Pulmonary cryptococcosis induces chitinase in the rat

<p>Abstract</p> <p>Background</p> <p>We previously demonstrated that chronic pulmonary infection with <it>Cryptococcus neoformans </it>results in enhanced allergic inflammation and airway hyperreactivity in a rat model. Because the cell wall of <it>C. neoformans </it>consists of chitin, and since acidic mammalian chitinase (AMCase) has recently been implicated as a novel mediator of asthma, we sought to determine whether such infection induces chitinase activity and expression of AMCase in the rat.</p> <p>Methods</p> <p>We utilized a previously-established model of chronic <it>C. neoformans </it>pulmonary infection in the rat to analyze the activity, expression and localization of AMCase.</p> <p>Results</p> <p>Our studies indicate that intratracheal inoculation of <it>C. neoformans </it>induces chitinase activity within the lung and bronchoalveolar lavage fluid of infected rats. Chitinase activity is also elicited by pulmonary infection with other fungi (e.g. <it>C. albicans</it>), but not by the inoculation of dead organisms. Enhanced chitinase activity reflects increased AMCase expression by airway epithelial cells and alveolar macrophages. Systemic cryptococcosis is not associated with increased pulmonary chitinase activity or AMCase expression.</p> <p>Conclusion</p> <p>Our findings indicate a possible link between respiratory fungal infections, including <it>C. neoformans</it>, and asthma through the induction of AMCase.</p

Heme oxygenase-1 prevents smoke induced B-cell infiltrates: a role for regulatory T cells?

<p>Abstract</p> <p>Background</p> <p>Smoking is the most important cause for the development of COPD. Since not all smokers develop COPD, it is obvious that other factors must be involved in disease development. We hypothesize that heme oxygenase-1 (HO-1), a protective enzyme against oxidative stress and inflammation, is insufficiently upregulated in COPD.</p> <p>The effects of HO-1 modulation on cigarette smoke induced inflammation and emphysema were tested in a smoking mouse model.</p> <p>Methods</p> <p>Mice were either exposed or sham exposed to cigarette smoke exposure for 20 weeks. Cobalt protoporphyrin or tin protoporphyrin was injected during this period to induce or inhibit HO-1 activity, respectively. Afterwards, emphysema development, levels of inflammatory cells and cytokines, and the presence of B-cell infiltrates in lung tissue were analyzed.</p> <p>Results</p> <p>Smoke exposure induced emphysema and increased the numbers of inflammatory cells and numbers of B-cell infiltrates, as well as the levels of inflammatory cytokines in lung tissue. HO-1 modulation had no effects on smoke induced emphysema development, or the increases in neutrophils and macrophages and inflammatory cytokines. Interestingly, HO-1 induction prevented the development of smoke induced B-cell infiltrates and increased the levels of CD4⁺CD25⁺T cells and Foxp3 positive cells in the lungs. Additionally, the CD4⁺CD25⁺T cells correlated positively with the number of Foxp3 positive cells in lung tissue, indicating that these cells were regulatory T cells.</p> <p>Conclusion</p> <p>These results support the concept that HO-1 expression influences regulatory T cells and indicates that this mechanism is involved in the suppression of smoke induced B-cell infiltrates. The translation of this interaction to human COPD should now be pursued.</p

Adverse Effect of Nano-Silicon Dioxide on Lung Function of Rats with or without Ovalbumin Immunization

BACKGROUND: The great advances of nanomaterials have brought out broad important applications, but their possible nanotoxicity and risks have not been fully understood. It is confirmed that exposure of environmental particulate matter (PM), especially ultrafine PM, are responsible for many lung function impairment and exacerbation of pre-existing lung diseases. However, the adverse effect of nanoparticles on allergic asthma is seldom investigated and the mechanism remains undefined. For the first time, this work investigates the relationship between allergic asthma and nanosized silicon dioxide (nano-SiO₂). METHODOLOGY/PRINCIPAL FINDINGS: Ovalbumin (OVA)-treated and saline-treated control rats were daily intratracheally administered 0.1 ml of 0, 40 and 80 µg/ml nano-SiO₂ solutions, respectively for 30 days. Increased nano-SiO₂ exposure results in adverse changes on inspiratory and expiratory resistance (Ri and Re), but shows insignificant effect on rat lung dynamic compliance (Cldyn). Lung histological observation reveals obvious airway remodeling in 80 µg/ml nano-SiO₂-introduced saline and OVA groups, but the latter is worse. Additionally, increased nano-SiO₂ exposure also leads to more severe inflammation. With increasing nano-SiO₂ exposure, IL-4 in lung homogenate increases and IFN-γ shows a reverse but insignificant change. Moreover, at a same nano-SiO₂ exposure concentration, OVA-treated rats exhibit higher (significant) IL-4 and lower (not significant) IFN-γ compared with the saline-treated rats. The percentages of eosinophil display an unexpected result, in which higher exposure results lower eosinophil percentages. CONCLUSIONS/SIGNIFICANCE: This was a preliminary study which for the first time involved the effect of nano-SiO₂ to OVA induced rat asthma model. The results suggested that intratracheal administration of nano-SiO₂ could lead to the airway hyperresponsiveness (AHR) and the airway remolding with or without OVA immunization. This occurrence may be due to the Th1/Th2 cytokine imbalance accelerated by the nano-SiO₂ through increasing the tissue IL-4 production

The role of epigenetic dysregulation in the epidemic of allergic disease

The epidemic of allergic disease in early life is one of the clearest indicators that the developing immune system is vulnerable to modern environmental changes. A range of environmental exposures epidemiologically associated with allergic disease have been shown to have effects on the foetal immune function in pregnancy, including microbial burden, dietary changes and environmental pollutants. Preliminary studies now suggest that these early effects on immune development may be mediated epigenetically through a variety of processes that collectively modify gene expression and allergic susceptibility and that these effects are potentially heritable across generations. It is also possible that rising rates of maternal allergy, a recognised direct risk factor for infant allergic disease, may be further amplifying the effects of environmental changes. Whilst effective prevention strategies are the ultimate goal in reversing the allergy epidemic, the specific environmental drivers, target genes, and intracellular pathways and mechanisms of early life immune programming are still unclear. It is hoped that identifying genes that are differentially regulated in association with subsequent allergic disease will assist in identifying causal pathways and upstream contributing environmental factors. In this way, epigenetic paradigms are likely to provide valuable insights into how the early environment can be modified to more favourably drive immune development and reverse the allergic epidemic

PATHOPHYSIOLOGY OF LUPUS NEPHRITIS:THE ROLE OF NUCLEOSOMES

Lupus nephritis is regarded as an immune complex mediated disease. Since anti-DNA antibodies are present in the circulation and in diseased glomeruli of patients with lupus nephritis, these antibodies have been assigned a pivotal role in the initiation of lupus nephritis. It remains however unclear how these antibodies become localized in the glomerulus. Contrary td the classical concept of glomerular deposition of DNA/anti-DNA complexes, it has been suggested that anti-DNA antibodies can interact with intrinsic glomerular antigens. Some anti-DNA antibodies can cross-react with heparan sulphate (HS), which is such an intrinsic constituent of the glomerular basement membrane (GBM). Serum HS reactivity coincides with the occurrence of lupus nephritis. It was found that this HS reactivity was exhibited by anti-DNA antibodies complexed to nucleosomes and not by the antibody itself. Nucleosomes are DNA/histone complexes, present in the nucleus, which are released by dying cells. The histone part of the nucleosome is responsible for the binding to the GBM. Recently, it has become clear that also anti-nucleosome antibodies can bind to HS in the GBM via nucleosomes. These nucleosome-containing immune complexes exhibit anti-DNA reactivity in ELISA and Farr assay. It is now thought that nucleosomes released by dying cells bind to anti-DNA or anti-nucleosome antibodies in the circulation, giving rise to nephritogenic immune complexes. Alternatively, nucleosomes may bind to the GBM and serve then as planted antigen for subsequent binding of antibodies via an in situ mechanism. Binding of antibodies via both mechanisms leads to complement activation and damage of the GBM. The recent finding of histones and DNA in glomerular depositions in lupus nephritis is in line with this hypothesis