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Background: Asthma and especially severe asthma affect women more frequently than men. Since asthma severity correlates with remodeling changes in the lung, a female propensity to remodeling could be expected. We studied whether our previous observation that female mice have more pronounced airway inflammation than males is associated with more pronounced remodeling in two models of chronic allergic asthma. Methods: Male and female BALB/c mice were (1) sensitized and subsequently challenged with ovalbumin (OVA) for 4 weeks, or (2) exposed to house dust mite (HDM) for 5 weeks. In both models, allergic inflammation, remodeling, antigen-specific IgE and methacholine (MCh) responsiveness were assessed. Results: Females had higher antigen-specific serum IgE levels, higher numbers of eosinophils and were more responsive to MCh. In the OVA model, females also had higher levels of Th2 cytokines in lung tissue than males. Both sexes developed similar airway remodeling (smooth muscle layer thickness, collagen III deposition and goblet cell hyperplasia) in the two models. Conclusions: Combining results of an OVA- and a HDM-induced mouse model of allergic airway inflammation, we have shown that more severe allergic inflammation in females is not accompanied with more pronounced airway remodeling. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

SUMMARY To examine the influence of genetics on the OVA-induced allergic inflammatory response in lungs we compared rats that are genetically Th2-predisposed (Brown Norway, inbred) or not genetically predisposed (Sprague Dawley, outbred). Rats were sensitized with ovalbumin (OVA) and challenged four weeks later with OVA aerosol. Eighteen hours after challenge, lung tissue was studied for evaluation of numbers of eosinophils, neutrophils, macrophages and mast cells, as well as for expression of P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells. From a separate portion of the pulmonary tissue, leucocytes were isolated to analyse numbers of IFNγ and IL-4 producing cells (ELISPOT assay) and frequencies of T-cell subsets and B cells. We found increased numbers of eosinophils and neutrophils in the lung, an increased number of IL-4 producing cells in lung cell isolates and increased levels of serum (OVA- specific)-IgE in both rat strains. In addition, expression of E-selectin and ICAM-1 was up regulated in both rat strains whereas expression of VCAM-1 was only up regulated in the BN rat. Although the ‘allergic’ Th2 response to OVA was detectable in both rat strains, it was more pronounced in the BN rat than in the SD rat. However, the SD rat, which is not predisposed to respond in either a Th2 or Th1-like way, appeared capable of mounting an allergic response to OVA. This suggests that other factors than genetic contribute to allergic disease. [ABSTRACT FROM AUTHOR]

The presence of anti-heparan sulphate (HS) reactivity in serum is closely related to the occurrence of nephritis in patients with systemic lupus erythematosus (SLE). Since patients with lupus nephritis in general also have high titres of anti-DNA antibodies, we wanted to clarify the relationship between anti-HS and anti-DNA reactivity in serum. Therefore, we studied longitudinally six patients with lupus nephritis who experienced 12 exacerbations of their disease, and five SLE patients without nephritis experiencing 10 periods of non-renal disease exacerbations. In addition, we tested single serum samples of another 24 patients obtained during a renal disease exacerbation and 22 sera of patients without nephritis. The sera of all patients were tested for anti- DNA (Farr assay) and anti-HS reactivity (ELISA). We confirmed that SLE patients during renal exacerbations have a significantly higher anti-HS reactivity than patients without nephritis (P < 0.003), In addition, patients with nephritis also had higher titres of anti-DNA antibodies during renal exacerbations than during non-renal exacerbations (P < 0.01). A correlation between anti- DNA and anti-HS reactivity was observed (r = 0.40, P < 0.02), which in itself explains the correlation between nephritis and anti-HS reactivity. Comparing sera from nephritis and nonnephritis patients matched for anti-DNA titre, we found no difference in anti-HS reactivity, and therefore must conclude that the anti-HS reactivity is a direct reflection of anti-DNA reactivity. [ABSTRACT FROM AUTHOR]

The article reports on the findings of a study conducted by pharmacologist Robert Henning and colleagues of the University of Groningen in Netherlands which examines how hibernating Syrian hamster lungs respond to low body temperatures. The study demonstrates that hibernating animals repeatedly allow their bodies to cool to temperatures above ambient, before rewarming and then recooling. It indicates that the hibernating hamsters had modified their lung structure in response to low temperatures.

A letter to the editor is presented in response to the article "Efficacy and Tolerability of MK-0974 (Telcagepant), a New Oral Antagonist of Calcitonin Gene-Related Peptide Receptor, Compared With Zolmitriptan for Acute Migraine: A Randomised, Placebo-Controlled, Parallel-treatment Trial," by T.W. Ho, M.D. Ferrari, D.W. Dodick, et al, published in the December 20, 2008 issue.

The relationship between autoantibody reactivities and nephritis in systemic lupus erythematosus (SLE) is unclear. We studied MRL/l mice which developed a considerable albuminuria (either mice with short (< 1 week) or heavy and prolonged (3 weeks) albuminuria) and compared them with non-albuminuric age-matched controls, with young (12 weeks old) non-albuminuric mice and with mice which were followed for 36 weeks and did not develop albuminuria. In a longitudinal prospective study on plasma samples we correlated a variety of anti-nuclear reactivities and reactivities against extracellular matrix (ECM) components, with the onset of albuminuria. We found that at the onset of albuminuria, anti-DNA was higher while anti-nucleosome and anti-H2A/H2B-DNA subnucleosome reactivities were lower compared with age-matched non-albuminuric mice. We also studied glomerular eluates of these mice in ELISA and in indirect immunofluorescence (IF). In the eluates we found with IF that anti-glomerular basement membrane (GBM)-tubular basement membrane (TBM) antibodies were already present in 12-week-old non-albuminuric mice. These eluates showed no anti-nuclear antibodies. In eluates of albuminuric mice more immunoglobulin was deposited, and anti-ECM, anti-DNA and anti-nucleosome reactivities were higher than in eluates of age-matched non-albuminuric mice. The deposition of anti-nucleosome antibodies preceded the deposition of anti-DNA antibodies since they were deposited to a greater extent in mice with a short albuminuria. We conclude that anti-GBM-TBM antibodies are the first autoantibodies that deposit in glomeruli of MRL/l mice at an early age. The onset of albuminuria is associated with additional deposition of both anti-ECM and anti-nuclear (anti-nucleosome and anti-DNA) antibodies, but the difference with non-albuminuric mice seems to be more quantitative than qualitative. [ABSTRACT FROM AUTHOR]

Chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are associated with changes in extracellular matrix (ECM) composition and abundance affecting the mechanical properties of the lung. This study aimed to generate ECM hydrogels from control, severe COPD [Global Initiative for Chronic Obstructive Lung Disease (GOLD) IV], and fibrotic human lung tissue and evaluate whether their stiffness and viscoelastic properties were reflective of native tissue. For hydrogel generation, control, COPD GOLD IV, and fibrotic human lung tissues were decellularized, lyophilized, ground into powder, porcine pepsin solubilized, buffered with PBS, and gelled at 37°C. Rheological properties from tissues and hydrogels were assessed with a low-load compression tester measuring the stiffness and viscoelastic properties in terms of a generalized Maxwell model representing phases of viscoelastic relaxation. The ECM hydrogels had a greater stress relaxation than tissues. ECM hydrogels required three Maxwell elements with slightly faster relaxation times (τ) than that of native tissue, which required four elements. The relative importance (Ri) of the first Maxwell element contributed the most in ECM hydrogels, whereas for tissue the contribution was spread over all four elements. IPF tissue had a longer-lasting fourth element with a higher Ri than the other tissues, and IPF ECM hydrogels did require a fourth Maxwell element, in contrast to all other ECM hydrogels. This study shows that hydrogels composed of native human lung ECM can be generated. Stiffness of ECM hydrogels resembled that of whole tissue, while viscoelasticity differed. [ABSTRACT FROM AUTHOR]

Background: Goblet cell metaplasia, a common feature of chronic obstructive pulmonary disease (COPD), is associated with mucus hypersecretion which contributes to the morbidity and mortality among patients. Transcription factors SAM-pointed domain-containing Ets-like factor (SPDEF) and forkhead box protein A2 (FOXA2) regulate goblet cell differentiation. This study aimed to (1) investigate DNA methylation and expression of SPDEF and FOXA2 during goblet cell differentiation and (2) compare this in airway epithelial cells from patients with COPD and controls during mucociliary differentiation. Methods: To assess DNA methylation and expression of SPDEF and FOXA2 during goblet cell differentiation, primary airway epithelial cells, isolated from trachea (non-COPD controls) and bronchial tissue (patients with COPD), were differentiated by culture at the air-liquid interface (ALI) in the presence of cytokine interleukin (IL)-13 to promote goblet cell differentiation. Results: We found that SPDEF expression was induced during goblet cell differentiation, while FOXA2 expression was decreased. Importantly, CpG number 8 in the SPDEF promoter was hypermethylated upon differentiation, whereas DNA methylation of FOXA2 promoter was not changed. In the absence of IL-13, COPD-derived ALI-cultured cells displayed higher SPDEF expression than control-derived ALI cultures, whereas no difference was found for FOXA2 expression. This was accompanied with hypomethylation of CpG number 6 in the SPDEF promoter and also hypomethylation of CpG numbers 10 and 11 in the FOXA2 promoter. Conclusions: These findings suggest that aberrant DNA methylation of SPDEF and FOXA2 is one of the factors underlying mucus hypersecretion in COPD, opening new avenues for epigenetic-based inhibition of mucus hypersecretion. [ABSTRACT FROM AUTHOR]

Prenatal smoke exposure is a risk factor for abnormal lung development and increased sex-dependent susceptibility for asthma and chronic obstructive pulmonary disease (COPD). Birth cohort studies show genome-wide DNA methylation changes in children from smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. The insulin-like growth factor (IGF) system plays an important role in lung development. We hypothesized that prenatal exposure to smoke induces lasting changes in promoter methylation patterns of Igf1 and Igf1r, thus influencing transcriptional activity and contributing to abnormal lung development. We measured and compared mRNA levels along with promoter methylation of Igf1 and Igf1r and their protein concentrations in lung tissue of 30-day-old mice that had been prenatally exposed to cigarette smoke (PSE) or filtered air (control). Body weight at 30 days after birth was measured as global indicator of normal development. Female PSE mice showed lower mRNA levels of Igf1 and its receptor (Igf1: P 0.05; Igf1r: P 0.03). Furthermore, CpG-site-specific methylation changes were detected in Igf1r in a sex-dependent manner and the body weight of female offspring was reduced after prenatal exposure to smoke, while protein concentrations were unaffected. Prenatal exposure to smoke induces a CpG-site-specific loss of Igf1r promoter methylation, which can be associated with body weight. These findings highlight the sex-dependent and potentially detrimental effects of in utero smoke exposure on DNA methylation and Igf1 and Igf1r mRNA levels. The observations support a role for Igf1 and Igf1r in abnormal development. [ABSTRACT FROM AUTHOR]

Exposure to cigarette smoke (CS) is the main risk factor for developing chronic obstructive pulmonary disease and can induce airway epithelial cell damage, innate immune responses, and airway inflammation. We hypothesized that cell survival factors might decrease the sensitivity of airway epithelial cells to CS-induced damage, thereby protecting the airways against inflammation upon CS exposure. Here, we tested whether Pim survival kinases could protect from CS-induced inflammation. We determined expression of Pim kinases in lung tissue, airway inflammation, and levels of keratinocyte-derived cytokine (KC) and several damage-associated molecular patterns in bronchoalveolar lavage in mice exposed to CS or air. Human bronchial epithelial BEAS-2B cells were treated with CS extract (CSE) in the presence or absence of Pim1 inhibitor and assessed for loss of mitochondrial membrane potential, induction of cell death, and release of heat shock protein 70 (HSP70). We observed increased expression of Pim1, but not of Pim2 and Pim3, in lung tissue after exposure to CS. Pim1- deficient mice displayed a strongly enhanced neutrophilic airway inflammation upon CS exposure compared with wild-type controls. Inhibition of Pim1 activity in BEAS-2B cells increased the loss of mitochondrial membrane potential and reduced cell viability upon CSE treatment, whereas release of HSP70 was enhanced. Interestingly, we observed release of S100A8 but not of double-strand DNA or HSP70 in Pim1-deficient mice compared with wild-type controls upon CS exposure. In conclusion, we show that expression of Pim1 protects against CS-induced cell death in vitro and neutrophilic airway inflammation in vivo. Our data suggest that the underlying mechanism involves CS-induced release of S100A8 and KC. [ABSTRACT FROM AUTHOR]

Rationale: A low prevalence of asthma and atopy has been shown in farmers and agricultural workers. However, in these workers, a higher prevalence of respiratory symptoms has been reported, in which T helper 1 (Th1) and/or Th17 responses may play a role. Aim: We investigated the effect of exposure to dust extracts (DEs) from different farms on airway inflammation and T-cell polarisation in a mouse model and assessed T-cell polarisation in agricultural workers from the same farms. Methods: DEs were prepared from settled dust collected at cattle and pig farms and bulb and onion industries. Mice were exposed to phosphate-buffered saline (PBS), DEs, house dust mite (HDM) or HDM+DE via nasal instillation, four times per week during 5 weeks. Hyperresponsiveness, airway inflammation, IgE levels and T-cell polarisation were assessed. Th-cell and T cytotoxic (Tc)-cell subsets were investigated in peripheral blood samples from 33 agricultural workers and 9 non-exposed controls. Results: DEs induced interleukin(IL)-17, IL-1ß and IL-6 in mouse lung homogenates. DE-exposed mice had more mixed inflammatory infiltrates in the lungs, and more neutrophils compared with PBS-exposed mice. DEs protected against the HDM-induced Th2 response and methacholine hyperresponsiveness. Interestingly, occupationally exposed humans had higher frequencies of Th cells spontaneously expressing IL-17 and interferon γ compared with controls. Conclusion: Chronic exposure to different types of farm dust induces a Th/Tc-17 inflammatory response in mice and agricultural workers. This may contribute to the low prevalence of Th2-related diseases but may constitute a risk for other chronic respiratory diseases. [ABSTRACT FROM AUTHOR]

Background: Adenosine is a signalling nucleoside that has been proposed to contribute to the pathogenesis of asthma. Adenosine is produced in inflammatory environments and acts via adenosine receptors (A1R, A2AR, A2BR, and A3R) expressed by a wide variety of cells, resulting in pro- and anti-inflammatory effects. Objective: To compare AR expression in asthma patients and healthy subjects, and to assess the effect of allergen challenge on AR expression of inflammatory cells and on cytokines in peripheral blood and sputum in asthma. Methods: Asthma patients underwent an allergen challenge, and blood and induced sputum samples were taken before and 24 h after allergen challenge to study inflammatory cells numbers, AR expression and cytokine production. Blood and sputum were investigated at one time point in healthy subjects. AR expression was measured by flow cytometry (blood) or on cytospins using immunocytochemistry (sputum). Cytokines (luminex, ELISA) and adenosine (HPLC) were measured in sputum supernatant. Results: The percentage of A2BR expressing neutrophils in sputum was lower in asthma patients than in healthy subjects ( P = 0.016). Allergen challenge decreased A1R and A2AR expression on neutrophils and A1R expression on T cells in peripheral blood (all P < 0.05). Allergen challenge increased IL-8 levels and eosinophil numbers ( P < 0.05), whereas it decreased thymic stromal lymphopoietin levels and the percentage of A1R expressing macrophages in induced sputum ( P < 0.05). Conclusions: Allergen challenge has a down-regulatory effect on AR expression in asthma, suggesting a contribution of adenosine-related effector mechanisms in the pathophysiology. [ABSTRACT FROM AUTHOR]

Background The effects of smoking on asthma pathogenesis are complex and not well studied. We have shown recently that 3 weeks of smoking attenuates ovalbumin (OVA)-induced airway inflammation in mice and that 4–6 months of smoking induces emphysema in mice without airway inflammation. Effects of combined long-term smoking and OVA exposure have not been investigated so far. Objective To study whether long-term smoking affects progression of allergic airway inflammation and/or enhances the development of emphysema in mice. Methods Mice were sensitized to OVA and challenged with saline or OVA aerosols for 6 months. From 2 months onwards, mice were also exposed to air or smoke. Lung tissue was analysed for extent of inflammation, emphysema, remodelling and for cytokine levels, and serum for OVA-specific IgE levels. Results Chronic OVA exposure of 6 months resulted in a T helper type 2 (Th2)-type inflammation with increased levels of IL-4, IL-5, IL-6 and infiltration of eosinophils, CD4+ T cells, macrophages and plasma cells. Smoking induced a Th17-type of airway inflammation, characterized by neutrophils, macrophages, B cells and increased levels of IL-17, IL-6, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor and monocyte chemoattractant protein-1. Concomittant smoking and OVA exposure resulted in inflammation similar to OVA exposure alone. OVA exposure increased IgE levels compared with saline exposure, and smoking did not further increase these levels. Conclusion We did not find evidence for increased inflammation, IgE levels or emphysema in mice with allergic airway inflammation after 4 months of smoking compared with non-smoking. However, a 4-month exposure to smoke alone did enhance neutrophilic airway inflammation characterized by high pulmonary IL-17 levels. A Th2 inflammatory environment due to OVA exposure may be one explanation as to why no further detrimental effects of smoking on allergic airway inflammation were found. [ABSTRACT FROM AUTHOR]

Background In humans the prevalence of asthma is higher among females than among males after puberty. The reason for this phenomenon is not clear. Objective We tested the hypothesis that female mice are more susceptible to the development of allergic asthma than male mice and studied allergic immune responses in the lung. Methods We compared allergic airway inflammation, i.e. methacholine (MCh) responsiveness, serum IgE, and cytokines, and the number of the different leucocytes in lungs of male and female BALB/c mice, twice-sensitized to ovalbumin (OVA) and subsequently challenged with OVA (OVA-mice) or phosphate-buffered saline (PBS-mice) aerosols on days 24–26, 30, and 31. Results OVA challenge significantly increased MCh responsiveness, numbers of eosinophils, CD4+ T cells, CD4+/CD25+ T cells, B cells, and levels of Thelper (Th)2 cytokines, total, and OVA-specific IgE. There was, however, also an effect of gender, with female mice responding to OVA challenges with higher numbers of eosinophils, CD4+ T cells, B cells, and levels of IL-4, IL-13, IFN-γ, total, and OVA-specific IgE than male mice. In contrast, female PBS-mice had significantly lower percentages of regulatory CD4+/CD25+ T cells than males (females 4.2±0.2% vs. males 5.3±0.1% of CD4+ T cells, P<0.05). Conclusion Female mice develop a more pronounced type of allergic airway inflammation than male mice after OVA challenge. The reduced percentage of regulatory T cells in the lungs of female PBS-mice may indicate that the level of these cells in the lung during the sensitization phase is important for the development and/or progression of an allergic immune response after multiple OVA challenges. [ABSTRACT FROM AUTHOR]