Dual role of interleukin-10 in the regulation of respiratory syncitial virus (RSV)-induced lung inflammation.

RSV lower respiratory tract infections (LRTI) are among the most common diseases necessitating hospital admission in children. In addition to causing acute respiratory failure, RSV infections are associated with sequelae such as secondary bacterial infections and reactive airway disease. One characteristic host response observed in severe RSV-induced LRTI and/or subsequent development of asthma is increased expression of interleukin (IL)-10. However, contradictory results have been reported regarding whether IL-10 inhibits asthmatic responses or intensifies the disease. We aimed to reconcile these discordant observations by elucidating the role of IL-10 in regulating the host response to RSV LRTI. In this study, we used a lung-specific, inducible IL-10 over-expression (OE) transgenic mouse model to address this question. Our results showed that the presence of IL-10 at the time of RSV infection not only attenuated acute inflammatory process (i.e. 24 h post-infection), but also late inflammatory changes [characterized by T helper type 2 (Th2) cytokine and chemokine expression]. While this result appears contradictory to some clinical observations where elevated IL-10 levels are observed in asthmatic patients, we also found that delaying IL-10 OE until the late immune response to RSV infection, additive effects rather than inhibitory effects were observed. Importantly, in non-infected, IL-10 OE mice, IL-10 OE alone induced up-regulation of Th2 cytokine (IL-13 and IL-5) and Th2-related chemokine [monocyte chemoattractant protein 1 (MCP-1), chemokine (C-C motif) ligand 3 (CCL3) and regulated upon activation normal T cell expressed and secreted (RANTES)] expression. We identified a subset of CD11b(+)CD11c(+)CD49b(+)F4/80(-)Gr-1(-) myeloid cells as a prinicipal source of IL-10-induced IL-13 production. Therefore, the augmented pathological responses observed in our 'delayed' IL-10 over-expression model could be attributed to IL-10 OE alone. Taken together, our study indicated dual roles of IL-10 on RSV-induced lung inflammation which appear to depend upon the timing of when elevated IL-10 is expressed in the lung.

Effects of physicochemical forms of phenazepam and Panavir on their action at ultra-low doses.

A concept of physicochemical forms of biologically active substances introduced in investigation of the action mechanism of ultra-low doses allows qualitative explanation of the main effects of ultra-low doses, chemical diversity of biologically active substances, and physical boundaries for these effects. Phenazepam was shown to possess activity in ultra-low doses only in disperse state, in the form of nanoparticles with a diameter <100-300 nm; these nanoparticles appear as micelles of surface active substances and solvated. Panavir possesses pharmacological activity in ultra-low doses and appears as nanoparticles with a diameter of 200-300 nm, which have uncompensated negative surface charge and polymer nature.

Simulation of melting in crystalline polyethylene.

We carry out a molecular dynamics simulation of the first stages of constrained melting in crystalline polyethylene (PE). When heated, the crystal undergoes two structural phase transitions: from the orthorhombic (O) phase to the monoclinic (M) phase, and then to the columnar (C), quasi-hexagonal, phase. The M phase represents the tendency to the parallel packing of planes of PE zigzags, and the C phase proves to be some kind of oriented melt. We follow both the transitions O→M and M→C in real time and establish that, at their beginning, the crystal tries (and fails) to pass into the partially ordered phases similar to the RI and RII phases of linear alkanes, correspondingly. We discuss the molecular mechanisms and driving forces of the observed transitions, as well as the reasons why the M and C phases in PE crystals substitute for the rotator phases in linear alkanes.

Deficiency of regulatory B cells increases allergic airway inflammation.

OBJECTIVE: To investigate the effect of the X-linked immunodeficiency (Xid) B cell defect on the response to the cockroach allergen in mice. METHODS: Two cockroach allergen immunization and challenge protocols were employed to sensitize CBA/J wild-type and CBA/CaHN-btk(-/-)xid/J (Xid) mice. Blood and tissue samples were collected 24 and 48 hrs after the last intratracheal antigen challenge and were analyzed for several parameters of allergic inflammation. RESULTS: Nearly equivalent amounts of serum IgE were detected in Xid and CBA/J mice after short-term antigen challenge despite the B cell deficiency in Xid mice. A decreased concentration of IgE was detected in CBA/J mice after repeated allergen challenges but not in the Xid mice. Correlating with the discrepancy in serum IgE levels, higher levels of IL-13, IL-5, IL-10 and CCL5 were measured in whole lung homogenates from allergen-challenged Xid mice compared to CBA/J mice. In addition, draining lymph node cells from Xid mice expressed elevated levels of IL-4, IL-5, IL-10 and IFNgamma mRNA compared to cells from CBA/J mice after in vitro culture with cockroach antigen. An increase in lung inflammation, interstitial eosinophilia and mucus production was also observed in allergen-challenged Xid mice. CD95L expression increased on B-1a cells following allergen challenge, which was accompanied by an increase in lung CD4(+) Th cell apoptosis in wild-type CBA/J mice. In contrast, Xid mice did not have an increase in CD4(+) T cell apoptosis following allergen challenge. CONCLUSIONS: These data suggest a regulatory role for B-1a cells in reducing cytokine production, pulmonary inflammation, and CD4(+) T cell survival during cockroach allergen-induced airway inflammation.

Inhibition of stem cell factor reduces pulmonary cytokine levels during allergic airway responses.

Stem cell factor (SCF) has a significant role in the inflammation and activation of allergic airway responses. When monoclonal anti-SCF was administered intratracheally during allergen challenge there was a significant alteration of eosinophil accumulation and airway hyperreactivity (AHR). Anti-SCF treatment also attenuated pulmonary cytokine and chemokine levels. In particular, there was an antibody dose-dependent decrease in interleukin (IL)-5 and tumour necrosis factor (TNF)-alpha. There was also a significant reduction of CCL2 and CCL5, which correlated with the reduction in AHR. Mice treated with anti-SCF demonstrated a significant decrease in pulmonary gob-5 gene expression, which has been shown to correlate to goblet cell hyperplasia/metaplasia relating to airway mucus production. Blocking SCF-mediated activation within the airway using a monoclonal antibody indicates that this cytokine may represent a viable target for therapeutic intervention that could affect multiple aspects of allergen-induced immunopathology.

Role of interleukin-12 and stat-4 in the regulation of airway inflammation and hyperreactivity in respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is a respiratory pathogen that can cause significant morbidity in infants and young children. Interestingly, the majority of children who acquire a RSV infection do not exhibit severe symptoms. Development of a Th1 response has been associated with resolution of symptoms in viral infections and may explain mild RSV illness. The current study investigated the cytokine response observed in mild disease in C57BL/6 mice that had low airway resistance and mucus production with little pulmonary inflammation. RSV infection in these mice was accompanied by a fourfold increase in interleukin-12(IL-12). Treatment of RSV-infected mice with anti-IL-12 resulted in an increase in airway hyperreactivity, mucus production, and airway inflammation (eosinophilia). Since IL-12 activation is dependent on Stat-4-mediated intracellular signal transduction, similar experiments were performed in Stat-4 deficient mice and demonstrated similar results to those obtained from anti-IL-12 treated mice. Again, there was an increase in airway hyperreactivity and mucus production, and goblet cell hypertrophy. These studies support the importance of IL-12 in the immune response to RSV infection resulting in resolution of disease and protection from inappropriate inflammatory responses.

[Characteristics of the functional state of the skin of humans in an enclosed environment with limited space]. / Osobennosti funktsional'nogo sostoianiia kozhnogo pokrova cheloveka v usloviiakh germetichno zamknutykh pomeshchenii malogo ob''ema.

Changes in man's skin that may influence its protective function were investigated depending on the environmental conditions. Man's exposure to a small sealed environment produced serious changes in the skin. As a result of 90-day enclosure, the desquamation rate and lipid concentration in the skin almost doubled, pH increased by unity, and its biological activity expressed by the redox potential (eH) diminished by nearly 100%. Thus the protective function of man's skin declined significantly after such exposure.

[Protective function of the skin]. / O zashchitnoi funktsii kozhnogo pokrova.

This paper reviews published data concerning the protective function of skin and discusses factors that may affect its bactericidal capability, including space flight factors that are known to reduce its protective effect. Various concepts of the mechanisms of the bactericidal function are discussed. It is shown that in an enclosed environment the species composition of the resident autoflora and pH value of the skin of an essentially healthy man may change. The qualitative composition of the water-oil film as a source of nutrition and a skin microflora environment is discussed. Its effect on the autoflora composition and localization in various skin areas and, consequently, on the bactericidal capability of different skin areas is described. The skin bactericidal function results from an interaction of various factors that should be taken into consideration when developing flight-oriented hygienic requirements because space flight induces changes in the skin status.

[Substantiation of the system of sanitary-hygienic procedures]. / Obosnovanie rezhima sanitarno-gigienicheskikh prostsedur.

Various aspects of endogenous contamination of the human skin are discussed. The contamination rate and intensity were measured by analyzing wash water obtained after sanitary-hygienic procedures (SHP) in which no detergents were used. It was found that endogenous contamination of the human skin reached its maximum 3-4 days after the previous SHP and then became stabilized. The wash water composition was shown to be independent of the skin type. The endogenous contamination level did not influence the bactericidal effect of the skin of healthy people. Due to complementary processes such as epidermis desquamation and sebum cutaneum, the role of which is different for different skin types, the amount of indigenous microorganisms is maintained at an optimal level irrespective of the skin type. It is concluded that water SHPs should be performed no more than once every four days. If they are conducted oftener than that, the normal function of the human skin may become deteriorated: epidermis desquamation increases drastically, skin state changes, and the concentration of indigenous microorganisms on the skin surface decreases as compared to the individual norm.

[Hygienic aspects of wash water reclamation systems]. / Gigienicheskie aspekty razrabotki sistem regeneratsii sanitarno-gigienicheskoi vody.

The quality of reclaimed wash water and the composition of used wash water can be best determined by pH, oxygen chemical index, electric conductivity and chlorides that show individual variations but are sex-independent. Wash water contained mostly staphylococci and small amounts of sarcines, diplococci and micrococci. The use of washing and disinfecting agents may significantly modify the microbial characteristics of wash water, reducing noticeably its microbial content and increasing the content of organic substances and chlorides due to chemicals they include and due to more effective removal of sebaceous secretion. It is indicated that chemical components of washing and disinfecting agents that produce organic contaminants should be given special attention when developing a wash water reclamation system.

[Composition of the water obtained after its sanitary and hygienic use by men and women]. / Issledovanie sostava vody, poluchennoi pri sanitarno-gigienicheskoi obrabotke muzhchin i zhenshchin.

The composition of wash water used by men and women was investigated. The results were exposed to multifactorial statistical analysis using the method of principal components. The investigation allowed the following conclusions to be made: 1) wash water used by men and women is comparable in composition; therefore the sex of the crewmembers of space vehicles can be disregarded when designing water reclamation systems; 2) three parameters, viz. oxidizability, electric conductivity and chloride content, can be adequately used to assess the quality of utilized wash water; 3) the composition of wash water is largely dependent on the health status of its users.