Tiotropium modulates transient receptor potential V1 (TRPV1) in airway sensory nerves: A beneficial off-target effect?⋆

BackgroundRecent studies have suggested that the long-acting muscarinic receptor antagonist tiotropium, a drug widely prescribed for its bronchodilator activity in patients with chronic obstructive pulmonary disease and asthma, improves symptoms and attenuates cough in preclinical and clinical tussive agent challenge studies. The mechanism by which tiotropium modifies tussive responses is not clear, but an inhibition of vagal tone and a consequent reduction in mucus production from submucosal glands and bronchodilation have been proposed.ObjectiveThe aim of this study was to investigate whether tiotropium can directly modulate airway sensory nerve activity and thereby the cough reflex.MethodsWe used a conscious cough model in guinea pigs, isolated vagal sensory nerve and isolated airway neuron tissue– and cell-based assays, and in vivo single-fiber recording electrophysiologic techniques.ResultsInhaled tiotropium blocked cough and single C-fiber firing in the guinea pig to the transient receptor potential (TRP) V1 agonist capsaicin, a clinically relevant tussive stimulant. Tiotropium and ipratropium, a structurally similar muscarinic antagonist, inhibited capsaicin responses in isolated guinea pig vagal tissue, but glycopyrrolate and atropine did not. Tiotropium failed to modulate other TRP channel–mediated responses. Complementary data were generated in airway-specific primary ganglion neurons, demonstrating that tiotropium inhibited capsaicin-induced, but not TRPA1-induced, calcium movement and voltage changes.ConclusionFor the first time, we have shown that tiotropium inhibits neuronal TRPV1-mediated effects through a mechanism unrelated to its anticholinergic activity. We speculate that some of the clinical benefit associated with taking tiotropium (eg, in symptom control) could be explained through this proposed mechanism of action

P2X7 Receptor and Caspase 1 Activation Are Central to Airway Inflammation Observed after Exposure to Tobacco Smoke

Chronic Obstructive Pulmonary Disease (COPD) is a cigarette smoke (CS)-driven inflammatory airway disease with an increasing global prevalence. Currently there is no effective medication to stop the relentless progression of this disease. It has recently been shown that an activator of the P2X7/inflammasome pathway, ATP, and the resultant products (IL-1β/IL-18) are increased in COPD patients. The aim of this study was to determine whether activation of the P2X7/caspase 1 pathway has a functional role in CS-induced airway inflammation. Mice were exposed to CS twice a day to induce COPD-like inflammation and the role of the P2X7 receptor was investigated. We have demonstrated that CS-induced neutrophilia in a pre-clinical model is temporally associated with markers of inflammasome activation, (increased caspase 1 activity and release of IL-1β/IL-18) in the lungs. A selective P2X7 receptor antagonist and mice genetically modified so that the P2X7 receptors were non-functional attenuated caspase 1 activation, IL-1β release and airway neutrophilia. Furthermore, we demonstrated that the role of this pathway was not restricted to early stages of disease development by showing increased caspase 1 activation in lungs from a more chronic exposure to CS and from patients with COPD. This translational data suggests the P2X7/Inflammasome pathway plays an ongoing role in disease pathogenesis. These results advocate the critical role of the P2X7/caspase 1 axis in CS-induced inflammation, highlighting this as a possible therapeutic target in combating COPD

An investigating into rodent models of asthma

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Роль бухгалтерского учета в управлении предприятия

Alum-independent OVA-induced airway hyperresponsiveness to 5-HT and IgE production. Male C57Bl/6 mice were sensitised with saline or OVA in the presence or absence of Alum and subsequently challenged with saline or OVA. Animals sensitised in the absence of Alum were placed in WBP chambers and airway responsiveness to 5-HT was assessed 3 days after final challenge (C). Data (n = 7–9) was expressed as mean Penh AUC ± S.E.M. Plasma levels of total IgE (A) and OVA-specific IgE (B) were assessed by ELISA 3 days after final OVA challenge. Data (n = 7–9) expressed as mean ± S.E.M. *p < 0.05 vs. relevant OVA sensitised/saline challenged controls, Mann-Whitney U-test. (DOC 168 kb

Additional file 1: of Characterisation of a murine model of the late asthmatic response

The ARRIVE Guidelines Checklist Animal Research: Reporting In Vivo Experiments. (PDF 1068 kb

Specific learning disabilities and its treatment and intervention

The aim of my thesis is to obtain an insight into the field of specific learning disabilities. The thesis has the character of a summary and it mainly concerns the comparison of existing knowledge and approaches to children with specific learning disabilities. This thesis should be used not only for academical purposes; it also should enable the reader to underestand the term, cause, symptoms, reeducation of specific learning disabilities, which improves the understanding of the life of people with this disability