Airway sensory C-fibres express TRPA1 channels which have recently been identified as a key chemosensory receptor for acrolein, a toxic and highly prevalent component of smoke. TRPA1 likely plays an intermediary role in eliciting a range of effects induced by acrolein including cough and neurogenic inflammation. Currently, it is not known whether acrolein-induced activation of TRPA1 produces other airway effects including relaxation of mouse airway smooth muscle. The aims of this study were to examine the effects of acrolein on airway smooth muscle tone in mouse isolated trachea, and to characterise the cellular and molecular mechanisms underpinning the effects of acrolein. Isometric tension recording studies were conducted on mouse isolated tracheal segments to characterise acrolein-induced relaxation responses. Release of the relaxant PGE₂ was measured by EIA to examine its role in the response. Use of selective antagonists/inhibitors permitted pharmacological characterisation of the molecular and cellular mechanisms underlying this relaxation response. Acrolein induced dose-dependent relaxation responses in mouse isolated tracheal segments. Importantly, these relaxation responses were significantly inhibited by the TRPA1 antagonists AP-18 and HC-030031, an NK₁ receptor antagonist RP-67580, and the EP₂ receptor antagonist PF-04418948, whilst completely abolished by the non-selective COX inhibitor indomethacin. Acrolein also caused rapid PGE₂ release which was suppressed by HC-030031. In summary, acrolein induced a novel bronchodilator response in mouse airways. Pharmacologic studies indicate that acrolein-induced relaxation likely involves interplay between TRPA1-expressing airway sensory C-fibres, NK₁ receptor-expressing epithelial cells, and EP₂-receptor expressing airway smooth muscle cells.

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IntroductionThe time burden of managing relapsing remitting multiple sclerosis (RRMS) for patients and healthcare staff is not well quantified despite its importance in treatment choice. Of interest were three higher efficacy RRMS therapies, cladribine tablets, alemtuzumab, and fingolimod because of their different modes of administration. Time and motion (T and M) surveys have previously been used to quantify time burden by asking respondents about duration of treatment administration. The objective is to determine the time taken by patients, nurses, neurologist and other specialists to treat RRMS with cladribine tablets, alemtuzumab and fingolimod using purposely developed T and M surveys.MethodsWe created two T and M surveys, one for neurologists and nurses, and another for patients. Surveys were informed by product information documents, validated by an MS nurse, and completed by telephone with patients (n=3), neurologists (n=3), and nurses (n=8) from eight MS clinics.ResultsThe overall mean time spent on treatment with cladribine tablets, fingolimod, and alemtuzumab extrapolated over 4 years was 25±3, 62±6, and 189±18 hours (p<0.0001, 1-way ANOVA, repeated measures). Neurologists’ overall time spent also favoured cladribine tablets (2.3±0.7 hours) over alemtuzumab (9.5±1.8 hours) and fingolimod (2.9±0.7 hours), (overall p=0.001). Similar results were found for nurses and patients, with the largest difference between therapies (favouring cladribine tablets) recorded for patients.ConclusionCladribine tablets were associated with a significantly lower overall time taken to treat RRMS compared to fingolimod and alemtuzumab. This warrants further research to determine if cladribine tablets could (a) increase productivity for doctors and nurses, and (b) improve patient quality of life by reducing the burden of managing their disease.

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