ISSN:1075-2765    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Immunomodulatory effects of prostaglandin E2(PGE2) have been documented bothin vitroandin vivo. Our previous studies have examined the effects of intravenously administered PGE2in mast-cell-mediated diseases, including aspirin-sensitive asthma and systemic mast-cell-activation syndrome. The basis for investigations of these particular diseases has been the hypothesis that the inhibition of cyclooxygenase removes one of its products, PGE2, that provides a critical restraint on the activation of the mast cell. Based on the beneficial effects of PGE2found in these studies, we have extended our investigations to an evaluation of misoprostol, the orally available analog of PGE1. Our preliminary studies with this drug are consistent with an inhibition of mast cell activation by misoprostol, an effect observed at doses higher than currently recommended for gastric protection. The findings from these initial trials have led to the development ofex vivowhole-blood assays that assess the pharmacodynamics of misoprostol's immunomodulatory actions, which support the concept of employing higher doses to obtain sustained systemic effects. To extend these results, we have undertaken double-blinded, placebo-controlled clinical investigations to examine the effects of the higher doses of misoprostol (300–600 μg QID) given chronically in aspirin-sensitive asthma and systemic mast cell activation. Although still ongoing, our studies have confirmed by a variety of clinical evaluations that the higher doses of misoprostol can be tolerated by many patients and appear to be safe. Based on our findings and those of others, further investigation of the therapeutic usefulness of this drug or other PGE analogs in allergic and immunologic diseases appears warranted.

ISSN:1075-2765    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

We investigated the effect of misoprostol on allergen-induced cutaneous immediate- and late-phase allergic reactions in a double-blind placebo-controlled randomized study. Sixteen dust-mite-allergic patients received misoprostol (200 μg) or placebo and then had skin testing on two different days. The immediate- and late-phase skin response was monitored for 6 h. Skin biopsy was obtained from five selected donors at 5 h.In vitrostudies included the effect of misoprostol on eosinophil chemotaxis, eosinophil survival, basophil histamine release, and cytokine production by lymphocytes. All subjects developed an immediate wheal reaction and a late-phase induration in response to dust-mite allergens after taking placebo. Misoprostol selectively inhibited the late-phase but not the immediate-phase response (p< 0.05). Histologic studies revealed a trend toward a reduced number of inflammatory cells in the skin dermis after misoprostol treatment. We also investigated the mechanism of action of misoprostolin vitro. Misoprostol significantly (p< 0.05) inhibited eosinophil chemotaxis and the production of granulocyte/macrophage colony-stimulating factor by lymphocytes at concentrations ≥ 10-8M. However, at significantly lower concentrations (≥ 10-12M), misoprostol blocked cytokine-stimulated eosinophil survival. Thus, misoprostol has potent antiallergic effects and blocks the cutaneous late-phase allergic inflammation.

ISSN:1075-2765    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Inhaled E series prostaglandins (PGEs) have been shown to modulate responses to both allergic and nonallergic provocation. Little is known about the effect of inhaled misoprostol on the airway and whether its antiasthmatic activity would be similar to other PGEs. In the present study, nebulized solutions of misoprostol and PGE2(0.3–300 μg ml-1) effectively blocked the acute bronchospasm due to inhaled antigen challenge in actively sensitized guinea pigs. A 300-μg ml-1solution nebulized for 10 s (about 0.25 ml), 5 min prior to challenge, provided nearly complete inhibition with significant reductions seen at 30 and 3 μg ml-1in certain experiments. Misoprostol treatment resulted in a significant reduction in the number of eosinophils present in bronchoalveolar lavage 24 h after antigen challenge. This combination of effects suggests that inhaled misoprostol may be effective in the treatment of the acute and chronic symptoms of asthma.

ISSN:1075-2765    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

The strategic localization of mast cells near blood vessels led us to investigate the involvement of these cells in IgG–antigen complex-mediated inflammation, using mast-cell-deficient mice and their congenic controls. Mast cells were extensively degranulated and contributed to neutrophil influx, plasma exudation, fibrin deposition, edema formation, and tissue damage. Leukotrienes and the tumor necrosis factor (TNF) from mast cells participated in neutrophil elicitation, and histamine and leukotrienes in plasma exudation, fibrin deposition, and edema formation. Reconstituting the deficient mice with mast cells restored the responses, confirming the role of mast cells and their mediators. Studies with decomplemented and C5-deficient mice indicate that mast cells were stimulated by complement early in the reaction and later by an unknown mechanism. The findings show that mast cells and their mediators, such as leukotrienes, histamine, and TNF, play an important role in the initiation of IgG–antigen complex-mediated inflammation.

ISSN:1075-2765    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Misoprostol was found to be an extremely potent inhibitor of immunologically induced histamine release from mast cells isolated from both the human colonic mucosa and submucosa/muscle. The dose-inhibition curves were bell shaped, with IC50values in the range 0.1–1 nM. The compound was relatively selective for these cell types. It was less active against rat peritoneal mast cells, which again exhibited a bell-shaped dose-inhibition curve, but with a maximal inhibition of only about 30%, and human basophil leucocytes, where the inhibition was progressive with an IC50of ∼ 1 μM. Very high concentrations of misoprostol (≥ 5 μM) induced histamine release from all of the cell types examined. Insofar as the colonic mast cells may represent the two human mast cell phenotypes so far identified (MCTand MCTC), these data suggest that the drug may have therapeutic applications in human allergic and inflammatory diseases in which these cells are involved.

ISSN:1075-2765    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Prostaglandins (PGs) regulate a wide variety of immunologic processes. We studied the activity of PGE1and two orally effective PGE1methyl ester analogs, misoprostol (MP) and enisoprost (EP), as inhibitors of interleukin-4 (IL-4) production in stimulated murine splenic T cellsin vitro. Effective suppression of IL-4 production was seen with all three agents with KI505 of 65 nM for MP and 20 nM for EP. IL-4 is primarily a product of type 2 T helper cells (Th2 cells) and plays an important role in regulating the biosynthesis of immunoglobulins, especially IgE. Thesein vitrostudies, taken together with the recent data of others on modulation of IgE responses by EP and MP in immunized micein vivo, suggest a possible role for these PGE1analogs in the treatment of IgE-mediated diseases in humans.

ISSN:1075-2765    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Immune complex initiation of inflammatory diseases is mediated, to a large extent, by Fcγ receptors. Recent data have underscored three essential points: (1) there is substantial structural diversity within three distinct families of Fcγ receptors; (2) there are functionally significant alleles of different receptor isoforms; and (3) each cell type has a unique distribution of Fcγ receptor isoforms. Structurally different Fcγ receptors utilize distinct signal transduction pathways. Thus, in clinical immune complex disease, consideration of the predominant cell type and receptor isoform involved, as well as the genotype of the individual patient, will be important in developing and applying targeted downregulatory agents such as misoprostol.

ISSN:1075-2765    

出版商:OVID    

年代:1995

数据来源: OVID

ISSN:1075-2765    

出版商:OVID    

年代:1995

数据来源: OVID

摘要:

Chronic inflammatory diseases of the gastrointestinal tract such as ulcerative colitis and Crohn's disease are characterized by mast cell proliferation and secretion of inflammatory mediators. The determinant(s) responsible for stimulating mast cells in the intestinal mucosa is not known. We investigated the interaction of mast cells with type 1 fimbriatedEscherichia coli, an opportunistic pathogen and a constituent of the normal indigenous microflora of the gut. Unlike a mutant derivative deficient in the FimH subunit of the fimbriae or nonfimbriatedE. coli, type 1 fimbriatedE. coliadhered avidly to mast cells. As a consequence of this interaction, the mast cells phagocytozed and killed adherent bacteria. The mast cell bactericidal activity involved generation of superoxide anion and acidification of phagocytic vacuoles. In addition, many of the mast cells had degranulated and released inflammatory mediators such as histamine. These observations have implications both for normal host defense and for the initiation and perpetuation of inappropriate inflammatory responses in the gastrointestinal tract.

ISSN:1075-2765    

出版商:OVID    

年代:1995

数据来源: OVID