Inhibitory effect of retinoic acid on proliferation, maturation and tryptase level in human leukemic mast cells (HMC-1).

Mast cells play important role in allergic inflammation by releasing histamine, tryptase and several inflammatory cytokines. Human leukemic mast cells (HMC-1) have been used to study mast cell mediator and their role in inflammatory mechanisms. HMC-1 contain and release several inflammatory mediators, of which the proteolytic enzyme tryptase is most characteristic. Retinoids, including retinoic acid, are naturally occurring and synthetic derivatives of vitamin A. All-trans-retinoic (ATRA) acid had been previously reported to inhibit cell proliferation, differentiation and apoptosis. In the present study, we investigated the effect of ATRA on the proliferation and secretion of tryptase in HMC-1. HMC-1 were treated with ATRA at 10(-4M), 10(-5M) or 10(-6M) for 3, 4 or 5 days in culture. Control HMC-1 were treated with equal amount of culture medium only. ATRA decreased the number of HMC-1 as compared to the control group. The same treatment for 3, 4 or 5 days also decreased intracellular tryptase levels. These results indicate that ATRA significantly inhibits both proliferation and growth as shown by the decreased intracellular tryptase levels in HMC-1. ATRA may be a useful agent in the treatment of mast cell proliferative disorders.

Potent mast cell degranulation and vascular permeability triggered by urocortin through activation of corticotropin-releasing hormone receptors.

Urocortin (Ucn) is related to corticotropin-releasing hormone (CRH), and both are released in the brain under stress where they stimulate CRH 1 and 2 receptors (CRHR). Outside the brain, they may have proinflammatory actions through activation of mast cells, which are located perivascularly close to nerve endings and degranulate in response to acute psychological stress. Here, we report that a concentration of intradermal Ucn as low as 10 nM induced dose-dependent rat skin mast cell degranulation and increased vascular permeability. This effect appeared to be equipotent to that of calcitonin gene-related peptide and neurotensin. Ucn-induced skin vasodilation was inhibited by pretreatment with the mast cell stabilizer disodium cromoglycate (cromolyn) and was absent in the mast cell-deficient W/Wv mice. The selective nonpeptide CRH receptor 1 antagonist, antalarmin and the nonselective peptide antagonist astressin both reduced vascular permeability triggered by Ucn but not that by Substance P or histamine. In contrast, the peptide antagonist alpha-helical CRH-(9-41) reduced the effect of all three. The vasodilatory effect of Ucn was largely inhibited by pretreatment with H1 receptor antagonists, suggesting that histamine is the major mediator involved in vitro. Neuropeptide depletion of sensory neurons, treatment with the ganglionic blocker hexamethonium, or in situ skin infiltration with the local anesthetic lidocaine did not affect Ucn-induced vascular permeability, indicating that its in situ effect was not mediated through the peripheral nervous system. These results indicate that Ucn is one of the most potent triggers of rat mast cell degranulation and skin vascular permeability. This effect of Ucn may explain stress-induced disorders, such as atopic dermatitis or psoriasis, and may lead to new forms of treatment.

A neurotensin receptor antagonist inhibits acute immobilization stress-induced cardiac mast cell degranulation, a corticotropin-releasing hormone-dependent process.

Stress worsens certain disorders such as migraines or asthma, and has also been implicated in sudden myocardial arrest. It was previously shown that acute psychological stress by immobilization results in dura mast cell degranulation, an effect blocked by pretreatment with antiserum against corticotropin-releasing hormone (CRH). Moreover, CRH was recently shown to induce skin mast cell degranulation. The effect of psychological stress was investigated on rat cardiac mast cells, because their release of coronary constrictive and proinflammatory molecules contributes to myocardial ischemia and possibly arrhythmias. Immobilization of rats for 30 min induced maximal cardiac mast cell degranulation as evidenced by light and electron microscopy. This effect was inhibited by pretreatment with the "antiallergic" drug sodium cromoglycate (cromolyn), which is thought to act primarily through mast cell stabilization. Mast cell degranulation was also blocked by preincubation with antiserum against CRH and was partially inhibited by a CRH type-1 receptor selective antagonist. Sensory neuropeptides did not appear to influence this effect, but a nonpeptide neurotensin receptor antagonist blocked stress-induced cardiac mast cell degranulation. This finding supports the involvement of neuropeptide neurotensin which is present in the heart and is known to trigger mast cell degranulation. These results indicate acute stress could result in local CRH and nonpeptide neurotensin release which could contribute to myocardial pathophysiology through direct or indirect release of cardiac mast cell mediators.

Changing seasonality of mortality from coronary heart disease.

CONTEXT: Coronary heart disease is the major cause of mortality in the United States. Factors associated with coronary risk are important to identify. Coronary mortality is greater during the winter months. OBJECTIVE: To investigate whether declining coronary mortality has been accompanied by a change in the seasonal pattern and to investigate the hypothesis that diminishing exposures to environmental cold and heat have affected the seasonal pattern. DESIGN: We used published data on coronary mortality by year to evaluate the time trend in the seasonal pattern. We fit a sine curve to the monthly frequency of deaths in each year and examined the trend over time in the ratio of the peak to the trough of the curve. SETTING: We used monthly coronary deaths in the United States from 1937 through 1991. Deaths by cause and month were not available by geographic area within the United States, but we were able to examine total monthly deaths in 2 regions with contrasting climates, New England and the South. OUTCOME MEASURES: We used the yearly peak-to-trough ratio as our primary outcome and assessed its trend over time by linear regression. We also depicted the time trends using polynomial smoothing. RESULTS: The peak-to-trough ratio diminished by about 2% per year until around 1970, when the trend reversed. In New England, the decline was steeper than in the South, as measured from all deaths. CONCLUSION: Seasonal patterns in coronary mortality in the United States have changed with time. These changes are compatible with the gradual expansion of adequate heating and the subsequent increased use of air-conditioning. Microclimatic influences on coronary mortality could explain in part the socioeconomic gradient of cardiovascular mortality.