RESUMO
The proteolytic fraction (P1G10) from Vasconcellea cundinamarcensis, displays gastric protective and healing activities in different skin lesions in mice and human. In an excisional model, this fraction accelerates resolution of lesions and modulates inflammatory mediators. Based on these data, we assessed its anti-inflammatory activity in murine colitis model, induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) adopted by its physiopathological similarity with human colitis. Twenty four hours after colitis induction followed by three days of treatment, P1G10 at 0.3 and 3.0 mg/Kg induced 30% increase in body weight (p < 0.0001) and ~80% reduction in colon macroscopic damage score (p < 0.05) compared to the untreated TNBS-induced colitis group. Histological analyses showed that 0.3 mg/Kg P1G10 reduced the inflammatory profile and tissue damage (47%, p < 0.05) when it was proteolytically active. Compared to TNBS group, 0.3 mg/Kg P1G10 reduced MPO activity (80%, p < 0.01), MCP-1 (47%, p < 0.05) and TNF-α (50%, no significant) and increased IL-10 (330%, p < 0.001) levels in the supernatant of colonic tissue homogenate. P1G10 treatment also reduced COX-2 expression (60%, p < 0.05) and metalloprotease-2 activity (39%, p < 0.05) while increased globet cell density (140%, p < 0.01), that contributes to mucus layer protection in colonic tissue. Taken together, these findings suggest that low doses of active P1G10 promotes lesion resolution, at least in part by its anti-inflammatory activity, in TNBS-colitis model.
Assuntos
Anti-Inflamatórios/farmacologia , Colite/induzido quimicamente , Colite/patologia , Látex/química , Proteólise , Animais , Caricaceae/química , Colite/enzimologia , Colo/efeitos dos fármacos , Colo/patologia , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Hexosaminidases/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Peroxidase/metabolismo , Ácido Trinitrobenzenossulfônico , Redução de Peso/efeitos dos fármacosRESUMO
AIM: The etiopathogenesis of inflammatory bowel disease (IBD) is unclear and further understanding of the mechanisms that regulate intestinal barrier integrity and function could give insight into its pathophysiology and mode of action of current drugs used to treat human IBD. Therefore, we investigated how intestinal inflammation affects Map kinase gene expression in rats, and if current intestinal anti-inflammatory drugs (sulphasalazine, prednisolone and azathioprine) act on these expressions. MATERIAL AND METHODS: Macroscopic parameters of lesion, biochemical markers (myeloperoxidase, alkaline phosphatase and glutathione), gene expression of 13Map kinases, and histologic evaluations (optic, electronic scanning and transmission microscopy) were performed in rats with colonic inflammation induced by trinitrobenzenesulphonic (TNBS) acid. KEY FINDINGS: The colonic inflammation was characterized by a significant increase in the expression of Mapk1, Mapk3 and Mapk9 accompanied by a significant reduction in the expression ofMapk6. Alterations inMapk expression induced by TNBS were differentially counteracted after treatment with sulphasalazine, prednisolone and azathioprine. Protective effects were also related to the significant reduction of oxidative stress, which was related to increase Mapk1/3 expressions, which were reduced after pharmacological treatment. SIGNIFICANCE: Mapk1, Mapk3,Mapk6 and Mapk9 gene expressionswere affected by colonic inflammation induced by TNBS in rats and counteracted by sulphasalazine, prednisolone and azathioprine treatments, suggesting that these genes participate in the pharmacological response produced for these drugs.
Assuntos
Anti-Inflamatórios/farmacologia , Azatioprina/farmacologia , Colite/tratamento farmacológico , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Prednisolona/farmacologia , Sulfassalazina/farmacologia , Animais , Colite/induzido quimicamente , Colite/enzimologia , Colite/patologia , Indução Enzimática/efeitos dos fármacos , Expressão Gênica , Masculino , Proteínas Quinases Ativadas por Mitógeno/genética , Ratos Wistar , Ácido TrinitrobenzenossulfônicoRESUMO
The nonsteroidal anti-inflammatory drugs (NSAIDs) have been widely used in the management of pain and inflammation. Unfortunately, they are associated with dose-dependent gastrointestinal (GI) adverse events ranging from dyspepsia to symptomatic and complicated ulcers. The mechanism of NSAID action is attributed to the cyclooxygenase (COX) inhibition. New anti-inflammatory drugs have been synthesized, such as selective COX-2 inhibitors, however, these drugs may present side effects, such as modification of the epithelial barrier. Inflammatory bowel disease (IBD) is a common chronic gastrointestinal disorder characterized by alternating periods of remission and active intestinal inflammation. A possible association between the use of NSAIDs and the relapse of IBD has been repeatedly suggested. For this reason, many studies are conducted with the use of COX-2 in experimental models. The objective of this review is to describe the role of NSAIDs and COX-2 inhibitors in different experimental models of colitis. We reviewed controlled trials, original articles, case reports and reviews. The role of selective inhibition of COX-2 in the inflammatory process and the course of experimental and human colitis is controversially discussed. In conclusion, the relative role of COX-2 selective inhibitors on human and experimental colitis remains to be explored. Thus, the use of COX-2 inhibitors in IBD should be considered with caution.
Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Colite/induzido quimicamente , Inibidores de Ciclo-Oxigenase 2/farmacologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Doença Crônica , Ensaios Clínicos como Assunto , Colite/enzimologia , Colite/patologia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Humanos , Isoenzimas/metabolismo , Prostaglandina-Endoperóxido Sintases/metabolismo , Prostaglandinas/fisiologiaRESUMO
Endometriosis commonly presents with symptoms that mimic chronic gastrointestinal disorders. The authors used the autotransplantion model of endometriosis in rats to investigate the possible underlying mechanisms. After the rats were killed, the presence of endometriotic vesicles, colonic inflammation, and white blood cell (WBC) numbers in the peritoneal fluid was determined. Sections of colon and of jejunum were collected for measurement of myeloperoxidase (MPO) activity and bacterial counts, and isometric recording in response to acetylcholine was measured in segments of longitudinal and circular smooth muscle. Experimental animals had significantly more colonic damage, MPO activity, and WBC numbers than controls did. There was no significant difference in the total bacterial load; however, experimental animals demonstrated an increased tension in the longitudinal muscle, which correlated with WBC numbers and colonic damage. In summary, this study presents evidence for a significant effect of peritoneal endometriosis on colonic function and integrity, which may help explain the gastrointestinal symptoms associated with this disease.