Interleukin-1 alpha, soluble interleukin-2 receptor, and IgG concentrations in cystic fibrosis treated with prednisolone

The cytokines interleukin-1 and interleukin-2 participate in the inflammatory response, and may contribute to hypergammaglobulinaemia G and the development of lung injury in cystic fibrosis. Anti-inflammatory treatment with corticosteroids may attenuate this response. The effect of a 12 week course of oral prednisolone on spirometry and serum concentrations of interleukin-1 alpha (IL-1 alpha), soluble interleukin-2 receptor (sIL-2R), and IgG was investigated in 24 children with cystic fibrosis. Prednisolone was administered, in a double blind and placebo controlled manner, at an initial dose of 2 mg/kg daily for 14 days and tapered to 1 mg/kg on alternate days for 10 weeks. The treated group (n = 12) experienced an increase in forced expiratory volume in one second and forced vital capacity at 14 days, however, these changes were smaller at 12 weeks. In the treated group, change in pulmonary function was associated with decreased serum IgG and cytokine concentrations. Prednisolone suppresses serum concentrations of these cytokines, which may participate in the inflammatory response, the excessive synthesis of IgG, and airflow obstruction observed in cystic fibrosis patients.     

Chronic variable stress induces supersensitivity of central α2-adrenoceptors which modulate the jaw-opening reflex in the rat

In a previous study, we found that the sensitivity of central postsynaptic α₂-adrenoceptors which modulate, in an inhibitory way, the activity of the jaw-opening reflex (JOR) is reduced after chronic repeated stress (tail pinch) in the rat. The aim of this study was to assess the effects of exposure to a chronic variable stress regime on these adrenoceptors. To do this, the digastric electromyographic responses elicited by orofacial electrical stimulation after the intravenous administration of cumulative doses (×3.3) of the α₂-adrenoceptor agonist, clonidine (0.1–10 000 μg/kg), were recorded. As expected, in unmanipulated control rats, clonidine inhibited the reflex, in a dose-dependent manner, until abolition (ED₅₀=17.3±2.2 μg/kg). Single tail pinch did not significantly alter the ability of clonidine to abolish the reflex. However, chronic variable stress led to an enhancement of the inhibitory effect of clonidine on the amplitude of JOR, resulting in a shift to the left of the dose-response curve in comparison with that of the control group (ED₅₀ was reduced by 37%, P=0.032), without affecting either the estimated maximum effect for the agonist or the slope of the inhibitory function. This in vivo result indicates that chronic variable stress leads to an increased sensitivity of central α₂-adrenoceptors which modulate JOR, in contrast to the desensitization of these adrenoceptors found after repeated exposure to the same stressor.     

Peripheral α2-adrenoceptor-mediated sympathoinhibitory effects of mivazerol

Summary— Mivazerol is a new compound that could potentially reduce perioperative cardiovascular morbidity and mortality in patients with or at risk of coronary disease and submitted to surgery. This action of mivazerol depends on a well documented centrally mediated reduction in sympathetic nerve activity, but a direct peripheral decrease in sympathetic neurotransmitter release induced by activation of prejunctional α₂-adrenoceptors located on sympathetic nerve endings could also contribute. To investigate this issue, the effects of mivazerol on the pressor, systemic and regional hemodynamic (pulsed Doppler technique) as well as on the cardiac responses to electrical stimulation of the spinal cord (SCS) were measured in pithed rats in the absence and in the presence of mivazerol. Mivazerol exerted strong sympathoinhibitory effects: SCS-induced increases in blood pressure, total peripheral resistance and heart rate were dose-dependently reduced by mivazerol, but among the regional vascular beds investigated, only the hindlimb vasoconstrictor responses were significantly drug-affected. All these sympathoinhibitory effects of mivazerol were abolished by prior yohimbine administration. Simultaneously, mivazerol did not induce any postjunctional adrenoceptor blockade as it did not affect noradrenaline cardiac and hemodynamic effects. On the contrary, through postjunctional α₂-adrenoceptor stimulation, mivazerol, in this pithed preparation, dose-dependently increased blood pressure, total peripheral and hindlimb vascular resistances, but heart rate was not affected. We conclude that, in the pithed rat, mivazerol exerts strong peripheral sympathoinhibitory effects. The mechanism involved is prejunctional α₂-adrenoceptor activation as i) mivazerol does not display any postsynaptic α-adrenoceptor blocking effect — it even behaves as a postsynaptic α₂-adrenoceptor agonist — and ii) yohimbine abolishes mivazerol's sympathoinhibitory effects. Thus, direct peripheral together with central mechanisms contribute to mivazerol's sympathoinhibitory effects and ultimately to its cardioprotective action.     

Repeated tail pinch leads to desensitization of postsynaptic α2-adrenoceptors which modulate the jaw-opening reflex in the rat

There are few in vivo studies which have investigated the modulation of central postsynaptic α ₂-adrenoceptors functionality provoked by stress. We assessed in the rat the effects of either single or repeated tail pinch on clonidine-induced inhibition of the jaw-opening reflex (JOR) via activation of postsynaptic central α ₂-adrenoceptors. At the end of each experimental period, the progressive inhibition of the digastric electromyographic responses elicited by orofacial electrical stimulation after the IV administration of cumulative doses (× 3.3) of clonidine (0.1–10 000 μg/kg) was recorded. Single tail pinch did not significantly modify the ability of the agonist to inhibit the JOR, although there was a tendency to decrease the basal amplitude of the reflex (a 40% reduction) immediately after exposure to the single stressor. However, the dose-response curve for clonidine-induced inhibition of the JOR was clearly shifted to the right in rats exposed to repeated tail pinch (ED₅₀ was increased by 152%, P < 0.0001) when compared with the unstressed control group, without affecting the slope of the inhibitory function and the estimated maximum effect for the agonist. These results show that repeated stress leads to a subsensitivity of the α ₂-adrenoceptors which modulate the JOR, suggesting the development of adaptive mechanisms in postsynaptic α ₂-adrenoceptors in response to stress. Received: 21 October 1997/Final version: 22 December 1997     

Beryllium: An etiologic agent in the induction of lung cancer,nonneoplastic respiratory disease,and heart disease among industrially exposed workers

On the basis of the clear demonstration of the carcinogenicity of beryllium in several animal species along with the suggestion of an increased risk of lung cancer mortality in humans exposed to beryllium, an epidemiologic study of workers exposed to beryllium at one production facility was undertaken. Within the limitations imposed by the selection of data for calculation of cause-specific expected mortality (use of U.S. white male cause-specific mortality rates with linear extrapolation of 1965–1967 to 1968–1975 vs use of cause-specific mortality rates for the county in which the study facility and the majority of its workers resided), the study demonstrated a statistically significant increased risk of respiratory disease (neoplastic and nonneoplastic) and of heart disease mortality. A possible explanation other than in terms of beryllium was sought for this excessive risk of cause-specific mortality among beryllium-exposed workers. The excessive risk of lung cancer mortality could not be related to an effect of age, chance, self-selection, study group selection, exposure to other agents in the study facility, or place of residence. On the basis of the frequency of cigarette smoking among those cohort members employed in 1967–1968 and the distribution of histologic types of lung cancer among deceased cohort members, it seems unlikely that cigarette smoking per se could have accounted for the increased risk of lung cancer among beryllium-exposed workers in the study cohort. Lifetime employment histories for members of the study cohort were not available, so that definitive statements about the role of other occupational exposures cannot be made. However, information on usual occupations as indicated on death certificates suggests that it is unlikely that some undefined occupational or environmental exposure other than to beryllium could account per se for the excessive lung cancer mortality. This interpretation is further supported by the residential stability of the study cohort in a county having a lung cancer rate significantly lower than that of the entire United States. The findings of a statistically significant excess of lung cancer mortality among cohort members in general (P < 0.05) and among workers observed 25 or more years since onset of beryllium exposure in particular (P < 0.01), when taken in context with the results of earlier animal bioassay and recent epidemiologic studies, are supportive of the hypothesis that beryllium is carcinogenic to man.