Lipopolysaccharide exacerbates functional and inflammatory responses to ovalbumin and decreases sensitivity to inhaled fluticasone propionate in a guinea-pig model of asthma

Background and Purpose Asthma exacerbations contribute to corticosteroid insensitivity. Lipopolysaccharide (LPS) is ubiquitous in the environment. It causes bronchoconstriction and airways inflammation and may therefore exacerbate allergen responses. This study examined whether LPS and ovalbumin co-administration could exacerbate the airways inflammatory and functional responses to ovalbumin in conscious guinea-pigs and whether these exacerbated responses were insensitive to inhaled corticosteroid treatment with fluticasone propionate. Experimental Approach Guinea-pigs were sensitized and challenged with ovalbumin and airways function recorded as specific airways conductance (sGaw) by whole body plethysmography. Airways inflammation was measured from lung histology and bronchoalveolar lavage. Airways hyperreactivity (AHR) to inhaled histamine was examined 24h after ovalbumin. LPS was inhaled alone or 24 or 48 hours before ovalbumin and combined with ovalbumin. Fluticasone propionate (0.05, 0.1, 0.5 or 1mg/ml) or vehicle (ethanol:DMSO:saline 30:30:40) was nebulised for 15 minutes twice daily for 6 days before ovalbumin or LPS exposure. Key Results Ovalbumin inhalation caused early (EAR) and late asthmatic responses (LAR), airways hypereactivity to histamine and influx of inflammatory cells into the lungs. LPS 48 hours before and co-administered with ovalbumin exacerbated the response with increased length of the EAR, prolonged response to histamine and elevated inflammatory cells. FP 0.5 and 1mg/ml reduced the LAR, AHR and cell influx with ovalbumin alone, but was ineffective when guinea-pigs were exposed to LPS before and with ovalbumin. Conclusions and Implications LPS exposure exacerbates airways inflammatory and functional responses to allergen inhalation and decreases corticosteroid sensitivity. Its widespread presence in the environment could contribute to asthma exacerbations and corticosteroid insensitivity in humans

Hope in dirt: report of the Fort Apache Workshop on Forensic Sedimentology Applications to Cultural Property Crime, 15—19 October 2018

A 2018 workshop on the White Mountain Apache Tribe lands in Arizona examined ways to enhance investigations into cultural property crime (CPC) through applications of rapidly evolving methods from archaeological science. CPC (also looting, graverobbing) refers to unauthorized damage, removal, or trafficking in materials possessing blends of communal, aesthetic, and scientific values. The Fort Apache workshop integrated four generally partitioned domains of CPC expertise: (1) theories of perpetrators’ motivations and methods; (2) recommended practice in sustaining public and community opposition to CPC; (3) tactics and strategies for documenting, investigating, and prosecuting CPC; and (4) forensic sedimentology—uses of biophysical sciences to link sediments from implicated persons and objects to crime scenes. Forensic sedimentology served as the touchstone for dialogues among experts in criminology, archaeological sciences, law enforcement, and heritage stewardship. Field visits to CPC crime scenes and workshop deliberations identified pathways toward integrating CPC theory and practice with forensic sedimentology’s potent battery of analytic methods

The duration of action of non-β(2)-adrenoceptor mediated responses to salmeterol

1. To investigate further the mechanism of the long duration of action of the selective β(2)-adrenoceptor agonist, salmeterol, we have determined the duration of action of some responses to salmeterol which are not mediated throughβ(2)-adrenoceptors. 2. In the presence of propranolol (1 μM), salmeterol (1–30 μM) caused concentration-related relaxation of superfused, pre-contracted strips of guinea-pig gastric fundus. On washing the tissues, these relaxant responses were rapidly lost, the time to 50% recovery being approximately 30 min. 3. In human neutrophils, salmeterol (1–100 μM) caused concentration-related inhibition of FMLP-induced O(2)(−) release. Propranolol (1 μM) had little or no effect on the inhibitory activity of salmeterol. Washing the cells twice over a 40 min period caused a marked reduction of the inhibitory activity of salmeterol. 4. In guinea-pig superfused trachea, in the absence of propranolol, infusions of (RS)-salmeterol (10–30 nM) and the less potent (S)-enantiomer of salmeterol (300–3000 nM) inhibited electrically-induced contractile responses. When the infusion was stopped, there was no recovery from the inhibitory responses within 200 min. In the presence of propranolol (1 μM), infusions of (RS)-salmeterol (10 μM) and (S)-salmeterol (10–100 μM) also inhibited the contractile responses, but, in contrast, on stopping the infusions differences were observed in recovery times. Thus no appreciable recovery was observed from the responses to (RS)-salmeterol, whereas a rapid loss of inhibition was observed on stopping the infusion of (S)-salmeterol, the time to 50% recovery being 30–35 min. 5. These relatively short-lasting effects of salmeterol which are not mediated through β(2)-adrenoceptors, contrast with the persistence of the responses which are mediated through β(2)-adrenoceptors seen in a variety of tissues, but are similar to the rate of dissociation of salmeterol observed from artificial membranes. These observations suggest that the sustained agonist activity of salmeterol is peculiar to responses mediated by β(2)-adrenoceptors

Picumeterol: dissociation of improvement in lung function and reduction of airways hyperresponsiveness in asthmatics

Aims The new potent and selective β2-adrenoceptor agonist, GR 114297A (picumeterol) is the R-enantiomer of the racemic form, GR 63411B. Picumeterol has been shown to produce long-lasting relaxation of airways smooth muscle both in vitro and in vivo. We assessed the intrinsic activity of picumeterol by increasing intracellular levels of c-AMP and compared this with isoprenaline and salbutamol