Smoking protects against ulcerative colitis (UC), and treatment with nicotine patches has a beneficial symptomatic effect in patients with UC. To find an explanation for this response to nicotine in UC, we assessed the effects of nicotine on cytokine production by mononuclear cells (MNC). MNC were isolated from peripheral blood from healthy volunteers. Non-adherent MNC were preincubated with varying concentrations of nicotine or prednisolone for 24 h followed by addition of phytohemagglutinin (10 ~xg/ml). The concentrations of interleukin 2 (IL-2) and tumour necrosis factor-et (TNFa) in the supernatants were determined by ELISA. Nicotine as well as prednisolone caused a significant inhibition of IL-2 and TNFet production. The maximum inhibition caused by nicotine was about 50% of that caused by prednisolone and was reached at concentrations equivalent to nicotine levels measured in plasma of smokers. These results indicate that nicotine exerts its immunoregulatory role through modulation of the cytokine production by non-adherent mononuclear cells.
We developed an in vitro organ bath method to measure permeability and contractility simultaneously in murine intestinal segments. To investigate whether permeability and contractility are correlated and influenced by mucosal damage owing to inflammation, BALB/c mice were exposed to a 10% dextran sulphate sodium (DSS) solution for 8 days to induce colitis. The effect of pharmacologically induced smooth muscle relaxation and contraction on permeability was tested in vitro. Regional permeability differences were observed in both control and 10% DSS-treated mice. Distal colon segments were less permeable to 3H-mannitol and 14C-PEG 400 molecules compared with proximal colon and ileum. Intestinal permeability in control vs. 10% DSS mice was not altered, although histologic inflammation score and IFN-gamma pro-inflammatory cytokine levels were significantly increased in proximal and distal colon. IL-1beta levels were enhanced in these proximal and distal segments, but not significantly different from controls. Any effect of pharmacologically induced contractility on intestinal permeability could not be observed. In conclusion, intestinal permeability and contractility are not correlated in this model of experimentally induced colitis in mice. Although simultaneous measurement in a physiological set-up is possible, this method has to be further validated.
1 The effects of indomethacin were investigated on haemodynamics, haematological and blood glucose values, and the release of tumour necrosis factor (TNF), platelet activating factor (PAF) and eicosanoids in anaesthetized pigs receiving 5 pgkg-' E. coli lipopolysaccharide (LPS) over 60min into the superior mesenteric artery. The animals were observed for an additional period of 2 h after the termination of LPS infusion.2 Eight of the 17 animals infused with LPS and not treated with indomethacin died within 30 min after the beginning of LPS infusion (non-survivors), while the other 9 survived the experimental period of 3 h though in a state of shock (survivors).3 No alterations were observed in plasma concentrations of PAF and eicosanoids (thromboxane B2 (TXB2), 6-keto prostaglandin F1l (6-keto PGF1a) and leukotriene B4 (LTB4)) in non-survivors. However, a marked increase was detected in TNF release. A significant, though transient, increase in concentrations of PAF, TNF and eicosanoids occurred in the survivors. The peak in the concentrations of PAF and TXB2 preceded the maximum in TNF values in survivors. 4 Another group of 7 LPS-infused pigs was treated with indomethacin (2mgkg-1, i.v. bolus 60min before the start of LPS infusion, followed by a continuous infusion of 3mgkg-h-1). This treatment prevented death and shock despite the high concentrations of circulating TNF and PAF. Concentrations of cyclo-oxygenase enzyme products were reduced, whereas LTB4 release was not affected. The effect of indomethacin on haemodynamic changes occurred earlier than on cyclo-oxygenase products. 5 In another group of 6 pigs indomethacin (2mg kg-1, i.v.) was given 20-25 min after the start of LPS infusion at which time mean arterial blood pressure (MABP) had decreased below 40 mmHg indicating imminent death. This indomethacin treatment immediately reversed the hypotension, restored the organ perfusion, delayed the haemoconcentration and thrombocytopenia and prevented death. However, TNF and PAF concentrations remained elevated. Concentrations of cyclo-oxygenase products studied were reduced by the end of the observation period, whereas LTB4 production was unaffected. 6 The decrease in MABP induced by exogenous PAF was temporarily prevented by indomethacin. 7 These data indicate that the beneficial effect of indomethacin in LPS-induced septic shock is related to cyclo-oxygenase inhibition as well as to a direct vasoconstrictor property of the drug.
The levels of the eicosanoids leukotriene B4, prostaglandin E2, prostacycline and thromboxane B2, the cytokines interleukin-1 beta, interleukin-6 and tumour necrosis factor-alpha and soluble intercellular adhesion molecule 1 were measured in ascites and plasma samples of patients with liver cirrhosis (53), peritoneal cancer (26) and spontaneous bacterial peritonitis (10) to assess their value as a possible diagnostic and prognostic parameter in the course of the disease. Soluble intercellular adhesion molecule 1, of the eicosanoids prostaglandin E2 and leukotriene B4, and the protein concentration in ascites were all significantly elevated in ascites of patients with peritoneal cancer in comparison to ascites of patients with liver cirrhosis. In ascites of patients with spontaneous bacterial infection interleukin-6 concentration was significantly elevated and the protein concentration was significantly lower in comparison to the other two groups. None of these parameters, however, seems to be of practical use as a diagnostic parameter, as there is an overlap between all the levels of these mediators in ascites of liver cirrhosis, peritoneal cancer and spontaneous bacterial peritonitis group. Soluble intercellular adhesion molecule 1 levels were much higher in plasma than in ascites, in contrast to interleukin-6 levels which were much higher in ascites than in plasma. Soluble intercellular adhesion molecule 1 in ascites correlated with soluble intercellular adhesion molecule 1 in plasma (r = 0.6926, P = 0.0001). Soluble intercellular adhesion molecule 1, interleukin-6 and the number of polymorphonuclear cells in peritoneal fluid correlated during episodes of infection in patients with a peritonitis. For this reason soluble intercellular adhesion molecule 1 and interleukin-6 could be of prognostic value for patients with peritonitis.
Indomethacin enhanced macrophage cytostasis against MOPC-315 tumor cells in vitro. The effect of indomethacin was inhibited by prostaglandin E2 and by the lipoxygenase inhibitor nordihydroguaiaretic acid. Prostaglandin E2 and nordihydroguaiaretic acid also inhibited indomethacin stimulation of macrophage thymidine incorporation. Indomethacin inhibited macrophage prostaglandin E2 formation and stimulated leukotriene B4 synthesis. Nordihydroguaiaretic acid inhibited leukotriene B4 production. Our data indicate that eicosanoids play a role in regulating macrophage cytostasis.
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