1,3 ou 10mg/Kg, i.p.), DMDC (doador de CO; 2,5, 7,5, 12,5 ou 25 μmol/Kg, i.p.) ou ZnPP I(inibidor da HO-1; 0,3, 1,0 ou 3,0 mg/kg. i.p.) uma hora antes da administraÃÃo por gavagem de etanol 50% (hemina, biliverdina, DMDC) ou 25% (ZnPP IX). Em outro grupo, os animais foram prÃ-tratados com ODQ (12,5 mg/kg, v.o) ou L-NAME (3 mg/Kg, v.o), trinta minutos antes dos tratamentos citados anteriormente. Depois de 1h, os camundongos foram sacrificados e os estÃmagos removidos para avaliaÃÃo das lesÃes gÃstricas (Image J). Protocolo 2: Camundongos foram prÃ-tratados hemina (3,0 mg/kg), biliverdina (3,0 mg/kg), DMDC (12,5 μmol/Kg) ou ZnPPIX (3,0 mg/Kg) uma hora antes da administraÃÃo de INDO 30 mg/Kg (hemina, biliverdina, DMDC) ou 10 mg/Kg (ZnPP IX). Em outro grupo os animais foram prÃ-tratados com ODQ (12,5 mg/kg, v.o) ou L-NAME (3 mg/Kg, v.o), trinta minutos antes dos tratamentos citados anteriormente. TrÃs horas depois, os camundongos foram sacrificados e os estÃmagos removidos para avaliaÃÃo das lesÃes gÃstrica, utilizando um paquÃmetro digital. Em todos os grupos experimentais, fragmentos da mucosa gÃstrica foram coletados para determinaÃÃo da concentraÃÃo de MDA, GSH e bilirrubina. Outra amostra de tecido foi retirada para analise microscÃpica e imunohistoquÃmica. A detecÃÃo das citocinas TNF-α, IL-1β e IL-10, bem como a atividade de MPO foram avaliados somente na gastropatia por INDO. Resultados: O etanol aumentou a expressÃo de enzima HO-1 e dos nÃveis de bilirrubina no tecido gÃstrico. Hemina, biliverdina ou DMDC reduziram a lesÃo gÃstrica, os nÃveis de MDA e o consumo de GSH induzido por etanol 50%. Os parÃmetros histolÃgicos, edema, hemorragia e perda de cÃlulas epiteliais, foram diminuÃdos na presenÃa de hemina, biliverdina ou DMDC. ZnPP IX amplificou o efeito do etanol 25%, aumentando a lesÃo gÃstrica, os nÃveis de MDA e o consumo de GSH. Os parÃmetros histolÃgicos tambÃm foram amplificados apÃs o tratamento com ZnPP IX. A concentraÃÃo de bilirrubina se mostrou elevada apenas na gastroproteÃÃo induzida por hemina e biliverdina, mas nÃo pelo DMDC. INDO aumentou a expressÃo da HO-1 e os nÃveis de bilirrubina na mucosa gÃstrica. Hemina, biliverdina ou DMDC reduziram a lesÃo gÃstrica, a atividade de MPO, os nÃveis de MDA e aumentaram a concentraÃÃo de GSH na gastropatia por INDO. Os parÃmetros histolÃgicos, edema, hemorragia, perda de cÃlulas epiteliais e a presenÃa de cÃlulas inflamatÃrias, foram inibidas pela hemina, biliverdina ou DMDC. ZnPP IX amplificou o efeito da INDO aumentando a lesÃo gÃstrica, a atividade de MPO, os nÃveis de MDA e o consumo de GSH. Os parÃmetros histolÃgicos tambÃm foram amplificados apÃs o tratamento com ZnPP IX. Bilirrubina se mostrou elevada apenas na gastroproteÃÃo induzida por hemina e biliverdina, mas nÃo pelo DMDC. Hemina, biliverdina e DMDC diminuÃram as concentraÃÃes de TNF-α e IL-1β e aumentaram a IL-10. ODQ e L-NAME reverteram o efeito protetor do DMDC, mas nÃo da biliverdina, na gastropatia induzida por etanol ou INDO. ConclusÃo: A via HO-1/biliverdina/CO participa do processo de defesa da mucosa gÃstrica contra lesÃes induzidas por etanol ou INDO. Na gastropatia por etanol, a proteÃÃo à dependente da aÃÃo antioxidante da bilirrubina e CO. Entretanto, no modelo de gastropatia por INDO, observamos uma aÃÃo antioxidante e antiinflamatÃria. Evidenciamos ainda que o mecanismo de aÃÃo gastroprotetor do CO, mas nÃo da biliverdina à dependente da via CO/GMPc/NOS. |
description |
Objective: To evaluate the protective effect of the heme-oxygenase 1 (HO-1)/biliverdin/CO pathway in models of gastropathy in mice, evaluating the role of the soluble guanylate cyclase (GCs) and of the constitutive NOS in this event. Methods: Protocol 1: Mice were pre-treated with hemin (HO-1 inducer; 1,3,10 mg/Kg, i.p.), biliverdin (HO-1 product; 1,3 or 10 mg/Kg., i.p.), DMDC (CO donor; 2.5, 7.5, 12.5 or 10 Âmol/Kg, i.p.) or ZnPP IX (HO-1 antagonist; 0,3, 1 or 3 mg/kg. i.p.), one hour before, gastric damage was induced by ethanol 50% (hemin, biliverdin, DMDC) or 25% (ZnPP IX). In another group, the animals were pre-treated with ODQ (12.5 mg/kg, v.o) or L-NAME (3 mg/Kg, v.o), thirty minutes before of the treatments cited previously. After 1h, the mice were sacrificed and the stomachs removed for evaluation of the gastric lesions (Image J). Protocol 2: Mice were pre-treated with hemin (3 mg/Kg, i.p.), biliverdin (3 mg/Kg., i.p.), DMDC (12,5 Âmol/Kg) or ZnPP IX (3,0 mg/kg), one hour before of the administration of INDO 30 mg/Kg (hemin, biliverdin, DMDC) or 10 mg/Kg (ZnPP IX). In another group, the animals were pre-treated with ODQ (12.5 mg/kg, v.o) or L-NAME (3 mg/Kg, v.o), thirty minutes before of the treatments cited previously. Three hours after, the mice were sacrificed and the stomachs removed for evaluation of the gastric lesions, utilizing a digital paquimetry. In all of the experimental groups, fragments of the gastric mucous were collected for determination of the concentration of MDA, GSH or bilirubin. Another samples of tissue was removed for microscopic analyzes and HO-1 expression by immunohistochemistry. The detection of the TNF-α, IL-1β, IL-10 and MPO activity were evaluated only in the INDO gastropathy. Results: Ethanol increased the expression of HO-1 and the levels of bilirrubin in the gastric tissue. Hemin, biliverdin and DMDC reduced gastric damage, MDA levels and GSH consume in ethanol 50%- induced gastropathy. The histological parameters, edema, hemorrhage and loses of epithelial cells, were diminished in the presence of hemin, biliverdin or DMDC. ZnPP IX amplified the ethanol-induced gastric lesion, increased MDA formation and decreased the GSH concentration in gastric mucosa. The histological parameters also were amplified after the handling with ZnPP IX. Bilirubin concentration was elevated during the protection induced by hemin and biliverdin, but not DMDC. INDO increased the HO-1 expression and the bilirrubin levels in the gastric mucosa. Hemin, biliverdin or DMDC reduced the gastric lesion, the MPO activity, and the MDA levels and increased the GSH concentration in the gastropathy INDO- induced. The histological parameters, edema, hemorrhage, loss of epithelial cells and the presence of inflammatory cells, were inhibited by hemin, biliverdin or DMDC. ZnPP IX amplified the effect of the INDO increasing the gastric lesion, the MPO activity, the MDA levels and the GSH consume. The histological parameters also were amplified after the handling with ZnPP IX. Bilirubin was shown elevated during the protection induced by hemin and biliverdin, but not DMDC. Hemin, biliverdin and DMDC diminished the TNF-α and IL-1β concentrations and increased the IL-10. ODQ and L-NAME completely abolished the DMDC protective gastric effect, but not biliverdin in the gastropathy ethanol or INDO- induced. Conclusion: HO-1/biliverdin/CO pathway plays a protective effect against ethanol or INDO-induced gastric damage. In the gastropathy by ethanol, the protection is dependent of the anti-oxidant action by bilirubin and CO. However, in the model of INDO gastropathy, we observe an anti-oxidant and anti-inflammatory action. The mechanism of gastro protective action of the CO, but not of the biliverdin, is dependent of the CO/ NOS/ GMPc pathway. |
publishDate |
2009 |
dc.date.issued.fl_str_mv |
2009-11-30 |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/doctoralThesis |
status_str |
publishedVersion |
format |
doctoralThesis |
dc.identifier.uri.fl_str_mv |
http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=6887 |
url |
http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=6887 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
application/pdf |
dc.publisher.none.fl_str_mv |
Universidade Federal do Cearà |
dc.publisher.program.fl_str_mv |
Programa de PÃs-GraduaÃÃo em Farmacologia |
dc.publisher.initials.fl_str_mv |
UFC |
dc.publisher.country.fl_str_mv |
BR |
publisher.none.fl_str_mv |
Universidade Federal do Cearà |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações da UFC instname:Universidade Federal do Ceará instacron:UFC |
reponame_str |
Biblioteca Digital de Teses e Dissertações da UFC |
collection |
Biblioteca Digital de Teses e Dissertações da UFC |
instname_str |
Universidade Federal do Ceará |
instacron_str |
UFC |
institution |
UFC |
repository.name.fl_str_mv |
-
|
repository.mail.fl_str_mv |
mail@mail.com |
_version_ |
1643295154066423808 |