Mechanism of histamine release from rat peritoneal mast cells

Summary The present communication endeavours to elucidate the mechanism of histamine release from rat peritoneal mast cells induced by selective histamine liberators.Of the different enzymatic processes involved in secretion the following are considered: ecto-ATPase activity in the mast cell, pro-esterase-esterase conversion during histamine secretion, cyclic AMP and microtubule association/dissociation, phospholipase A₂ and the effect of phospholipid metabolites on secretion, N-methyl transferase and the methylation of phospholipids and the phosphorylation and desphosphorylation of proteins.     

The questionable use of albumin for the prevention of ovarian hyperstimulation syndrome in an IVF programme: a randomized placebo-controlled trial

BACKGROUND: The role of intravenous (IV) albumin administration in the prevention of ovarian hyperstimulation syndrome (OHSS) and in the improvement of IVF conception outcomes was evaluated in a prospective, randomized, placebo-controlled double blind study. METHODS: Ninety-eight women were enrolled in the study and were consecutively assigned to either a treatment group or a control group. Eleven patients were lost to follow-up after assignment. Of the remaining 87 women, 46 received albumin on the day of oocyte retrieval, and 41 received 0.9% sodium chloride solution as a placebo control. Outcome measures included OHSS incidence rates and pregnancy rates in the two trial groups. RESULTS: Four of the 46 patients in the study group developed severe OHSS and six developed moderate OHSS. In the control group, one of the 41 developed severe OHSS and five developed moderate OHSS. The difference in OHSS incidence rates between the two groups was not statistically significant [relative risk (RR) = 1.49, 95% CI = 0.59-3.73]. Fourteen patients (30%) in the intervention group conceived, compared with 16 patients (39%) in the control group. The difference in conception rates between the two groups was not statistically significant (RR = 0.78, 95% CI = 0.44-1.39). CONCLUSIONS: Albumin appears to have no positive effect on OHSS or conception rates, while its use carries the risk of undesirable side effects, including exacerbation of ascites in OHSS, nausea, vomiting, febrile reaction, allergic reaction, anaphylactic shock and risk of virus and prion transmission. We suggest that this form of treatment should not be included in the prevention of OHSS.     

Different modulation by histamine of IL-4 and interferon-gamma (IFN-γ) release according to the phenotype of human Th0, Th1 and Th2 clones

Histamine, an important inflammatory mediator in allergic diseases and asthma, has been reported to have modulator effects on T cells, suggesting that the bronchial microenvironment may regulate the function of resident T cells. We examined the effect of histamine on the release of the Th2-associated cytokines IL-4 and IL-5 and the Th1-associated cytokine IFN-γ by 30 CD4⁺ T cell clones from peripheral blood or bronchial biopsy of one atopic subject. Based on the IL-4/IFN-γ ratio, the clones were ascribed to the Th2 (ratio >1), Th0 (ratio 0.1 and 1) or Th1 (ratio <0.1) phenotype. Histamine inhibited IFN-γ production by Th1-like cells (P<0.02, Kruskall–Wallis), especially from bronchial biopsy, but had no effect on IL-4 release. Regarding Th0 clones, histamine inhibited IL-4 production (P<0.02) in a dose-dependent manner and slightly inhibited IFN-γ production, but had no effect on Th2-like cells. Histamine had a heterogeneous and insignificant effect on IL-5 production. The H₂-receptor antagonist ranitidine completely reversed the inhibition of IL-4 and IFN-γ production, whereas the agonist dimaprit mimicked this effect. In contrast, H₁- and H₃-receptor agonists and antagonists had no significant effect. These data demonstrate that histamine has different effects on IL-4 and IFN-γ release by T helper cells according to their phenotype via H₂-receptors. This study extends the immunomodulatory effects of histamine which may contribute to the perpetuation of airway inflammation in asthma.     

Interaction of Adenosine 5‘-Triphosphate (ATP) with Histamine Release Induced by Compound 48/80

The histamine releasing action of compound 48/80 disappeared after pretreatment of rat mast cells with ATP in the absence of divalent cations. The inhibitory action was evident already with 2 μM of ATP, provided the cells were preincubated with ATP for short periods of time prior to the addition of 48/80. When mast cells were exposed to 48/80 combined with ATP more than 10 μM of ATP was needed to induce inhibition of histamine release. This inhibitory effect was found to be specific for ATP compared with various organic phosphorous compounds tested and was not mimicked by EDTA. With concentrations of ATP less than 10 μM the sensitivity to the action of 48/80 was spontaneously restored after prolonged preincubation of the cells with ATP. The experimental findings suggest that ATP, in the absence of divalent cations, induced configurational changes of the plasma membrane of the mast cells so that 48/80 could no longer exert its degranulating and histamine releasing action.     

Down-regulation of monocyte functions by treatment of healthy adults with 1 alpha,25 dihydroxyvitamin D3.

A number of in vitro studies suggest an immunoregulatory role of 1 alpha,25 Dihydroxyvitamin D3 (1,25-(OH)2D3). The hormone inhibits production of interleukin-2 and immunoglobulin, and it blocks lymphocyte proliferation. Diverse effects on monocyte functions have been reported. However, immunological effects of 1,25-(OH)2D3 have not been substantiated in vivo. Six healthy male volunteers, aged 28-45 yr, were treated orally with 1,25-(OH)2D3 (tabl. Rocaltrol), 1 microgram twice daily for 7 days. Blood and urine samples were collected before and 7 days after initiation of treatment. Blood mononuclear cells from individuals treated with 1,25-(OH)2D3 showed a significantly reduced production of both interleukin-1 alpha (45%) and tumor necrosis factor-alpha (58%) (both measured by ELISA). Interleukin-6, production, measured by the B9 cell assay, was reduced in five individuals (78%), and unchanged in one. There was no effect on the release of interleukin-1 beta. There was no measurable effect on interleukin-2, interferon gamma or immunoglobulin production, or on mitogen-induced proliferation of blood mononuclear cells. Serum-osteocalcin and urine excretion of calcium were increased to 131 and 173%, respectively. The serum-calcium and serum-phosphate levels were unchanged.     

Onset of action of pimecrolimus cream 1% in the treatment of atopic eczema in infants

BACKGROUND: Data on the efficacy of pimecrolimus cream 1% within the first days of treatment are scarce, as in previous studies, the first postbaseline assessment was performed only after 1 week. OBJECTIVE: We sought to investigate the onset of action of pimecrolimus cream 1% in infants with mild to very severe atopic eczema. METHODS: We used pimecrolimus cream 1% (n = 129) or vehicle cream (n = 66) administered in a double-blind manner for 4 weeks and then open-label pimecrolimus cream 1% for 12 weeks, with a 4-week follow-up period. RESULTS: Pimecrolimus cream 1% reduced the mean Eczema Area and Severity Index at 4 weeks by 71.5% compared with an increase of 19.4% with vehicle ( P < .001). The reduction in the Eczema Area and Severity Index with pimecrolimus cream 1% was significant at day 4 (38.5% vs 17.6% increase with vehicle). Significant improvements in caregivers' assessments of pruritus and sleep loss were observed with pimecrolimus cream 1% by day 2 ( P < .03) and day 3 ( P = .002), respectively, compared with vehicle. Responses to pimecrolimus cream 1% were sustained during the open-label phase, and pimecrolimus cream 1% was well tolerated. Symptoms of atopic eczema returned gradually after discontinuation. CONCLUSION: Pimecrolimus cream 1% was well tolerated and effective in patients with mild to very severe atopic eczema, with rapid onset of action and no disease rebound after discontinuation.     

Potentiation of neurotransmitter release coincides with potentiation of phosphatidyl inositol turnover. A possible in vitro model for long term potentiation

Carbachol (CCh) a cholinergic agonist which hydrolyses phosphatidyl-inositol bisphosphate (PIP2) to produce the breakdown products inositol trisphosphate (IP3) and diacylglycerol (DAG) was tested for its ability to induce [3H]norepinephrine ([3H]NE) release and to accumulate [3H]inositol phosphate ([3H]IP) under normal and membrane depolarizing conditions. Our results suggest two major points: first, muscarinic acetylcholine receptor (mAChR) agonists and depolarizing agents (of which KCl is the most effective) act in concert to induce potentiation of PI turnover and potentiation of neurotransmitter release. The simultaneous presence of both a depolarizing agent and a receptor agonist is obligatory for eliciting potentiatory effect. Facilitation of release by muscarinic agonist and K+, added together, was 2 to 5-fold above additivity and the levels of [3H]IP accumulated were 3-5-fold above additivity by K+ and CCh. Enhancement of release and of [3H]IP formation is reversed by pirenzepine, a muscarinic (MI) specific antagonist, Kdiss = 0.4 and 0.8 microM, respectively. Second, synergy of IP accumulation in correlation with synergy of neurotransmitter release elicited by mAChR activation and membrane depolarization, suggests a possible role for phospholipase C (PLC) in the bifurcating control of neurotransmitter release and for the involvement of PLC and voltage sensitive channels in mediation of long-term potentiation (LTP).