The aetiology of experimental fibrosing alveobronchiolitis induced in rats by paprika dust.

The effect of a single intratracheal dose of respirable paprika (Hungarian) dust, paprika dust extract, and cellulose dust on the lungs of rats was examined sequentially one and three months after a treatment. Treatment with respirable paprika and cellulose dusts resulted in alveobronchiolitis at the end of the first month and fibrotic changes at the end of the third month. As the extract of paprika dust caused no histopathological alterations, it is assumed that the high cellulose content of paprika was responsible for the histological reactions.     

Evidence that transmitter can be released from regions of the nerve cell other than presynaptic axon terminal: axonal release of acetylcholine without modulation

Release of acetylcholine from isolated preganglionic axons of sympathetic nerve trunk (cervical preganglionic sympathetic branch) of the cat was studied. In response to depolarization (KCl, 48.4 mM) acetylcholine was released into the eserinized Krebs solution. This release was shown to be dependent on extracellular Ca2+. Electrical stimulation (1 Hz) enhanced the release of acetylcholine from the isolated axonal preparation. The release by stimulation proved to be tetrodotoxin-sensitive and Ca2+-dependent. Evidence has been obtained that the acetylcholine released from sympathetic nerve trunks originates from the axon and not from Schwann cells: 5 days after section of the nerve, there was no release in response to stimulation. The release of acetylcholine from the axon is unlike that from axon terminals in that the rate of release cannot be enhanced by the inhibition of Na, K-adenosine 5'-triphosphatase (ouabain 2 X 10(-5) M) and cannot be modulated by noradrenaline (10(-6) M) or by morphine. Furthermore, although isolated nerve trunks took up [3H]choline by a hemicholinium-sensitive process, no radioactivity could be released upon electrical stimulation. It is suggested that the release of acetylcholine is not confined to axon terminals, but that it can be non-synaptically released by depolarization from axons provided Ca2+ is present.     

Elevated Complement Factor H Levels in Asthmatic Sputa

Background

The alternative pathway of the complement system is known to play a role in the generation of asthmatic airway inflammation, but its regulatory complement protein, factor H has not been investigated in this disease.

Purpose

Our aim was to determine the local bronchial complement factor H (CFH) levels in asthma, and to investigate its relationship with complement activation, systemic CFH concentrations and clinical characteristics of patients.

Methods

Induced sputum and plasma were collected from 21 healthy and 26 asthmatic subjects, and complement factor H and SC5b-9 concentrations were assessed by ELISA. Total protein concentrations were determined by biuret-reaction based microassay system from induced sputa.

Results

CFH was detectable in 81 % of healthy and 100 % of asthmatic subjects, while SC5b-9 exceeded the detection limit in 62 % of healthy subjects and 85 % of asthmatic patients. Sputum CFH concentrations and CFH/protein ratios were increased in samples from asthmatic patients, and correlated with loss of lung function, asthma control, severity and medication intensity, but not with plasma CFH concentrations. Sputum CFH/protein ratios were in positive correlation also with sputum eosinophilic cell counts in asthma. SC5b-9 concentrations were not higher in the asthmatic sputa, although they correlated with sputum CFH concentrations.

Conclusions

CFH level is elevated on asthmatic airway surface, and may be associated with uncontrolled inflammation in asthma.     

Cardiac electrophysiological effects of citalopram in guinea pig papillary muscle comparison with clomipramine

The effect of citalopram, a selective serotonin reuptake inhibitor (SSRI) antidepressant, was studied on cardiac action potential configuration and compared with that of the tricyclic antidepressant (TCA) clomipramine. Conventional microelectrode techniques were used in right ventricular papillary muscle preparations of the guinea pig. Citalopram caused a concentration-dependent (10-100 microM) shortening of action potential duration (APD), depression of plateau and overshoot potential, and reduction of maximum velocity of depolarization (V(max)). No significant changes in resting membrane potential were observed. Similar results were obtained with clomipramine; however, reduction of V(max) and overshoot was more pronounced with clomipramine, whereas citalopram caused relatively greater shortening of APD. Effects of both drugs were partly reversible. The results indicate that the SSRI antidepressant citalopram, similarly to TCA compounds, alters cardiac action potential configuration in guinea pig ventricular muscle, probably owing to inhibition of cardiac Na(+) and Ca(2+) channels. Differences in cardiac side effects of the two drugs may be related to their different actions on cardiac action potential configuration.     

Combined pulmonary toxicity of cadmium chloride and sodium diethyldithiocarbamate

The pulmonary toxicity of sodium diethyldithiocarbamate and cadmium chloride, each separately and in combination, was compared in Sprague-Dawley rats after single intratracheal instillation in sequential experiments by chemical, immunological and morphological methods. With combined exposure, the cadmium content of the lungs increased permanently relative to that of the lungs of just cadmium-treated animals. Immunoglobulin levels of the whole blood did not change, whereas in bronchoalveolar lavage the IgA and IgG levels increased significantly. Morphological changes were characteristic of the effects of cadmium but were more extensive and more serious than in the case of cadmium administration alone: by the end of the first month, interstitial fibrosis, emphysema and injury of membranes of type I pneumocytes developed and hypertrophy and loss of microvilli in type II pneumocytes were detectable. These results showed that although dithiocarbamates as chelating agents are suitable for the removal of cadmium from organisms, they alter the redistribution of cadmium within the organism, thereby increasing the cadmium content in the lungs, and structural changes are more serious than observed upon cadmium exposure alone.     

Effect of acute alcohol intake on certain cardiovascular functions in healthy young males

.15, 0.25 and 0.5 g/kg alcohol in the form of 40% brandy in one week intervals was consumed by eight healthy, regularly trained young men volunteers. Blood alcohol level, blood pressure and ECG were registered before and 30, 60 and 90 min after, each alcohol consumption. The cardiac output was measured with a radiocirculographic method before and 45 min after alcohol consumption. The cardiac index, stroke volume, stroke index, and total peripheral resistance (TPR) were calculated. With increase of the alcohol dose the blood alcohol level increased, while cardiac output, cardiac index, stroke volume, stroke index, and the systolic blood pressure fell. The other parameters examined--heart rate, diastolic blood pressure, TPR among others--remained unchanged. The ECG was normal. The highest no effect alcohol dose was less than 0.15 g/kg (0.1, k/kg). It is concluded that, depending on the dose, alcohol has practically no effect on the majority of the heart-functions, however, in the range of 0.1 to 0.5 g/kg it has a depressive influence, i.e. lowers the pump-function of the heart and, at 0.5 g/kg the arterial blood pressure.     

Post-partum prolongation of the atrial repolarization in rabbit.

Female sexual steroids are known to modify the expression of various K+ channels and thus they can alter cardiac repolarization. In the present work, using conventional microelectrode techniques, action potential characteristics were studied in atrial myocardium isolated from virgin, late pregnant, early (1-3 days) post-partum and late (2-3 weeks) post-partum rabbits. No changes in action potential configuration were observed during pregnancy. However, the duration, overshoot and amplitude of action potentials were significantly increased in the early (1-3 days) post-partum period. Resting potential and maximum rate of depolarization remained unchanged. The observed changes were transient, normal action potential characteristics were obtained at weeks 2-3 post-partum. 4-aminopyridine (1 mmol L(-1)). caused a marked lengthening of action potential duration in all preparations obtained from non-pregnant and pregnant rabbits, whereas this 4-aminopyridine-induced prolongation was moderate in those preparations excised from the hearts of early post-partum animals. Action potential configuration was not affected by pinacidil (10 micromol L(-1)) or glibenclamide (5 micromol L(-1)) in non-pregnant or pregnant animals. In preparations obtained from early post-partum rabbits, pinacidil significantly shortened action potential duration, which was reverted by glibenclamide. The lengthening of action potential duration together with the decreased sensitivity to 4-aminopyridine observed in early post-partum animals may probably be caused by reduction of the transient outward K+ current at this stage. The results also suggest that electrophysiological alterations in the early post-partum period may probably be more pronounced than those associated with pregnancy itself.     

Endothelial dysfunction is a potential contributor to multiple organ failure and mortality in aged mice subjected to septic shock: preclinical studies in a murine model of cecal ligation and puncture

Introduction

The goal of the current study was to investigate the effect of aging on the development of endothelial dysfunction in a murine model of sepsis, and to compare it with the effect of genetic deficiency of the endothelial isoform of nitric oxide synthase (eNOS).

Methods

Cecal ligation and puncture (CLP) was used to induce sepsis in mice. Survival rates were monitored and plasma indices of organ function were measured. Ex vivo studies included the measurement of vascular function in thoracic aortic rings, assessment of oxidative stress/cellular injury in various organs and the measurement of mitochondrial function in isolated liver mitochondria.

Results

eNOS deficiency and aging both exacerbated the mortality of sepsis. Both eNOS-deficient and aged mice exhibited a higher degree of sepsis-associated multiple organ dysfunction syndrome (MODS), infiltration of tissues with mononuclear cells and oxidative stress. A high degree of sepsis-induced vascular oxidative damage and endothelial dysfunction (evidenced by functional assays and multiple plasma markers of endothelial dysfunction) was detected in aortae isolated from both eNOS^−/− and aged mice. There was a significant worsening of sepsis-induced mitochondrial dysfunction, both in eNOS-deficient mice and in aged mice. Comparison of the surviving and non-surviving groups of animals indicated that the severity of endothelial dysfunction may be a predictor of mortality of mice subjected to CLP-induced sepsis.

Conclusions

Based on the studies in eNOS mice, we conclude that the lack of endothelial nitric oxide production, on its own, may be sufficient to markedly exacerbate the severity of septic shock. Aging markedly worsens the degree of endothelial dysfunction in sepsis, yielding a significant worsening of the overall outcome. Thus, endothelial dysfunction may constitute an early predictor and independent contributor to sepsis-associated MODS and mortality in aged mice.