RESUMO
Intestinal mucositis is an important toxic side effect of 5-fluorouracil (5-FU) treatment. Saccharomyces boulardii is known to protect from intestinal injury via an effect on the gastrointestinal microbiota. The objective of the present study was to evaluate the effect of S. boulardii on intestinal mucositis induced by 5-FU in a murine model. Mice were divided into saline, saline (control)+5-FU or 5-FU+S. boulardii (16 × 109 colony-forming units/kg) treatment groups, and the jejunum and ileum were removed after killing of mice for the evaluation of histopathology, myeloperoxidase (MPO) activity, and non-protein sulfhydryl group (mainly reduced glutathione; GSH), nitrite and cytokine concentrations. To determine gastric emptying, phenol red was administered orally, mice were killed 20 min after administration, and the absorbance of samples collected from the mice was measured by spectrophotometry. Intestinal permeability was measured by the urinary excretion rate of lactulose and mannitol following oral administration. S. boulardii significantly reversed the histopathological changes in intestinal mucositis induced by 5-FU and reduced the inflammatory parameters: neutrophil infiltration (control 1·73 (SEM 0·37) ultrastructural MPO (UMPO)/mg, 5-FU 7·37 (SEM 1·77) UMPO/mg and 5-FU+S. boulardii 4·15 (SEM 0·73) UMPO/mg); nitrite concentration (control 37·00 (SEM 2·39) µm, 5-FU 59·04 (SEM 11·41) µm and 5-FU+S. boulardii 37·90 (SEM 5·78) µm); GSH concentration (control 477·60 (SEM 25·25) µg/mg, 5-FU 270·90 (SEM 38·50) µg/mg and 5-FU+S. boulardii 514·00 (SEM 38·64) µg/mg). Treatment with S. Boulardii significantly reduced the concentrations of TNF-α and IL-1ß by 48·92 and 32·21 % in the jejunum and 38·92 and 61·79 % in the ileum. In addition, S. boulardii decreased the concentrations of chemokine (C-X-C motif) ligand 1 by 5-fold in the jejunum and 3-fold in the ileum. Interestingly, S. boulardii reduced the delay in gastric emptying (control 25·21 (SEM 2·55) %, 5-FU 54·91 (SEM 3·43) % and 5-FU+S. boulardii 31·38 (SEM 2·80) %) and induced the recovery of intestinal permeability (lactulose:mannitol ratio: control 0·52 (SEM 0·03), 5-FU 1·38 (SEM 0·24) and 5-FU+S. boulardii 0·62 (SEM 0·03)). In conclusion, S. boulardii reduces the inflammation and dysfunction of the gastrointestinal tract in intestinal mucositis induced by 5-FU.
Assuntos
Modelos Animais de Doenças , Íleo/imunologia , Mucosa Intestinal/imunologia , Jejuno/imunologia , Mucosite/dietoterapia , Prebióticos , Saccharomyces/imunologia , Animais , Anti-Inflamatórios não Esteroides/imunologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Citocinas/metabolismo , Regulação para Baixo , Fezes/química , Esvaziamento Gástrico , Fármacos Gastrointestinais/imunologia , Fármacos Gastrointestinais/uso terapêutico , Glutationa/metabolismo , Íleo/metabolismo , Íleo/microbiologia , Íleo/patologia , Absorção Intestinal , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Jejuno/metabolismo , Jejuno/microbiologia , Jejuno/patologia , Masculino , Camundongos , Mucosite/imunologia , Mucosite/metabolismo , Mucosite/microbiologia , Infiltração de Neutrófilos , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Distribuição Aleatória , Saccharomyces/crescimento & desenvolvimentoRESUMO
OBJECTIVE: This study assessed gene expression by quantitative polymerase chain reaction of inflammatory- [interleukin (IL)-12, tumor necrosis factor-alpha (TNF-alpha), IL-4, and IL-10] and osteoclastogenesis-related factors [receptor activator of NF-kappaB ligand (RANKL) and osteoprotegerin (OPG)] in sites exhibiting different severities of peri-implant disease. MATERIAL AND METHODS: Peri-implant soft tissue biopsies (n=48) were harvested from healthy implant (HI), mucositis (MC), initial peri-implantitis (IP) and severe peri-implantitis (SP) sites. RESULTS: IL-12 and TNF-alpha mRNA levels were higher in SP, followed by IP and MC (P <0.05). IL-4 was higher in HI, followed by MC, SP and IP (P <0.05). IL-10 was the lowest in HI, while no differences were detected among the diseased groups (P>0.05). OPG mRNA levels were higher in HI, followed by IP, SP and MC, whereas RANKL was increased as the peri-implantitis severity increased (P<0.05). The highest OPG/RANKL ratio was observed in HI and the lowest in SP (P<0.01). CONCLUSION: These findings suggest that expressions of inflammatory- and osteoclastogenesis-related factors may play an important role in the onset and severity of the peri-implant diseases.
Assuntos
Citocinas/metabolismo , Implantes Dentários/efeitos adversos , Mucosite/metabolismo , Osteoclastos/imunologia , Periodontite/metabolismo , Adulto , Análise de Variância , Diferenciação Celular/imunologia , Citocinas/imunologia , Feminino , Regulação da Expressão Gênica/imunologia , Regulação da Expressão Gênica/fisiologia , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-12/genética , Interleucina-12/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Arcada Edêntula/imunologia , Arcada Edêntula/reabilitação , Masculino , Pessoa de Meia-Idade , Mucosite/etiologia , Mucosite/imunologia , Osteoclastos/metabolismo , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Periodontite/etiologia , Periodontite/imunologia , Ligante RANK/genética , Ligante RANK/metabolismo , RNA Mensageiro/análise , Valores de Referência , Índice de Gravidade de Doença , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: The objectives of this study were to clinically and immunologically assess the effects of mechanical anti-infective therapies for mucositis and peri-implantitis and to compare the levels of cytokines in untreated and treated peri-implant diseased sites to healthy ones. METHODS: Titanium dental implants were assigned to one of the following groups: healthy (n = 10) = control; mucositis (n = 10) = mechanical debridement using abrasive sodium carbonate air-powder and resin curets; and peri-implantitis (n = 20) = open surgical debridement using abrasive sodium carbonate air-powder and resin curets. Visible plaque accumulation, marginal bleeding, bleeding on probing, suppuration, and probing depth were assessed at baseline for all groups and at 3 months after therapies for diseased groups. At these times, the total amounts of interleukin (IL)-4, -10, and -12, tumor necrosis factor-alpha (TNF-alpha), receptor activator of nuclear factor-kappa B ligand (RANKL), and osteoprotegerin (OPG) in the peri-implant crevicular fluid (PICF) were measured by enzyme-linked immunosorbent assay. RESULTS: At 3 months, the anti-infective treatments resulted in a significant improvement in all clinical parameters for mucositis and peri-implantitis (P <0.05). Moreover, the total amounts of TNF-alpha in PICF were significantly higher in untreated diseased implants compared to healthy ones, and the OPG/RANKL ratio was higher for healthy implants than for untreated peri-implantitis (P <0.05). TNF-alpha levels were significantly reduced for both diseased groups (P <0.05), achieving the same level as the healthy group at 3 months after therapies (P >0.05). CONCLUSION: The proposed anti-infective therapies may locally modulate the levels of TNF-alpha and the OPG/RANKL ratio and improve clinical parameters around peri-implant tissues.
Assuntos
Citocinas/análise , Implantes Dentários/efeitos adversos , Líquido do Sulco Gengival/química , Periodontite/imunologia , Periodontite/terapia , Estomatite/imunologia , Estomatite/terapia , Adulto , Idoso , Anti-Infecciosos Locais/uso terapêutico , Estudos de Casos e Controles , Clorexidina/uso terapêutico , Implantação Dentária Endóssea/efeitos adversos , Índice de Placa Dentária , Raspagem Dentária , Feminino , Humanos , Interleucinas/análise , Masculino , Pessoa de Meia-Idade , Antissépticos Bucais/uso terapêutico , Mucosite/etiologia , Mucosite/imunologia , Mucosite/terapia , Osteoprotegerina/análise , Índice Periodontal , Periodontite/etiologia , Ligante RANK/análise , Estomatite/etiologia , Fator de Necrose Tumoral alfa/análiseRESUMO
The symptomatic phases of many inflammatory diseases are characterized by migration of large numbers of neutrophils (PMN) across a polarized epithelium and accumulation within a lumen. For example, acute PMN influx is common in diseases of the gastrointestinal system (ulcerative colitis, Crohn's disease, bacterial enterocolitis, gastritis), hepatobiliary system (cholangitis, acute cholecystitis), respiratory tract (bronchial pneumonia, bronchitis, cystic fibrosis, bronchiectasis), and urinary tract (pyelonephritis, cystitis). Despite these observations, the molecular basis of leukocyte interactions with epithelial cells is incompletely understood. In vitro models of PMN transepithelial migration typically use N-formylated bacterial peptides such as fMLP in isolation to drive human PMNs across epithelial monolayers. However, other microbial products such as lipopolysaccharide (LPS) are major constituents of the intestinal lumen and have potent effects on the immune system. In the absence of LPS, we have shown that transepithelial migration requires sequential adhesive interactions between the PMN beta2 integrin CD11b/CD18 and JAM protein family members. Other epithelial ligands appear to be abundantly represented as fucosylated proteoglycans. Further studies indicate that the rate of PMN migration across mucosal surfaces can be regulated by the ubiquitously expressed transmembrane protein CD47 and microbial-derived factors, although many of the details remain unclear. Current data suggests that Toll-like receptors (TLR), which recognize specific pathogen-associated molecular patterns (PAMPs), are differentially expressed on both leukocytes and mucosal epithelial cells while serving to modulate leukocyte-epithelial interactions. Exposure of epithelial TLRs to microbial ligands has been shown to result in transcriptional upregulation of inflammatory mediators whereas ligation of leukocyte TLRs modulate specific antimicrobial responses. A better understanding of these events will hopefully provide new insights into the mechanisms of epithelial responses to microorganisms and ideas for therapies aimed at inhibiting the deleterious consequences of mucosal inflammation.
Assuntos
Movimento Celular/fisiologia , Células Epiteliais/fisiologia , Mucosite/imunologia , Neutrófilos/fisiologia , Receptores Toll-Like/fisiologia , Movimento Celular/imunologia , Células Epiteliais/imunologia , Humanos , Mucosa/imunologia , Mucosa/fisiologia , Neutrófilos/imunologiaRESUMO
The symptomatic phases of many inflammatory diseases are characterized by migration of large numbers of neutrophils (PMN) across a polarized epithelium and accumulation within a lumen. For example, acute PMN influx is common in diseases of the gastrointestinal system (ulcerative colitis, Crohn's disease, bacterial enterocolitis, gastritis), hepatobiliary system (cholangitis, acute cholecystitis), respiratory tract (bronchial pneumonia, bronchitis, cystic fibrosis, bronchiectasis), and urinary tract (pyelonephritis, cystitis). Despite these observations, the molecular basis of leukocyte interactions with epithelial cells is incompletely understood. In vitro models of PMN transepithelial migration typically use N-formylated bacterial peptides such as fMLP in isolation to drive human PMNs across epithelial monolayers. However, other microbial products such as lipopolysaccharide (LPS) are major constituents of the intestinal lumen and have potent effects on the immune system. In the absence of LPS, we have shown that transepithelial migration requires sequential adhesive interactions between the PMN beta2 integrin CD11b/CD18 and JAM protein family members. Other epithelial ligands appear to be abundantly represented as fucosylated proteoglycans. Further studies indicate that the rate of PMN migration across mucosal surfaces can be regulated by the ubiquitously expressed transmembrane protein CD47 and microbial-derived factors, although many of the details remain unclear. Current data suggests that Toll-like receptors (TLR), which recognize specific pathogen-associated molecular patterns (PAMPs), are differentially expressed on both leukocytes and mucosal epithelial cells while serving to modulate leukocyte-epithelial interactions. Exposure of epithelial TLRs to microbial ligands has been shown to result in transcriptional upregulation of inflammatory mediators whereas ligation of leukocyte TLRs modulate specific antimicrobial responses. A better understanding of these events will hopefully provide new insights into the mechanisms of epithelial responses to microorganisms and ideas for therapies aimed at inhibiting the deleterious consequences of mucosal inflammation.