Daniela Mokra

Complexity and time asymmetry of heart rate variability are altered in acute mental stress.

We aimed to study the complexity and time asymmetry of short-term heart rate variability (HRV) as an index of complex neurocardiac control in response to stress using symbolic dynamics and time irreversibility methods. ECG was recorded at rest and during and after two stressors (Stroop, arithmetic test) in 70 healthy students. Symbolic dynamics parameters (NUPI, NCI, 0V%, 1V%, 2LV%, 2UV%), and time irreversibility indices (P%, G%, E) were evaluated. Additionally, HRV magnitude was quantified by linear parameters: spectral powers in low (LF) and high frequency (HF) bands. Our results showed a reduction of HRV complexity in stress (lower NUPI with both stressors, lower NCI with Stroop). Pattern classification analysis revealed significantly higher 0V% and lower 2LV% with both stressors, indicating a shift in sympathovagal balance, and significantly higher 1V% and lower 2UV% with Stroop. An unexpected result was found in time irreversibility: significantly lower G% and E with both stressors, P% index significantly declined only with arithmetic test. Linear HRV analysis confirmed vagal withdrawal (lower HF) with both stressors; LF significantly increased with Stroop and decreased with arithmetic test. Correlation analysis revealed no significant associations between symbolic dynamics and time irreversibility. Concluding, symbolic dynamics and time irreversibility could provide independent information related to alterations of neurocardiac control integrity in stress-related disease.

Biomarkers in acute lung injury.

Acute respiratory distress syndrome (ARDS) and its milder form acute lung injury (ALI) may result from various diseases and situations including sepsis, pneumonia, trauma, acute pancreatitis, aspiration of gastric contents, near-drowning etc. ALI/ARDS is characterized by diffuse alveolar injury, lung edema formation, neutrophil-derived inflammation, and surfactant dysfunction. Clinically, ALI/ARDS is manifested by decreased lung compliance, severe hypoxemia, and bilateral pulmonary infiltrates. Severity and further characteristics of ALI/ARDS may be detected by biomarkers in the plasma and bronchoalveolar lavage fluid (or tracheal aspirate) of patients. Changed concentrations of individual markers may suggest injury or activation of the specific types of lung cells-epithelial or endothelial cells, neutrophils, macrophages, etc.), and thereby help in diagnostics and in evaluation of the patients clinical status and the treatment efficacy. This chapter reviews various biomarkers of acute lung injury and evaluates their usefulness in diagnostics and prognostication of ALI/ARDS.

Vagal function indexed by respiratory sinus arrhythmia and cholinergic anti-inflammatory pathway

The autonomic nervous system, in particular vagal function, plays an important role in a wide range of somatic and mental disorders. Cardiac vagal function can be indexed by the respiratory sinus arrhythmia (RSA) - oscillations in heart rate linked to respiration mediated predominantly by fluctuations of vagus nerve efferent traffic originating in the nucleus ambiguus. Moreover, the neurocardiac vagal modulation has been shown to be related to physiological adaptability/flexibity and emotional regulation. Thus, greater vagal withdrawal during stressors and subsequent recovery should be indicative of a more flexible physiological response system. Importantly, the vagal inhibitory function plays a key role in the regulation of allostatic processes including the immune response (cholinergic anti-inflammatory pathway). Decreased cardiovagal function (lower RSA) was shown to be associated with increased proinflammatory markers and acute-phase proteins indicating increased allostatic load and poor health. Thus, the study of the vagal-immune interactions could help illuminate the pathway via which psychosocial factors may influence health and disease.

Glucocorticoids in the treatment of neonatal meconium aspiration syndrome

Meconium aspiration syndrome is a serious neonatal disease with complex pathophysiology. With respect to the contribution of meconium-induced lung edema, inflammation and vasoconstriction on the course of the disease, glucocorticoids are increasingly used in the treatment of MAS despite the fact that principal questions on the choice of GCs derivative, mode of delivery and dosing have not been answered yet. To bring a complex insight into the topic, this article reviews the pathomechanisms of MAS, mechanisms of action of GCs, as well as the advantages and disadvantages of GCs administration in experimental models and newborns with MAS.

Effects of selective inhibition of PDE4 and PDE7 on airway reactivity and cough in healthy and ovalbumin-sensitized guinea pigs.

Phosphodiesterases (PDEs) are enzymes responsible for degradation of cAMP and cGMP in cells. Thus, PDE inhibitors may have significant clinical benefit in respiratory diseases associated with inflammation. The aim of the present study was to evaluate the effects of selective PDE4 (rolipram, ROL) and PDE7 inhibitors (BRL50481, BRL) on citric acid-induced cough, in vivo and in vitro airway smooth muscle reactivity in both healthy and ovalbumin sensitized guinea pigs. The drugs tested were administered intraperitoneally to male guinea pigs once daily for 7 days - ROL 1 mg/kg, BRL 1 mg/kg, and ROL+BRL 0.5 mg/kg. Double chamber whole body plethysmography was used for the evaluation of citric acid (0.6 M)-induced cough and specific airway resistance. An organ bath method was used for the measurement of tracheal and lung tissue strip contractions evoked by cumulative doses (10(-8)-10(-3) mol/L) of acetylcholine (ACH) and histamine (HIS). In healthy guinea pigs, the only significant relaxation was observed after ROL in ACH-induced contractions in vitro and the effect on cough was negligible. In ovalbumin-sensitized animals, more pronounced in vitro relaxing effects of BRL in HIS-induced contractions and of combination (ROL+BRL) in ACH-induced contractions were observed, with similar results in vivo, and no significant change in the number of cough efforts was observed in any of the groups tested. The results suggest that PDE4 and PDE7 inhibitors have stronger anti-inflammatory effects compared with direct effects on smooth muscle and cough, with a potential benefit of their concomitant administration.

Immunological aspects of phosphodiesterase inhibition in the respiratory system

Phosphodiesterases (PDEs) are known as a super-family of 11 isoenzymes, which can exert various functions based on their organ distribution. Aside from non-selective PDE inhibitors (methylxanthines, e.g. theophylline) used many years in clinical settings, increasing attention is focused on the involvement of selective PDE inhibitors in therapy of obstructive airway diseases associated with chronic inflammation. There are mostly PDE3, PDE4, and PDE7 isoforms present in the respiratory system. This paper describes the mechanisms of action, adverse effects, and potential clinical use of both non-selective and selective PDE inhibitors. The focus of the review is on the influence of PDE inhibitors on the immune system.

How to overcome surfactant dysfunction in meconium aspiration syndrome

Surfactant dysfunction in meconium aspiration syndrome (MAS) is caused by meconium components, by plasma proteins leaking through the injured alveolocapillary membrane and by substances originated in meconium-induced inflammation. Surfactant inactivation in MAS may be diminished by several ways. Firstly, aspirated meconium should be removed from the lungs to decrease concentrations of meconium inhibitors coming into the contact with surfactant in the alveolar compartment. Once the endogenous surfactant becomes inactivated, components of surfactant should be substituted by exogenous surfactant at a sufficient dose, and surfactant administration should be repeated, if oxygenation remains compromised. To delay the inactivation by inhibitors, exogenous surfactants may be enriched with surfactant proteins, phospholipids, or other substances such as polymers. Finally, to diminish an adverse action of products of meconium-induced inflammation on both endogenous and exogenously delivered surfactant, anti-inflammatory drugs may be administered. A combined therapeutic approach may result in better outcome in patients with MAS and in lower costs of treatment.

Rapid cardiovascular effects of dexamethasone in rabbits with meconium-induced acute lung injury

Glucocorticoids may improve lung function in newborns with meconium aspiration syndrome (MAS), but information on the acute side effects of glucocorticoids in infants is limited. In this study using a rabbit model of MAS, we addressed the hypothesis that systemic administration of dexamethasone causes acute cardiovascular changes. Adult rabbits were treated with 2 intravenous doses of dexamethasone (0.5 mg/kg each) or saline at 0.5 h and 2.5 h after intratracheal instillation of human meconium or saline. Animals were oxygen-ventilated for 5 h after the first dose of treatment. Blood pressure, heart rate, and short-term heart rate variability (HRV) were analyzed during treatment, for 5 min immediately after each dose, and for the 5 h of the experiment. In the meconium-instilled animals, dexamethasone increased blood pressure, decreased heart rate, increased HRV parameters, and caused cardiac arrhythmia during and immediately after administration. In the saline-instilled animals, the effect of dexamethasone was inconsistent. In these animals, the acute effects of dexamethasone on blood pressure and cardiac rhythm were reversed after 30 min, whereas heart rate continued to decrease and HRV parameters continued to increase for 5 h after the first dose of dexamethasone. These effects were more pronounced in meconium-instilled animals. If systemic glucocorticoids are used in the treatment of MAS, cardiovascular side effects of glucocorticoids should be considered.

Effects of long-term oxygen treatment on α-ketoglutarate dehydrogenase activity and oxidative modifications in mitochondria of the guinea pig heart

ObjectiveOxygen therapy is used for the treatment of various diseases, but prolonged exposure to high concentrations of O2 is also associated with formation of free radicals and oxidative damage.MethodsIn the present study we compared α-ketoglutarate dehydrogenase (KGDH) activity and mitochondrial oxidative damage in the hearts of guinea pigs after long-term (17 and 60 h) oxygenation with 100% normobaric O2 and with partially negatively (O2 neg) or positively (O2 posit) ionized oxygen.ResultsInhalation of O2 led to significant loss in KGDH activity and thiol group content and accumulation of bityrosines. Inhalation of O2 neg was accompanied by more pronounced KGDH inhibition, possibly due to additional formation of protein-lipid conjugates. In contrast, O2 posit prevented loss in KGDH activity and diminished mitochondrial oxidative damage.ConclusionsThese findings suggest that oxygen treatment is associated with impairment of heart energy metabolism and support the view that inhalation of O2 posit optimizes the beneficial effects of oxygen therapy.

The long-term administration of Orai 1 antagonist possesses antitussive, bronchodilatory and anti-inflammatory effects in experimental asthma model.

The best-studied store-operated Ca2+ channels (SOCs), Ca2+ release activated Ca2+ (CRAC) channels, are activated by depleting endoplasmic reticulum Ca2+ pool and mediate Ca2+ influx vitally important for Ca2+ restoration and many cellular function. CRAC channels were identified on immune and airway smooth muscle (ASM) cells. Emerging evidence points to its involvement in allergic airways diseases. This article evaluated therapeutic potency of CRAC antagonist in experimental animal model of allergic asthma. Allergic asthma, induced by repetitive exposure of guinea pigs to ovalbumine, was followed by 14 days therapy by CRAC antagonist (3-fluoropyridine-4-carboxylic acid, FPCA). In vivo changes of specific airways resistance (sRaw) evaluated bronchodilatory effect of FPCA and salbutamol. The method of citric acid-induced cough reflex assessed antitussive activity of FPCA and codeine. The measurement of exhaled NO (ENO), expression of inducible NO-synthase (iNOS) by RT-PCR and immunohistochemical staining of airways tissue verified anti-inflammatory effect of FPCA. Long-term administration of FPCA resulted in significant cough suppression and bronchodilation, both comparable to the effect of control drugs. FPCA significantly decreased ENO and iNOS expression, which together with immunohistochemical analysis validated its anti-inflammatory effect. Presented data confirmed CRAC channels as a promising target for treatment of respiratory diseases associated with allergic inflammation.