Inhalation Challenge Research Articles

Protocol for a double-blind crossover randomised controlled trial to investigate inhalation CHallenge to assess Inducible Laryngeal Obstruction (CH-ILO)

Current ILO diagnosis is dependent on an individual being symptomatic. If results prove citric acid inhalation challenge agent provokes ILO it will provide new insights into neuronal mechanisms and support development of a standardised diagnostic test.IntroductionInducible laryngeal obstruction (ILO) remains a poorly understood condition in part due to lack of understanding about the underlying neuronal mechanisms. Many suffer delayed confirmed diagnosis as no standardised assessment exists. Based on previous work, we propose citric acid (CA) is the most appropriate inhalation agent for inducing upper airway reflex responses, with a view to developing an inhalation challenge test for ILO.Methods and analysisA single-centre, double-blind crossover study. The primary objective is to identify if CA inhalation challenge provokes laryngeal obstruction in patients with confirmed ILO. We will recruit: 10 participants with ILO, 10 with refractory chronic cough (RCC), 10 healthy controls. Each will undergo two inhalation challenges during laryngoscopy, with ascending concentrations of citric acid or saline control; participants will be randomised sequentially by a computer-generated schedule to determine order of delivery. Follow up is a telephone consultation. Randomisation and preparation of challenge agents will be by an unblinded study team member, not involved in data analysis. Challenge agents will only be unblinded on study completion. Log10concentration of CA evoking ILO will be compared between patient groups using a one-way ANOVA, comparing participants with ILO and participants with RCC to healthy controls.ConclusionThis will be the first randomised controlled trial to investigate the role of inhalation challenge as an assessment tool to evoke laryngeal obstruction in patients with confirmed ILO. If results prove citric acid inhalation challenge agent provokes ILO it will provide new insights into neuronal mechanisms and support development of a standardised diagnostic test.

Evaluation and Application of the Work-Related Asthma Screening Questionnaire—Long Version (WRASQ-L)

BackgroundThe Work-related Asthma (WRA) Screening Questionnaire (Long-Version)(WRASQ-L)TM is a screening questionnaire that could improve recognition of WRA. ObjectiveTo conduct a definitive evaluation of the WRASQ-LTM to justify its implementation in clinical settings. MethodsEmployed adults aged 18-75 years with asthma confirmed by objective measures and the ability to take time off work were eligible. Participants completed the WRASQ-LTM then monitored their peak expiratory flow at and away from work or completed a specific inhalation challenge test. Data were classified as WRA or non-WRA by two asthma specialists, blinded to WRASQ-LTM answers. Sensitivity (SN), specificity (SP), positive and negative predictive values (PPV and NPV, respectively) and Youden’s index were calculated for cut-offs of a positive screen. ResultsOf 106 participants (47.1±7.1 years (mean ± SD); 60 (57%) female), 14 (17%) were classified as WRA and were significantly younger in age than non-WRA participants (p=0.043). The questionnaire has high SN and NPV (90.9% and 93.1%, respectively), but low PPV and SP (32.1% and 26.0%, respectively). ConclusionsThe WRASQ-LTM has high SN and NPV. High SN is of primary interest to ensure that few false negative screens are missed and those with potential WRA are identified and continue to specialist care. The SN indicates utility of the questionnaire in clinical settings. Further benefits of the tool include its potential to prompt for education on the symptom-workplace relationship, workplace exposures, personal protective equipment use, and collect exposure and occupational history.

Release of ATP in the lung evoked by inhalation of irritant gases in rats.

Adenosine triphosphate (ATP) can be released into the extracellular milieu from various types of cells in response to a wide range of physical or chemical stresses. In the respiratory tract, extracellular ATP is recognized as an important signal molecule and trigger of airway inflammation. Chlorine (Cl2), sulfur dioxide (SO2), and ammonia (NH3) are potent irritant gases and common industrial air pollutants due to their widespread uses as chemical agents. This study was carried out to determine if acute inhalation challenges of these irritant gases, at the concentration and duration simulating the accidental exposures to these chemical gases in industrial operations, triggered the release of ATP in the rat respiratory tract; and if so, whether the level of ATP in bronchoalveolar lavage fluid (BALF) evoked by inhalation challenge of a given irritant gas was elevated by chronic allergic airway inflammation. Our results showed: 1) inhalation of these irritant gases caused significant increases in the ATP level in BALF, and the magnitude of evoked ATP release was in the order of Cl2 > SO2 > NH3. 2) Chronic airway inflammation induced by ovalbumin-sensitization markedly elevated the ATP level in BALF during baseline (breathing room air) but did not potentiate the release of ATP in the lung triggered by inhalation challenges of these irritant gases. These findings suggested a possible involvement of the ATP release in the lung in the regulation of overall airway responses to acute inhalation of irritant gases and the pathogenesis of chronic allergic airway inflammation.NEW & NOTEWORTHY Extracellular adenosine triphosphate (ATP) is a contributing factor and signaling molecule of airway inflammation. This study demonstrated for the first time that the ATP release in the lung was markedly elevated after acute inhalation challenges of three common industrial air pollutants; the order of the response magnitude was chlorine > sulfur dioxide > ammonia. These findings provided new information and improved our understanding of the adverse pulmonary effects caused by accidental inhalation exposures to these irritant gases.

Der Nachweis beruflich verursachter Allergien ist ein komplexes Unterfangen: ein Fallbeispiel

The detection of occupational allergies is a complex undertaking: A case study According to the recommendations for the diagnosis of occupational asthma, suspected cases require a confirmed asthma diagnosis, work-associated symptoms, evidence of sensitization to an occupational allergen and a close relationship between the occupation and the symptoms. In addition to a detailed medical history, several examinations and tests and a differentiated consideration of them are required in order to arrive at a final expert assessment. We report the case of a 58-year-old butcher who had been complaining of shortness of breath and coughing at his workplace in a slaughterhouse for 5 years. It was only after extensive investigations and a detailed medical history that a powdered kebab spice used in an adjacent room was suspected as the potential allergen. Diagnostic tests showed that the patient was sensitized to the spice. While the specific inhalation challenge (SIC) with kebab spice did not elicit an asthmatic reaction, a non-specific bronchial hyperreactivity in the insured person was observed. On the day after the SIC, the bronchial hyperreactivity was increased by a factor of three and there were further indications of eosinophilic or allergic reaction. In summary, the individual diagnostic components led to the assessment of this case as allergic occupational asthma. This case illustrates that an assessment of the individual diagnostic components in the diagnosis of occupational asthma is quite complex and not without pitfalls. Keywords: occupational asthma – diagnosis – sensitization – bronchial hyperreactivity

Zinc fever in a painter and varnisher: a case report

BackgroundZinc fever is well described in medical literature, particularly in workers after handling zinc-containing materials at high temperatures e.g., in the welding of hot-dip galvanized steel sheets. It is not known whether zinc fever also occurs at low temperatures.Case presentationWe present the case of a 33-year-old Caucasian atopic painter and varnisher with work-related dyspnea, sweating, as well as multiple occurrences of fever. He was sent to Institute for Prevention and Occupational medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA) for the evaluation of isocyanate asthma, but an inhalative challenge with hexamethylene diisocyanate was negative. Since symptoms were closely related to the use of zinc coatings at room temperature without adequate protective measures, the diagnosis of zinc fever was made. After exposure cessation the worker immediately became symptom-free. The work as painter and varnisher may be associated with various exposures to hazardous substances. Besides solvents, epoxy compounds and isocyanates, which can cause obstructive respiratory diseases; additionally, zinc-containing agents should be considered as health hazards.ConclusionsThis case demonstrates that zinc fever may occur also after application of zinc coatings by spray painting at low temperatures.

Impact of Ongoing Treatment With Inhaled Corticosteroids During Specific Inhalation Challenges for Diagnosing Occupational Asthma

BackgroundSpecific inhalation challenge tests (SIC) are still the reference test for diagnosing sensitizer-induced occupational asthma (SIOA). The European Respiratory Society recommends the cessation of inhaled corticosteroids (ICS) 72h prior to SIC. ObjectiveTo assess the effect of an ongoing ICS treatment during SIC on the maximum fall in FEV1, change in methacholine PC20 as well as sputum eosinophil counts after exposure to the suspected agent. MethodsWe performed a retrospective analysis using a database of cases referred to our center for suspected SIOA from 1999 to 2022. The results of the SIC were compared between subjects treated with ICS during SIC and steroid-naïve subjects. ResultsSix-hundred and seventy-one individuals underwent SIC in the laboratory. Three hundred and eighteen were treated with ICS, whereas 353 were steroid naïve. The proportion of subjects with a positive SIC was greater among ICS treated subjects (39. 6%) compared to steroid-naïve subjects (27.5%, p<0.001). A treatment with ICS did not influence the outcome of the SIC. There was no difference in the change in PC20 or percentage of sputum eosinophils after SIC between steroid-treated and steroid-naïve subjects. ConclusionAn ongoing ICS treatment during a SIC did not affect the occurrence of an asthmatic reaction, the change in airway responsiveness or eosinophilic inflammation after exposure to the suspected agent in subjects who have been treated with ICS for a long period of time.

Controlled human exposures to diesel exhaust or particle-depleted diesel exhaust with allergen modulates transcriptomic responses in the lung

The evidence associating traffic-related air pollution (TRAP) with allergic asthma is growing, but the underlying mechanisms for this association remain unclear. The airway epithelium is the primary tissue exposed to TRAP, hence understanding its interactions with TRAP and allergen is important. Diesel exhaust (DE), a paradigm of TRAP, consists of particulate matter (PM) and gases. Modern diesel engines often have catalytic diesel particulate filters to reduce PM output, but these may increase gaseous concentrations, and their benefits on human health cannot be assumed. We conducted a randomized, double-blinded, crossover study using our unique in vivo human exposure system to investigate the effects of DE and allergen co-exposure, with or without particle depletion as a proxy for catalytic diesel particulate filters, on the airway epithelial transcriptome. Participants were exposed for 2 h before an allergen inhalation challenge, with each receiving filtered air and saline (FA-S), filtered air and allergen (FA-A), DE and allergen (DE-A), or particle-depleted DE and allergen (PDDE-A), over four different occasions, each separated by a 4-week washout period. Endobronchial brushings were collected 48 h after each exposure, and total RNA was sequenced. Differentially expressed genes (DEGs) were identified using DESeq2, followed by GO enrichment and pathway analysis. FA-A, DE-A, and PDDE-A exposures significantly modulated genes relative to FA-S, with 462 unique DEGs identified. FA-A uniquely modulated the highest number (↑178, ↓155), followed by DE-A (↑44, ↓23), and then PDDE-A exposure (↑15, ↓2); 6 DEGs (↑4, ↓2) were modulated by all three conditions. Exposure to PDDE-A resulted in modulation of 285 DEGs compared to DE-A exposure, further revealing 26 biological process GO terms, including “cellular response to chemokine” and “inflammatory response”. The transcriptional epithelial response to diesel exhaust and allergen co-exposure is enriched in inflammatory mediators, the pattern of which is altered upon particle depletion.

Identifying vagal bronchopulmonary afferents mediating cough response to inhaled sulfur dioxide in mice.

Sulfur dioxide (SO2), a common environmental and industrial air pollutant, possesses a potent effect in eliciting cough reflex, but the primary type of airway sensory receptors involved in its tussive action has not been clearly identified. This study was carried out to determine the relative roles of three major types of vagal bronchopulmonary afferents [slowly adapting receptors (SARs), rapidly adapting receptors (RARs), and C-fibers] in regulating the cough response to inhaled SO2. Our results showed that inhalation of SO2 (300 or 600 ppm for 8 min) evoked an abrupt and intense stimulatory effect on bronchopulmonary C-fibers, which continued for the entire duration of inhalation challenge and returned toward the baseline in 1-2 min after resuming room air-breathing in anesthetized and mechanically ventilated mice. In stark contrast, the same SO2 inhalation challenge generated a distinct and consistent inhibitory effect on both SARs and phasic RARs; their phasic discharges synchronized with respiratory cycles during the baseline (breathing room air) began to decline progressively within 1-3 min after the onset of SO2 inhalation, ceased completely before termination of the 8-min inhalation challenge, and then slowly returned toward the baseline after >40 min. In a parallel study in awake mice, inhalation of SO2 at the same concentration and duration as that in the nerve recording experiments evoked cough responses in a pattern and time course similar to that observed in the C-fiber responses. Based on these results, we concluded that stimulation of vagal bronchopulmonary C-fibers is primarily responsible for triggering the cough response to inhaled SO2.NEW & NOTEWORTHY This study demonstrated that inhalation of a high concentration of sulfur dioxide, an irritant gas and common air pollutant, completely and reversibly inhibited the neural activities of both slowly adapting receptor and rapidly adapting receptor, two major types of mechanoreceptors in the lungs with their activities conducted by myelinated fibers. Furthermore, the results of this study suggested that stimulation of vagal bronchopulmonary C-fibers is primarily responsible for triggering the cough reflex responses to inhaled sulfur dioxide.

Longitudinal changes in serum immunoglobulin G testing in patients with fibrotic avian hypersensitivity pneumonitis

BackgroundEvaluation of the antigen responsible for fibrotic hypersensitivity pneumonitis (HP) is challenging. Serum immunoglobulin (Ig) G testing against HP-associated antigens is performed. Although single-serum IgG testing has been investigated, multiple-serum IgG testing has not yet been studied.MethodsThis study included patients who underwent histopathological examination and positive inhalation challenge test as well as those with moderate or high HP guideline confidence level. Serum IgG testing against pigeon serum was conducted twice using two methods: enzyme linked-immunosorbent assay (ELISA) and ImmunoCAP. The association between changes in serum IgG antibody titers and changes in forced vital capacity (FVC) and other parameters was investigated.ResultsIn this study, 28 patients (mean age, 64.5 years; mean FVC, 85.3%) with fibrotic avian HP were selected, of whom 20 and 8 underwent surgical lung biopsy and transbronchial lung cryobiopsy, respectively. Of the 28 patients, 19 had been keeping birds for more than 6 months. A correlation was observed between the annual changes in serum IgG antibody titers by ELISA and changes in relative FVC (r = − 0.6221, p < 0.001). Furthermore, there was a correlation between the annual changes in serum IgG antibody titers by ImmunoCAP and changes in relative FVC (r = − 0.4302, p = 0.022). Multiple regression analysis revealed that the change in serum IgG antibody titers by both ELISA and ImmunoCAP also influenced the relative FVC change (p = 0.012 and p = 0.015, respectively). Moreover, 13 patients were given additional treatments between the first and second blood test; however, the additional treatment group was not significantly different in relative FVC change compared to the group with no additional treatment (p = 0.982).ConclusionsIn patients with fibrotic avian HP, the annual changes in serum IgG testing were correlated with FVC changes, highlighting the importance of serum IgG testing over time.

Diagnostic Accuracy of Specific IgE Against Wheat and Rye in Flour-Induced Occupational Asthma

Assessment of IgE-mediated sensitization to flour allergens is widely used to investigate flour-induced occupational asthma. The diagnostic efficiency of detecting specific IgE antibodies (sIgEs) against wheat and rye flour, however, has not been thoroughly compared with other diagnostic procedures. We sought to evaluate the diagnostic accuracy of sIgE against wheat and rye compared with specific inhalation challenge (SIC) with flour as the reference standard. This retrospective multicenter study included 264 subjects who completed an SIC with flour in eight tertiary centers, of whom 205 subjects showed a positive SIC result. Compared with SIC, sIgE levels of 0.35 kUA/L or greater against wheat and rye provided similar sensitivities (84% to 85%, respectively), specificities (71% to 78%), positive predictive values (91% to 93%), and negative predictive values (56% to 61%). Increasing the threshold sIgE value to 5.10 kUA/L for wheat and to 6.20 kUA/L for rye provided a specificity of 95% or greater and further enhanced the positive predictive value to 98%. Among subjects with a positive SIC, those who failed to demonstrate sIgE against wheat and rye (n= 26) had significantly lower total serum IgE level and blood and sputum eosinophil counts and a lesser increase in postchallenge FeNO compared with subjects with a detectable sIgE. High levels of sIgE against wheat and/or rye flour strongly support a diagnosis of flour-induced occupational asthma without the need to perform an SIC. The absence of detectable sIgE against wheat and rye in subjects with a positive SIC seems to be associated with lower levels of TH2 biomarkers.

BLEscope: A Bluetooth Low Energy (BLE) Microscope for Wireless Multicontrast Functional Imaging.

Recent advances in low-power wireless-capable system-on-chips (SoCs) have accelerated diverse Internet of Things (IoT) applications, encompassing wearables, asset monitoring, and more. Concurrently, the field of neuroimaging has experienced escalating demand for lightweight, untethered, low-power systems capable of imaging in small animals. This article explores the feasibility of using a low-power asset monitoring system as the basis of a new architecture for fluorescence and hemodynamic contrast-based wireless functional imaging. The core system architecture hinges on the fusion of a Bluetooth Low Energy (BLE) 5.2 SoC and a low-power 560×560, 8-bit monochrome CMOS image sensor module. Successful integration of a multicontrast optical front-end consisting of a fluorescence channel (FL) and an intrinsic optical signal (IOS) channel resulted in the creation of a wireless microscope called 'BLEscope'. Next, we developed a wireless (i.e. BLE) protocol to remotely operate the BLEscope via a laptop and acquire in vivo images at 1 frame per second (fps). We then conducted a comprehensive characterization of the BLEscope to assess its optical capabilities and power consumption. We report a new benchmark for continuous wireless imaging of ∼1.5 hours with a 100 mAh battery. Via the FL channel of the BLEscope, we successfully tracked the kinetics of an intravenously injected fluorescent tracer and acquired images of fluorescent brain tumor cells in vivo. Via the IOS channel, we characterized the differential response of normal and tumor-associated blood vessels to a carbogen gas inhalation challenge. When miniaturized, the BLEscope will result in a new class of low-power, implantable or wireless microscopes that could transform preclinical and clinical neuroimaging applications.

Occupational asthma, rhinitis and contact urticaria from greenhouse work.

The current knowledge about occupational allergic diseases among greenhouse workers is scant. To describe greenhouse workers' occupational allergic diseases. We identified 28 greenhouse workers with occupational allergic diseases in 2002-2020 by conducting a systematic search in the patient register of the Finnish Institute of Occupational Health. All the patients worked in tomato- or cucumber-growing greenhouses and showed immunoglobulin-E-mediated sensitization to occupational agents. Specific inhalation challenges or workplace peak expiratory flow monitoring confirmed occupational asthma (OA), nasal allergen challenges confirmed occupational rhinitis (OR) and open skin tests confirmed occupational contact urticaria (OCU). Most patients had more than one occupational disease and were sensitized to several workplace agents. Tomato plants were the most common cause of occupational diseases and induced 22 allergic diseases in 14 patients. Cucumber plants caused occupational diseases in 10 patients (3 OA, 7 OR and 6 OCU). The pest control mite Amblyseius swirskii and a mixture of parasitic wasps Encarsia formosa and Eretmocerus eremicus both induced two OA cases. Three patients had an occupational disease caused by storage mites and three others had a work-related systemic reaction to a bumblebee sting. The greenhouse workers typically suffered from several occupational allergic diseases and were sensitized to cultivated plants, various pest control organisms and storage mites. All these can cause OA and OR, but in this study, OCU was only induced by cultivation plants. Cucumber plant is a novel cause of OA and OR, and A. swirskii is a novel cause of OA.

Chronic cough: is the end nigh?

Chronic cough (lasting more than 8 weeks) is a common condition with substantial psychosocial impact. Despite huge efforts following robust guidelines, chronic cough in many patients remains refractory or unexplained (RU-CC). Recent insights support a significant role for cough hypersensitivity in RU-CC, including neuropathophysiological evidence from inhalational cough challenge testing, functional magnetic resonance imaging, and airway nerve biopsy. Along with improved approaches to measuring cough, this knowledge has developed in tandem with repurposing neuromodulator medications, including gabapentin, and evidence for non-pharmacological treatments. Most significantly, there is now a pipeline for novel classes of drugs specifically for chronic cough. The P2X3 receptor antagonist gefapixant is the first such drug to be approved in Europe. However, challenges persist. The field of chronic cough needs more robust epidemiological data, enhanced diagnostic tools, further well-designed clinical trials accounting for the effects of placebo, and treatments with minimal side-effects. Addressing these challenges are novel chronic cough registries, improved International Classification of Diseases (10th revision) coding, genetic testing options and further mechanistic studies. This Viewpoint article discusses these facets and considers how, whilst the end of chronic cough may not be imminent for all patients, the evolving landscape looks increasingly optimistic.

The rLVS ΔcapB/iglABC vaccine provides potent protection in Fischer rats against inhalational tularemia caused by various virulent Francisella tularensis strains

ABSTRACT Francisella tularensis is one of the several biothreat agents for which a licensed vaccine is needed. To ensure vaccine protection is achieved across a range of virulent F. tularensis strains, we assembled and characterized a panel of F. tularensis isolates to be utilized as challenge strains. A promising tularemia vaccine candidate is rLVS ΔcapB/iglABC (rLVS), in which the vector is the LVS strain with a deletion in the capB gene and which additionally expresses a fusion protein comprising immunodominant epitopes of proteins IglA, IglB, and IglC. Fischer rats were immunized subcutaneously 1–3 times at 3-week intervals with rLVS at various doses. The rats were exposed to a high dose of aerosolized Type A strain Schu S4 (FRAN244), a Type B strain (FRAN255), or a tick derived Type A strain (FRAN254) and monitored for survival. All rLVS vaccination regimens including a single dose of 107 CFU rLVS provided 100% protection against both Type A strains. Against the Type B strain, two doses of 107 CFU rLVS provided 100% protection, and a single dose of 107 CFU provided 87.5% protection. In contrast, all unvaccinated rats succumbed to aerosol challenge with all of the F. tularensis strains. A robust Th1-biased antibody response was induced in all vaccinated rats against all F. tularensis strains. These results demonstrate that rLVS ΔcapB/iglABC provides potent protection against inhalational challenge with either Type A or Type B F. tularensis strains and should be considered for further analysis as a future tularemia vaccine.

Anti-Allergic Inflammatory Effect of Agarum cribrosum and Its Phlorotannin Component, Trifuhalol A, against the Ovalbumin-Induced Allergic Asthma Model.

Asthma is a chronic inflammatory disease involving structural changes to the respiratory system and severe immune responses mediated by allergic cytokines and pro-inflammatory mediators. Agarum cribrosum (AC) is a kind of seaweed which contains a phlorotannin, trifuhalol A. To evaluate its anti-allergic inflammatory effect against asthma, an ovalbumin inhalation-induced mouse asthma model was used. Histologic observations proved that trifuhalol A is minimizing the lung and tracheal structure changes as well as the infiltration of eosinophils and mast cells against ovalbumin inhalation challenge. From the serum and bronchoalveolar lavage fluid, ovalbumin-specific IgE and Th2-specific cytokines, IL-4, -5, and -13, were reduced with trifuhalol A treatment. In addition, IL-1β, IL-6, and TNF-α concentrations in lung homogenate were also significantly reduced via trifuhalol A treatment. Taken together, trifuhalol A, isolated from AC, was able to protect lung and airways from Th2-specific cytokine release, and IgE mediated allergic inflammation as well as the attenuation of IL-1β, IL-6, and TNF-α in lung, which results in the suppression of eosinophils and the mast cells involved asthmatic pathology.

Exhaled breath particles as a novel tool to study lipid composition of epithelial lining fluid from the distal lung

BackgroundSurfactant phospholipid (PL) composition plays an important role in lung diseases. We compared the PL composition of non-invasively collected exhaled breath particles (PEx) with bronchoalveolar lavage (BAL) and induced sputum (ISP) at baseline and following endotoxin (LPS) challenges.MethodsPEx and BAL were collected from ten healthy nonsmoking participants before and after segmental LPS challenge. Four weeks later, PEx and ISP were sampled in the week before and after a whole lung LPS inhalation challenge. PL composition was analysed using mass spectrometry.ResultsThe overall PL composition of BAL, ISP and PEx was similar, with PC(32:0) and PC(34:1) representing the largest fractions in all three sample types (baseline PC(32:0) geometric mean mol%: 52.1, 56.9, and 51.7, PC(34:1) mol%: 11.7, 11.9 and 11.4, respectively). Despite this similarity, PEx PL composition was more closely related to BAL than to ISP. For most lipids comparable inter-individual differences in BAL, ISP, and PEx were found. PL composition of PEx was repeatable. The most pronounced increase following segmental LPS challenge was detected for SM(d34:1) in BAL (0.24 to 0.52 mol%) and following inhalation LPS challenge in ISP (0.45 to 0.68 mol%). An increase of SM(d34:1) following segmental LPS challenge was also detectable in PEx (0.099 to 0.103 mol%). The inhalation challenge did not change PL composition of PEx.ConclusionOur data supports the peripheral origin of PEx. The lack of PL changes in PEx after inhalation challenge might to be due to the overall weaker response of inhaled LPS which primarily affects the larger airways. Compared with BAL, which always contains lining fluid from both peripheral lung and central airways, PEx analysis might add value as a selective and non-invasive method to investigate peripheral airway PL composition.Trial registrationNCT03044327, first posted 07/02/2017.

Variants in transient receptor potential channels and toll-like receptors modify airway responses to allergen and air pollution: a randomized controlled response human exposure study

BackgroundEnvironmental co-exposure to allergen and traffic-related air pollution is common globally and contributes to the exacerbation of respiratory diseases. Individual responses to environmental insults remain variable due to gene-environment interactions.ObjectiveThis study examined whether single nucleotide polymorphisms (SNPs) in lung cell surface receptor genes modifies lung function change and immune cell recruitment in allergen-sensitized individuals exposed to diesel exhaust (DE) and allergen.MethodsIn this randomized, double-blinded, four-arm, crossover study, 13 allergen-sensitized participants underwent allergen inhalation challenge following a 2-hour exposure to DE, particle-depleted diesel exhaust (PDDE) or filtered air (FA). Lung function tests and bronchoscopic sample collection were performed up to 48 h after exposures. Transient receptor potential channel (TRPA1 and TRPV1) and toll-like receptor (TLR2 and TLR4) risk alleles were used to construct an unweighted genetic risk score (GRS). Exposure-by-GRS interactions were tested using mixed-effects models.ResultsIn participants with high GRS, allergen exposure was associated with an increase in airway hyperresponsiveness (AHR) when co-exposed to PDDE (p = 0.03) but not FA or DE. FA and PDDE also were associated with a relative increase in macrophages and decrease in lymphocytes in bronchoalveolar lavage.ConclusionsTRPs and TLRs variants are associated with increased AHR and altered immune cellularity in allergen-exposed individuals. This effect is blunted by DE exposure, suggesting greater influence of unmeasured gene variants as primary meditators of a particulate-rich co-exposure.Trial registrationThe study was registered with ClinicalTrials.gov on December 20, 2013 (NCT02017431).

Sphingosine-1-phosphate induces airway smooth muscle hyperresponsiveness and proliferation

The emerging role of sphingosine-1-phosphate (S1P) in regulating smooth muscle functions has led to the exploration of the possibility that this sphingolipid could represent a potential therapeutic target in asthma and other lung diseases. Several studies in animal surrogates have suggested a role for S1P-mediated signalling in the regulation of airway smooth muscle contraction, airway hyperresponsiveness and airway remodelling but evidence from human studies is lacking. We have compared the responsiveness of the airways to S1P in healthy and asthmatic individuals in vivo, in isolated human airways ex vivo and in murine airways dissected from healthy and house dust mite (HDM) sensitised animals. Airway responsiveness was measured by spirometry during inhalation challenges and by wire myography in airways isolated from human and mouse lungs. Thymidine incorporation and calcium mobilisation assays were used to study human airway smooth muscle cell responses. S1P did not induce contraction of airways isolated from healthy and HDM exposed mice, nor in human airways. Similarly, there was no airway constriction observed in healthy and asthmatic subjects in response to increasing concentrations of inhaled S1P. However, 30 minutes exposure to S1P induced a significant, concentration-dependent enhancement of airway reactivity to methacholine and to histamine in murine and human airways respectively. HDM-sensitised mice demonstrated a significant increase in methacholine responsiveness which was not further enhanced by S1P treatment. S1P also concentration-dependently enhanced proliferation of human airway smooth muscle cells, an effect mediated through the S1P type 2 receptor, as shown by selective antagonism and S1PR2 siRNA knockdown. Our data suggest that S1P released locally into the airways may be involved in the regulation of airway smooth muscle hyperresponsiveness and hyperplasia, defining a novel target for future therapies.

Does a laboratory-based CO2 challenge induce a hypothalamic-pituitary-adrenal (HPA) axis stress response in healthy adults?

A methodological limitation to studying hypothalamic-pituitary-adrenal (HPA) axis functioning is that there are few laboratory-based tasks that consistently induce a stress response. Moreover, most tasks use a socially-evaluative approach to eliciting a stress response. The aim of the current study was to test whether a CO2 inhalation challenge (originally designed to induce panic symptoms) produces a robust HPA-axis stress response. Forty-eight adults (mean age = 25.6; 69% women; 73% white) were recruited from a local university in the mid-southern part of the United States. Participants were asked to complete a 35% CO2 inhalation challenge. Six saliva samples were collected to measure cortisol responses to the task (a pre-stress baseline sample followed by 5 post-stress samples). Linear mixed effects modeling was used to examine whether there was a significant increase in cortisol following the challenge. There was substantial between-subjects variability in cortisol responses to the challenge. That said, the mean group cortisol response indicated that participants experienced an increase in cortisol 15-30 minutes post-challenge and a subsequent decrease in cortisol 45-60 minutes post-challenge (linear effect, b=0.007, p<0.001; quadratic effect, b=-0.0001, p<0.001). On average, there was a 53% increase in cortisol from baseline and nearly two-thirds of participants had at least a 45% increase in cortisol. The data suggest that a CO2 inhalation challenge can be used to induce a cortisol stress response among healthy participants and offers an alternative laboratory-based task that does not rely on socially-evaluative cues to induce stress.

Hypersensitivity pneumonitis: Principles in diagnosis and management.

Hypersensitivity pneumonitis: Principles in diagnosis and management.