RESUMO
Vitamin C can be used to overcome oxidative stress and ease pain in chronic pancreatitis. But its use is deprecated in conditions of tissue iron overload, because its bioactive form, ascorbate, can accelerate free-radical reactions that are driven by transition metals. We measured iron, ascorbate and copper in Sowetan Blacks (RSA) with chronic pancreatitis, obtaining serum/plasma from 14 consecutive patients and 15 controls. Compared with data from corresponding groups in Manchester, African samples had less ascorbate (p < 0.0001), but more caeruloplasmin (p < 0.0001). African and British controls had comparable iron and iron-binding capacity. Plasma from African patients had less ascorbate than that from African controls (p < 0.005) and in six samples, ferritin exceeded 300 micrograms/l (677 pmol/l). Low-molecular-mass iron or copper, capable of participating in free radical reactions, was not detected. British patients, had similar caeruloplasmin levels to African patients but higher ascorbate levels. There is no evidence of iron overload in our African samples. Outwardly healthy controls from Soweto have elevated levels of caeruloplasmin, possibly to compensate for dietary deficiency of ascorbate. Persistent oxidative stress is a unifying feature of chronic pancreatitis, but its degree is higher in African than British patients. Supplements of vitamin C should be safe in Blacks of southern Africa.
Assuntos
Ácido Ascórbico/sangue , Cobre/sangue , Ferro/sangue , Pancreatite/sangue , Adulto , Idoso , Ácido Ascórbico/uso terapêutico , Estudos de Casos e Controles , Ceruloplasmina/análise , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , África do SulRESUMO
Four indices of free radical activity were measured in fasting serum/plasma samples from 14 consecutive blacks with clinically quiescent chronic pancreatitis and 15 outwardly healthy hospital personnel at Soweto, the township near Johannesburg in South Africa. The patients had higher serum levels than did controls of lipid isomerisation (P < 0.002) and peroxidation (P < 0.05) markers, with lower plasma levels of glutathione (P < 0.0001) and bioactive fraction of vitamin C (P < 0.002). Lipid peroxide and non-bioavailable vitamin C concentrations in Sowetan patients were significantly higher than in their counterparts from Manchester, UK (P < 0.0001, P < 0.0005, respectively). These differences mirrored those in controls in that outwardly healthy Sowetans had much higher serum lipid peroxide levels than Manchester controls (P < 0.001) and much lower plasma concentration of vitamin C (P < 0.001) and hence of the bioavailable fraction ascorbate (P < 0.0002). Heightened free radical activity is thus a common denominator in chronic pancreatitis irrespective of geography, or putative aetiological factors whether alcoholism or idiopathic, since that ratio was approximately 95:5 at Johannesburg and 50:50 at Manchester. The further finding of subclinical oxidative stress in Sowetan controls and the endemic nature of chronic pancreatitis in that area supports the hypothesis that oxidative stress may be involved in its pathogenesis.
Assuntos
Ácido Ascórbico/sangue , Peróxidos Lipídicos/sangue , Pancreatite/sangue , Adulto , Biomarcadores/sangue , População Negra , Cromatografia Líquida de Alta Pressão/métodos , Doença Crônica , Estudos de Coortes , Inglaterra , Feminino , Radicais Livres/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Valores de Referência , África do Sul , População UrbanaRESUMO
The overlapping features of the acquired diseases acute pancreatitis and chronic pancreatitis on the one hand, and of chronic pancreatitis and pancreatic involvement in the congenital condition cystic fibrosis on the other, suggest that the basic mechanism of pancreatic injury may be the same in each illness. We propose that pancreatic oxidant stress is the common denominator and, furthermore, that this is facilitated by a shortfall of micronutrient antioxidants in the face of heightened free radical activity through different sources. If so antioxidant supplements should alleviate symptoms. This deduction was supported by an exploratory dose-seeking study that spanned five years in 20 patients with recurrent (non-gall stone) acute or chronic pancreatitis and confirmed by a 20-week double-blind placebo-controlled crossover trial of the successful combination (daily doses of 600 micrograms organic selenium, 0.54 g vitamin C, 9000 IU B-carotene, 270 IU vitamin E and 2 g methionine) in a further 20 cases. A randomised trial of glutathione precursors, given intravenously for 24 hours after admission in patients with a first attack of acute pancreatitis, is in progress. Long-term trials of oral antioxidant formulas are planned in patients with cystic fibrosis.
Assuntos
Antioxidantes/uso terapêutico , Fibrose Cística/tratamento farmacológico , Pancreatite/tratamento farmacológico , Fibrose Cística/patologia , Radicais Livres , Humanos , Pancreatite/patologiaRESUMO
The response of primed T cells to keyhole limpet haemocyanin (KLH) was used to compare the characteristics of antigen presentation by lymphoid dendritic cells, splenic and peritoneal macrophages. In a similar manner to macrophages, purified dendritic cells could be pulsed with antigen and subsequently fixed by brief glutaraldehyde fixation and still retain antigen presenting activity. Also, as previously reported for macrophages, presentation could be inhibited by chloroquine. These functional experiments suggested that the pathway of antigen presentation in dendritic cells and macrophages was similar or identical. However, biochemical studies, using radiolabelled antigen, showed that dendritic cells do not significantly degrade large proteins such as KLH to TCA-soluble form, but partially hydrolyse them to smaller peptide fragments. The significance of these results in terms of a model of the cellular pathways of antigen presentation is discussed.
Assuntos
Células Apresentadoras de Antígenos/imunologia , Tecido Linfoide/imunologia , Macrófagos/imunologia , Linfócitos T/imunologia , Animais , Células Apresentadoras de Antígenos/efeitos dos fármacos , Antígenos/imunologia , Cloroquina/farmacologia , Relação Dose-Resposta Imunológica , Glutaral , Hemocianinas/metabolismo , Tecido Linfoide/citologia , Tecido Linfoide/metabolismo , Camundongos , Camundongos Endogâmicos CBA , Mitose , Receptores Fc/análiseRESUMO
High concentrations of lipid peroxidation (free-radical oxidation) products have been found in bile from patients with recurrent pancreatitis, and the principal component, after hydrolysis, has been identified as an isomerised form of linoleic acid -- typical concentration 25 mmol/l, compared with 4 mmol/l in controls. Chromatographically identical products can be generated by peroxidising linoleic acid using an ultraviolet (UV) source in the presence of albumin, whereas peroxidation by lipoxidase without albumin results in a constellation of products that bear no resemblance to those in biological fluids. These facts, and the suspicion that reflux of abnormal bile may be an initiating mechanism in acute pancreatitis, led us to investigate the effects of linoleic acid peroxidation products in the rat pancreas. Two concentrations of ultraviolet-peroxidised linoleic acid were used (3.6 mmol/l or 25 mmol/l, in a 2.09% solution of bile salts containing albumin 10 g/l) to simulate the human findings and, for comparison, the effects of lipoxidase-peroxidised linoleic acid, 25 mmol/l (in the 2.09% bile salt solution but without albumin), were also studied. 100 microliter of test solution was infused retrogradely into the pancreatic duct using a syringe pump. The results were assessed microscopically at 3-h intervals, and histologically at 12 h: if the animal died before the end of the experiment, the time of death was recorded. Both forms of peroxidised linoleic acid, 25 mmol/l, caused a greater degree of pancreatic injury than that produced by bile salts alone (e.g., macroscopic score at 3 h: ultraviolet, P less than 0.001; lipoxidase, P less than 0.05). Non-peroxidised linoleic acid 25 mmol/l caused less damage than ultraviolet-peroxidised linoleic acid 25 mmol/l, both macroscopically (3 h: P less than 0.01; 12 h: P less than 0.05) and on histology (P less than 0.01). Pancreatic haemorrhage was not a feature.
Assuntos
Ácidos Linoleicos , Peróxidos Lipídicos/toxicidade , Pâncreas/patologia , Pancreatite/induzido quimicamente , Doença Aguda , Animais , Ácidos e Sais Biliares/toxicidade , Ácido Linoleico , Masculino , Oxirredutases , Pâncreas/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Raios UltravioletaRESUMO
Using validated double-marker techniques to quantitate tryptic secretion we found that the mean 10-min output of trypsin in duodenal juice after a test meal was very similar to the peak 10-min output of trypsin after pancreozymin (2 Crick-Harper-Raper units/kg, Boots) both in controls as well as in non-diabetic patients with idiopathic chronic pancreatitis. These results show that the disproportionate reduction in mean tryptic activity after endogenous compared with exogenous stimulation in chronic pancreatitis is not due to impaired release of cholecystokinin-pancreozymin from the small intestine, nor to refractoriness of the pancreas to endogenously released hormone: instead, it is due to overdilution of secreted pancreatic enzymes because of accelerated gastric emptying, with or without gastric acid hypersecretion.