Endoplasmic reticulum (ER) stress and consequent unfolded protein response (UPR) are important in inflammation but have been poorly explored in asthma. We used a mouse model of allergic airway inflammation (AAI) with features of asthma to understand the role of ER stress and to explore potential therapeutic effects of inhaled chemical chaperones, which are small molecules that can promote protein folding and diminish UPR. UPR markers were initially measured on alternate days during a 7-day daily allergen challenge model. UPR markers increased within 24 hours after the first allergen challenge and peaked by the third challenge, before AAI was fully established (from the fifth challenge onward). Three chemical chaperones-glycerol, trehalose, and trimethylamine-N-oxide (TMAO)-were initially administered during allergen challenge (preventive regimen). TMAO, the most effective of these chemical chaperones and 4-phenylbutyric acid, a chemical chaperone currently in clinical trials, were further tested for potential therapeutic activities after AAI was established (therapeutic regimen). Chemical chaperones showed a dose-dependent reduction in UPR markers, airway inflammation, and remodeling in both regimens. Our results indicate an early and important role of the ER stress pathway in asthma pathogenesis and show therapeutic potential for chemical chaperones.

No abstract

reusable-part condenser [4], and results obtained by others using a non-reusable-part condenser and mass spectrometry (MS) [7].The data mentioned previously demonstrate that the cleaning procedure with Milton does not alter the metabolic profiles of EBC, and that NMR spectroscopy is suitable for investigating EBC samples.By using an Anacon condenser (Biostec, Valencia, Spain), different results have been reported [7]. Collection devices are an important source of variability of EBC biomarkers [2, 3, 8]. The principal variability factors include cooling temperature [9] and condenser materials [2]. For example, a warm-up during condensation is observed when RTube or Anacon are used (condensers using a disposable collection kit), whereas EcoScreen cools down slightly during the procedure [8, 9]. Such differences affect biomarker concentrations [2, 9]. More importantly, there was no correlation between biomarkers measured in EBC collected with EcoScreen and Anacon condensers [9], and there was only an ,60% correlation between biomarkers measured in EBC collected with RTube and Anacon condensers; although both used a disposable collection kit [9]. However, as no NMR details were found (i.e. the operating magnetic field, the number of acquisitions, the possible use of a cryoprobe, and the detection limit), it is difficult to conclude that NMR spectroscopy cannot be used to analyse EBC samples because it does not have the sensitivity required to observe the endogenous metabolites in the EBC [7]. With our spectrometer set-up, we have estimated a detection limit that is notably low for NMR-based metabolomics [10].In conclusion, our cleaning procedure of EBC collection set-up does not generate artificial signals in the metabolic profile of EBC. Furthermore, NMR-based metabolomics are suitable for identifying specific EBC metabolites and are potentially useful for characterising the metabolic fingerprints of patients with respiratory diseases. Although a head-to-head comparison of different condensers is required, the combination of different reference analytical techniques, including NMR and MS, might consolidate ''breathomics'' as a new noninvasive approach to the assessment of patients with respiratory disease with important diagnostic and therapeutic implications.

No abstract

No abstract