Anti-inflammatory and antioxidant effect of cerium dioxide nanoparticles immobilized on the surface of silica nanoparticles in rat experimental pneumonia.

A massage with the potent counter-inflammatory material, cerium dioxide nanoparticles, is promising and the antioxidant properties of CeO2 are considered the main, if not the only, mechanism of this action. Nevertheless, the elimination of ceria nano-particles from the organism is very slow and there is a strong concern for toxic effect of ceria due to its accumulation. To overcome this problem, we engineered a combined material in which cerium nanoparticles were immobilized on the surface of silica nanoparticles (CeO2 NP), which is shown to be easily removed from an organism and could be used as carriers for nano-ceria. In our study particle size was 220±5nm, Zeta-potential -4.5mV (in water), surface charge density -17.22µC/cm2 (at pH 7). Thirty-six male Wistar rats, 5 months old and 250-290g were divided into four groups: 1) control; 2) CeO2 NP treatment; 3) experimental pneumonia (i/p LPS injection, 1mg/kg); and 4) experimental pneumonia treated with CeO2 NP (4 times during the study in dosage of 0.6mg/kg with an orogastric catheter). Gas exchange and pulmonary ventilation were measured four times: 0, 1, 3 and 24h after LPS injection in both untreated and CeO2 NP-treated animals. The mRNA of TNF-α, Il-6, and CxCL2 were determined by RT-PCR. ROS-generation in blood plasma and lung tissue homogenates were measured by means of lucigenin- and luminol-enhanced chemiluminescence. Endotoxemia in the acute phase was associated with: (1) pathological changes in lung morphology; (2) increase of ROS generation; (3) enhanced expression of CxCL2; and (4) a gradual decrease of VO2 and VE. CeO2 NP treatment of intact animals did not make any changes in all studied parameters except for a significant augmentation of VO2 and VE. CeO2 NP treatment of rats with pneumonia created positive changes in diminishing lung tissue injury, decreasing ROS generation in blood and lung tissue and decreasing pro-inflammatory cytokine expression (TNF-α, Il-6 and CxCL2). Oxygen consumption in this group was increased compared to the LPS pneumonia group. In our study we have shown anti-inflammatory and antioxidant effects of CeO2 NP. In addition, this paper is the first to report that CeO2 NP stimulates oxygen consumption in both healthy rats, and rats with pneumonia. We propose the key in understanding the mechanisms behind the phenomena lies in the property of CeO2 NP to scavenge ROS and the influence of this potent antioxidant on mitochondrial function. The study of biodistribution and elimination of СеО2NP is the purpose of our ongoing study.

[Two types of gas exchange disorders in children with bronchial asthma]. / O dvukh tipakh narusheniia gazoobmena pri bronkhial'noi astme u detei.

The main parameters of gas exchange, respiration and hemodynamics have been studied in children aged 9-14 during the acute period of bronchial asthma. Two types of gas exchange disturbances (hyperreactive type characterized by O2 consumption increase, and hyporeactive one--by O2 consumption decrease) have been revealed in the beginning of the acute period. It is shown that by the end of this period the O2 consumption has normalized in children of both groups and has become the same as in in healthy ones. The main pathogenetic mechanisms of hypoxic state development in these two types of gas exchange disturbances are discussed.

[Phase changes of energy metabolism during adaptation to immobilization stress].

In stress, it was showed the organ and tissue changes associated with damage by lipid peroxides, and the disrupted barrier function. As a consequence, it was to lead to a syndrome of "stress-induced lung" and violation of oxygen delivery to the tissues and hypoxia. Purpose of the study was to investigate the dynamics of changes in gas exchange, blood glucose, body temperature, oxidant and antioxidant system activity, as well as mitochondrial respiration by Chance under the influence of chronic stress (6-hour immobilization daily for 3 weeks). It was identified 4 phase changes of energy metabolism in the dynamics of chronic stress. In the first phase, hypomethabolic, instability oxidative metabolism, decreased oxidation of NAD-dependent substrates, significant elevation of FAD-dependent substrates oxidation and low MRU were found. The activity of superoxide dismutase (MnSOD) was increased; it was occurred on a background low activity of glutathione peroxidase, and of misbalanced antioxidant system. After seven immobilizations, second phase-shift in energy metabolism, was observed, and then the third phase (hypermetabolic) started. It was characterized by gradual increase in oxidative metabolism, the restoration of oxidation of NAD-dependent substrates, MRU, as well as optimizing balance of oxidant and antioxidant systems. The fourth phase was started after 15 immobilizations, and characterized by the development of adaptive reactions expressed in increased tolerance of energy metabolism to the impact of immobilization. The results are correlated with changes in the dynamics of blood corticosterone. Thus, it was found the phase character of the energy metabolism rebuilding during the chronic stress.

[The effect of mild hypobaric hypoxia regime on expression of factor induced by hypoxia in the rat neocortex].

Using quantitative immunohistochemistry, modifications of HIF-1alpha expression in neocortex of rats exposed to various modes of mild hypobaric hypoxia (MHH) (1,3 and 6 episodes) differed in their neuroprotective efficacy have been studied. It has been shown that three-trial MHH being the most effective neuroprotective mode when used as a preconditioning produces most considerable changes in HIF-1 by substantial up-regulation of its regulatory alpha-subunit expression in the rat neocortex. Present findings support the hypothesis on important roles of HIF-1 in the mechanisms of brain hypoxic tolerance induced by the hypoxic preconditioning with three-trial MHH.

[Involvement of transcriptional factor induced by hypoxia in the neuronal mechanisms of adaptation to psychoemotional and hypoxic stress].

Using quantitative immunohistochemistry, neuronal expression of alpha-subunit of the transcriptional factor HIF-1 in hippocampus and neocortex of rats in response to pathogenic psychoemotional (model of posttraumatic stress disorder, PTSD) and hypoxic (severe hypobaric hypoxia, 180 Torr, 3 h), as well as to neuroprotective exposures to hypoxic pre- and postconditioning has been studied. Elongated overexpression of HIF-1alpha in hippocampus and neocortex of rats in response to the psychoemotional stress in PTSD paradigm, but not hypoxic stress, has been observed. Hypoxic pre- and postconditioning with mild hypobaric hypoxia (360 Torr, 2 h, 3 trials spaced at 24 h), those induced adaptation to the psychoemotional stress, abolished the elongated HIF-1alpha overexpression. Hypoxic postconditioning which improved structure and functional rehabilitation following severe hypoxic stress up-regulated HIF-1alpha expression in the brain neurons of rats survived severe hypoxia. The findings indicate that transcription factor HIF-1 is particularly involved in the processes of adaptation/ maladaptation to the action of injurious stresses, but its role depends upon the nature of stressor.

[Continuous adaptation of rats to hypobaric hypoxia prevents stressor hyperglycemia and optimizes mitochondrial respiration under acute hypoxia].

Oxygen consumption, glucose blood level and liver mitochondrial respiration were investigated in male Wistar rats permanently living in middle altitude (2100 m, Elbrus region). The animals were characterized by reduced body oxygen consumption and blood glucose level, as well as by intensified utilization of NAD-dependent substrates in mitochondrial respiratory chain with increasing indices of ADP-stimulated respiration in comparison with plains rats. As a result of adaptive rebuilding of oxidative metabolism in rats--inhabitants of midlands, the nature and severity of metabolic responses to acute hypoxia were also changed. After lifting in barochamber to a "height" of 5600 m during 3 hours, plains rats transiently demonstrated hypometabolic and hyperglycemic reactions. A rapid adaptation of mitochondrial function occurred due to increase in the rate of FAD-dependent substrate oxidation accompanied by a decrease in the effectiveness of phosphorylation. In midland rats, by contrast, hypoglycemic reaction was developed, and further reduction of aerobic metabolism was limited. Rapid adaptation of mitochondrial function to acute hypoxia in those rats was more intense than in the plains animals. This was achieved by a significant increase in the rate of NAD-dependent substrate oxidation, especially lipids, and an improved efficiency of mitochondrial respiration and an increased economy of oxygen utilization.

[Phase changes in energy metabolism during periodic hypoxia].

Male Wistar rats were exposed to periodic hypobaric hypoxia (PHH), by "lifting" in barochamber at "altitude" 5600 m for 1 h every 3 days (6 séances). The dynamics of changes in oxygen consumption (VO2), and body temperature (Tm), as well as in HIF-1alpha and HIF-3alpha gene expression, and mitochondrial respiration in the ventricles of the heart was studied. On the basis of the data we identified four phases of the physiological changes. The first phase, hypometabolic (1-3 séances), is characterized by decrease in VO2 and Tm, induction of HIF-1alpha and HIF-3alpha with delayed transient stimulation of metabolism in response to each séance of hypoxia. In heart mitochondria, V3 and V4 are increased, but V3/V4 and ADP/O are reduced. During the second phase, transitional (3-4 séances), there is reorganization of metabolism and decrease its hypoxic reactivity. The third phase, hypermetabolic (4-5 séances), is characterized by intensification of metabolism and compensation of hypoxic disorders. The fourth phase (after 5 séance) - is a state of metabolic adaptation with normalization of VO2 and Tm, expression of HIF-1alpha and HIF-3alpha, mitochondrial respiration, increased NAD-dependent oxidation of carbohydrate and lipid substrates. Thus, during PHH consequent rebuilding of processes of oxygen transport, tissue respiration and thermogenesis occurs, mediated by induction of the HIF subunits.

[Changes in the local nonspecific immune response to post-traumatic inflammation during treatment]. / Zminy mistsevoï nespetsyfichnoï rezystentnosti u posttravmatychnomu vohnyshchi v dynamitsi likuvannia.

Clinical investigation have been done in adult patients with broken mandible during 3 weeks of conservative treatment with aluminum splints (1st group, n = 17) or steel splints (2nd group, n = 16) in comparison with health adults (control group, n = 18). The neutrophil emigration into alterative locus and their degranulation as well as phagocytic activity of peripheral blood neutrophils were tested. It was found that aluminum splint application caused the intensive inflammation and then the depression of local host defense reactions. Treatment with steel splints did not lead to neutrophil function depletion or to hyper-intensification of inflammatory reaction in patients. The increased values of neutrophil reactions were normalized in this group at the final period of the treatment. The examined trial ensures our accurate method in treatment of patients with broken mandible. The determination of local host defense state may be proposed as preferable simple express-method of evaluation of immune status, treatment efficiency and prognosis in these patients.