Caracterização do perfil de cicatrização das úlceras gástricas em animais com obesidade induzida por dieta hiperlipídica e a ação do citral
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2022-08-24
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Universidade Estadual Paulista (Unesp)
Resumo
A obesidade causa um quadro inflamatório de baixo grau que pode resultar em agravamentos de distúrbios do trato gastrointestinal e maior dificuldade no processo de cicatrização em úlceras gástricas. Apesar de alguns estudos terem investigado a relação entre obesidade e as úlceras gástricas, ainda não existe uma relação clara estabelecida entre essas duas doenças. Diante desse cenário, este trabalho tem dois objetivos principais: Caracterizar o perfil de cicatrização de lesões gástricas em animais eutróficos e obesos e avaliar os efeitos farmacológicos do citral sobre a cicatrização. Para caracterização do perfil de cicatrização foram usados camundongos Swiss machos e para avaliação da ação do citral foram usados camundongos C57Bl-J6. Em ambos experimentos, os animais foram divididos em 2 grupos: Dieta padrão (SD) e dieta hiperlipídica (HFD) e após 12 semanas de ingestão das dietas, os animais passaram por cirurgia de indução de úlcera gástrica por ácido acético. Para comparação do perfil de cicatrização entre animais SD e HFD, os estômagos dos animais foram coletados em cinco períodos pós-indução: 1, 3, 7, 10 ou 14 dias. Também avaliamos a ação do citral em três doses: 25, 100 ou 300 mg/kg durante a fase inicial e tardia da cicatrização, 3 e 10 dias subsequentes de tratamento, respectivamente. Para esse experimento foram incluídos os grupos: controle negativo tratados com veículo (Tween 80 a 1%, 10 mL/kg) e controle positivo tratados com Lansoprazol (30 mg/kg). Todos os estômagos foram coletados para análise morfológica macroscópica, zimografia para quantificação de metaloproteinases de matriz 2 e 9 (MMP-2 e 9) e quantificação por imunoensaio multiplex de IL-1b, TNF-a, VEGF-A, C e D, EGF, HGF e FGF-2. Como resultado, observamos que houve desaceleração da fase inicial da cicatrização em animais que receberam HFD em relação aos animais alimentados com SD. Essa alteração foi seguida de redução da atividade de MMP-9 no mesmo grupo após sete dias de indução da lesão. Os perfis de fatores de crescimento também se mostraram diferentes entre animais que receberam diferentes dietas, principalmente o VEGF-D e EGF. Ao avaliar a ação do citral, verificamos que entre os animais alimentados com HFD, apenas os grupos que receberam citral nas doses de 100 e 300 mg/kg apresentaram redução significativa da área da base da úlcera entre 3 e 10 dias após a indução da lesão. No grupo tratado com citral na dose de 100 mg/kg, a progressão da cicatrização foi acompanhada por redução da atividade de MMP-9. As diferenças observadas no progresso de cicatrização e nas atividades de MMP-2 e 9 podem ser explicadas pelas diferentes respostas em animais alimentados com SD e HFD sobre as concentrações de IL-1b e TNF-a, citocinas que promovem resposta aguda no processo inflamatório. Consequentemente, os fatores de crescimento VEGF-A, VEGF-C, VEGF-D, EGF e HGF responderam de diferentes formas aos tratamentos administrados nos grupos SD e HFD. Desta forma, podemos concluir que a ingestão de diferentes dietas interfere no processo de cicatrização de úlceras gástricas e altera as respostas farmacológicas no tratamento das úlceras. O citral promoveu maior taxa de cicatrização apenas em camundongos obesos, quando comparado com os outros tratamentos. Essa mudança foi acompanhada por uma diminuição na MMP-9 tecidual e por modulação da ativação da MMP-2.
Obesity causes a low-grade inflammatory condition that can impair gastrointestinal tract disorders and greater difficulty in the healing process in gastric ulcers. Although some studies have investigated the relationship between obesity and gastric ulcers, there is still no clear relationship established between these two diseases. Given this scenario, this work has two main objectives: Characterize the healing profile of gastric lesions in eutrophic and obese animals and evaluate the pharmacological effects of citral on healing process. To characterize the healing profile, male Swiss mice were used and to evaluate the action of citral, C57Bl-J6 mice were used. In both experiments, the animals were divided into 2 groups: standard diet (SD) and high fat diet (HFD) and after 12 weeks of ingestion of the diets, the animals underwent gastric ulcer induction surgery. To compare the healing profile between SD and HFD animals, the animals' stomachs were collected at five post-induction periods: 1, 3, 7, 10 or 14 days. We also evaluated the action of citral at three doses: 25, 100 or 300 mg/kg during the early and late stages of healing, 3 and 10 subsequent days of treatment, respectively. For this experiment, the groups were included: negative control treated with vehicle (1% Tween 80, 10 mL/kg) and positive control treated with Lansoprazole (30 mg/kg). All stomachs were collected for macroscopic morphological analysis, zymography for quantification of matrix metalloproteinases 2 and 9 (MMP-2 and 9) and quantification by multiplex immunoassay of IL-1β, TNF-α, VEGF-A, C and D, EGF, HGF and FGF-2. As a result, we observed that there was a deceleration of the initial phase of healing in animals that received HFD compared to animals fed with SD. This change was followed by a reduction in MMP-9 activity in the same group after seven days of injury induction. The growth factor profiles were also different between animals that received different diets, mainly VEGF-D and EGF. When evaluating the action of citral, we found that among the animals fed with HFD, only the groups that received citral at doses of 100 and 300 mg/kg showed a significant reduction in the area of the ulcer base between 3 and 10 days after the induction of the lesion. In the group treated with citral at a dose of 100 mg/kg, healing progression was accompanied by a reduction in MMP-9 activity. The differences observed in the healing progress and in the activities of MMP-2 and 9 can be explained by the different responses in animals fed with SD and HFD on the concentrations of IL-1β and TNF-α, cytokines that promote an acute response in the inflammatory process. Consequently, the growth factors VEGF-A, VEGF-C, VEGF-D, EGF and HGF responded differently to treatments administered in the SD and HFD groups. Thus, we can conclude that the intake of different diets interferes with the healing process of gastric ulcers and alters the pharmacological responses in the treatment of ulcers. Citral promoted a higher healing rate only in obese mice, when compared to the other treatments. This change was accompanied by a decrease in tissue MMP-9 and by modulation of MMP-2 activation.
Obesity causes a low-grade inflammatory condition that can impair gastrointestinal tract disorders and greater difficulty in the healing process in gastric ulcers. Although some studies have investigated the relationship between obesity and gastric ulcers, there is still no clear relationship established between these two diseases. Given this scenario, this work has two main objectives: Characterize the healing profile of gastric lesions in eutrophic and obese animals and evaluate the pharmacological effects of citral on healing process. To characterize the healing profile, male Swiss mice were used and to evaluate the action of citral, C57Bl-J6 mice were used. In both experiments, the animals were divided into 2 groups: standard diet (SD) and high fat diet (HFD) and after 12 weeks of ingestion of the diets, the animals underwent gastric ulcer induction surgery. To compare the healing profile between SD and HFD animals, the animals' stomachs were collected at five post-induction periods: 1, 3, 7, 10 or 14 days. We also evaluated the action of citral at three doses: 25, 100 or 300 mg/kg during the early and late stages of healing, 3 and 10 subsequent days of treatment, respectively. For this experiment, the groups were included: negative control treated with vehicle (1% Tween 80, 10 mL/kg) and positive control treated with Lansoprazole (30 mg/kg). All stomachs were collected for macroscopic morphological analysis, zymography for quantification of matrix metalloproteinases 2 and 9 (MMP-2 and 9) and quantification by multiplex immunoassay of IL-1β, TNF-α, VEGF-A, C and D, EGF, HGF and FGF-2. As a result, we observed that there was a deceleration of the initial phase of healing in animals that received HFD compared to animals fed with SD. This change was followed by a reduction in MMP-9 activity in the same group after seven days of injury induction. The growth factor profiles were also different between animals that received different diets, mainly VEGF-D and EGF. When evaluating the action of citral, we found that among the animals fed with HFD, only the groups that received citral at doses of 100 and 300 mg/kg showed a significant reduction in the area of the ulcer base between 3 and 10 days after the induction of the lesion. In the group treated with citral at a dose of 100 mg/kg, healing progression was accompanied by a reduction in MMP-9 activity. The differences observed in the healing progress and in the activities of MMP-2 and 9 can be explained by the different responses in animals fed with SD and HFD on the concentrations of IL-1β and TNF-α, cytokines that promote an acute response in the inflammatory process. Consequently, the growth factors VEGF-A, VEGF-C, VEGF-D, EGF and HGF responded differently to treatments administered in the SD and HFD groups. Thus, we can conclude that the intake of different diets interferes with the healing process of gastric ulcers and alters the pharmacological responses in the treatment of ulcers. Citral promoted a higher healing rate only in obese mice, when compared to the other treatments. This change was accompanied by a decrease in tissue MMP-9 and by modulation of MMP-2 activation.
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Palavras-chave
Úlcera gástrica, Citral, Obesidade, Cicatrização