Novel PDE4 inhibitors derived from Chinese medicine Forsythia

Cyclic adenosine monophosphate (cAMP) is a crucial intracellular second messenger molecule that converts extracellular molecules to intracellular signal transduction pathways generating cell- and stimulus-specific effects. Importantly, specific phosphodiesterase (PDE) subtypes control the amplitude and duration of cAMP-induced physiological processes and are therefore a prominent pharmacological target currently used in a variety of fields. Here we tested the extracts from traditional Chinese medicine, Forsythia suspense seeds, which have been used for more than 2000 years to relieve respiratory symptoms. Using structural-functional analysis we found its major lignin, Forsynthin, acted as an immunosuppressant by inhibiting PDE4 in inflammatory and immune cell. Moreover, several novel, selective small molecule derivatives of Forsythin were tested in vitro and in murine models of viral and bacterial pneumonia, sepsis and cytokine-driven systemic inflammation. Thus, pharmacological targeting of PDE4 may be a promising strategy for immune-related disorders characterized by amplified host inflammatory response

Use of a total traffic count metric to investigate the impact of roadways on asthma severity: a case-control study

<p>Abstract</p> <p>Background</p> <p>This study had two principal objectives: (i) to investigate the relationship between asthma severity and proximity to major roadways in Perth, Western Australia; (ii) to demonstrate a more accurate method of exposure assessment for traffic pollutants using an innovative GIS-based measure that fully integrates all traffic densities around subject residences.</p> <p>Methods</p> <p>We conducted a spatial case-control study, in which 'cases' were defined as individuals aged under 19 years of age with more severe asthma (defined here as two or more emergency department contacts with asthma in a defined 5-year period) versus age- and gender-matched 'controls' with less severe asthma (defined here as one emergency department contact for asthma). Traffic exposures were measured using a GIS-based approach to determine the lengths of the roads falling within a buffer area, and then multiplying them by their respective traffic counts.</p> <p>Results</p> <p>We examined the spatial relationship between emergency department contacts for asthma at three different buffer sizes: 50 metres, 100 metres and 150 metres. No effect was noted for the 50 metre buffer (OR = 1.07; 95% CI: 0.91-1.26), but elevated odds ratios were observed with for crude (unadjusted) estimates OR = 1.21 (95% CI: 1.00-1.46) for 100 metre buffers and OR = 1.25 (95% CI: 1.02-1.54) for 150 metre buffers. For adjusted risk estimates, only the 150 metre buffer yielded a statistically significant finding (OR = 1.24; 95% CI:1.00-1.52).</p> <p>Conclusions</p> <p>Our study revealed a significant 24% increase in the risk of experiencing multiple emergency department contacts for asthma for every log-unit of traffic exposure. This study provides support for the hypothesis that traffic related air pollution increases the frequency of health service contacts for asthma. This study used advanced GIS techniques to establish traffic-weighted buffer zones around the geocoded residential location of subjects to provide an accurate assessment of exposure to traffic emissions, thereby providing a quantification of the ranges over which pollutants may exert a health effect.</p

Differential Muc2 and Muc5ac secretion by stimulated guinea pig tracheal epithelial cells in vitro

BACKGROUND: Mucus overproduction is a characteristic of inflammatory pulmonary diseases including asthma, chronic bronchitis, and cystic fibrosis. Expression of two mucin genes, MUC2 and MUC5AC, and their protein products (mucins), is modulated in certain disease states. Understanding the signaling mechanisms that regulate the production and secretion of these major mucus components may contribute significantly to development of effective therapies to modify their expression in inflamed airways. METHODS: To study the differential expression of Muc2 and Muc5ac, a novel monoclonal antibody recognizing guinea pig Muc2 and a commercially-available antibody against human MUC5AC were optimized for recognition of specific guinea pig mucins by enzyme-linked immunosorbent assay (ELISA), Western blot, and immunohistochemistry (IHC). These antibodies were then used to analyze expression of Muc2 and another mucin subtype (likely Muc5ac) in guinea pig tracheal epithelial (GPTE) cells stimulated with a mixture of pro-inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interferon- γ (IFN-γ)]. RESULTS: The anti-Muc2 (C4) and anti-MUC5AC (45M1) monoclonal antibodies specifically recognized proteins located in Muc2-dominant small intestinal and Muc5ac-dominant stomach mucosae, respectively, in both Western and ELISA experimental protocols. IHC protocols confirmed that C4 recognizes murine small intestine mucosal proteins while 45M1 does not react. C4 and 45M1 also stained specific epithelial cells in guinea pig lung sections. In the resting state, Muc2 was recognized as a highly expressed intracellular mucin in GPTE cells in vitro. Following cytokine exposure, secretion of Muc2, but not the mucin recognized by the 45M1 antibody (likely Muc5ac), was increased from the GPTE cells, with a concomitant increase in intracellular expression of both mucins. CONCLUSION: Given the tissue specificity in IHC and the differential hybridization to high molecular weight proteins by Western blot, we conclude that the antibodies used in this study can recognize specific mucin subtypes in guinea pig airway epithelium and in proteins from GPTE cells. In addition, Muc2 is highly expressed constitutively, modulated by inflammation, and secreted differentially (as compared to Muc5ac) in GPTE cells. This finding contrasts with expression patterns in the airway epithelium of a variety of mammalian species in which only Muc5ac predominates

Assessing the distribution of volatile organic compounds using land use regression in Sarnia, "Chemical Valley", Ontario, Canada

<p>Abstract</p> <p>Background</p> <p>Land use regression (LUR) modelling is proposed as a promising approach to meet some of the challenges of assessing the intra-urban spatial variability of ambient air pollutants in urban and industrial settings. However, most of the LUR models to date have focused on nitrogen oxides and particulate matter. This study aimed at developing LUR models to predict BTEX (benzene, toluene, ethylbenzene, m/p-xylene and o-xylene) concentrations in Sarnia, 'Chemical Valley', Ontario, and model the intra-urban variability of BTEX compounds in the city for a community health study.</p> <p>Method</p> <p>Using Organic Vapour Monitors, pollutants were monitored at 39 locations across the city of Sarnia for 2 weeks in October 2005. LUR models were developed to generate predictor variables that best estimate BTEX concentrations.</p> <p>Results</p> <p>Industrial area, dwelling counts, and highways adequately explained most of the variability of BTEX concentrations (<it>R</it>²: 0.78 – 0.81). Correlations between measured BTEX compounds were high (> 0.75). Although most of the predictor variables (e.g. land use) were similar in all the models, their individual contributions to the models were different.</p> <p>Conclusion</p> <p>Yielding potentially different health effects than nitrogen oxides and particulate matter, modelling other air pollutants is essential for a better understanding of the link between air pollution and health. The LUR models developed in these analyses will be used for estimating outdoor exposure to BTEX for a larger community health study aimed at examining the determinants of health in Sarnia.</p

Transgenic overexpression of β2-adrenergic receptors in airway epithelial cells decreases bronchoconstriction

Airway epithelial cells express β2-adrenergic receptors (β2-ARs), but their role in regulating airway responsiveness is unclear. With the Clara cell secretory protein (CCSP) promoter, we targeted expression of β2-ARs to airway epithelium of transgenic (CCSP-β2-AR) mice, thereby mimicking agonist activation of receptors only in these cells. In situ hybridization confirmed that transgene expression was confined to airway epithelium, and autoradiography showed that β2-AR density in CCSP-β2-AR mice was approximately twofold that of nontransgenic (NTG) mice. Airway responsiveness measured by whole body plethysmography showed that the methacholine dose required to increase enhanced pause to 200% of baseline (ED200) was greater for CCSP-β2-AR than for NTG mice (345 ± 34 vs. 157 ± 14 mg/ml; P < 0.01). CCSP-β2-AR mice were also less responsive to ozone (0.75 ppm for 4 h) because enhanced pause in NTG mice acutely increased to 77% over baseline (P < 0.05) but remained unchanged in the CCSP-β2-AR mice. Although both groups were hyperreactive to methacholine 6 h after ozone exposure, the ED200 for ozone-exposed CCSP-β2-AR mice was equivalent to that for unexposed NTG mice. These findings show that epithelial cell β2-ARs regulate airway responsiveness in vivo and that the bronchodilating effect of β-agonists results from activation of receptors on both epithelial and smooth muscle cells.link_to_subscribed_fulltex