Vitamin D3 protects against nitrogen mustard-induced apoptosis of the bronchial epithelial cells via activating the VDR/Nrf2/Sirt3 pathway.

Respiratory system injury is the main cause of mortality for nitrogen mustard (NM)-induced damage. Previous studies indicate that reactive oxygen species (ROS) participates in NM-mediated respiratory injuries, but the detailed mechanism is not quite clear. Human bronchial epithelial cell lines 16HBE and BEAS-2B were treated with HN2, a type of NM. In detail, it was shown that HN2 treatment induced impaired cell viability, excessive mitochondrial ROS production and enhanced cellular apoptosis in bronchial epithelial cells. Moreover, impaired Sirt3/SOD2 axis was observed upon HN2 treatment, with decreased Sirt3 and increased acetylated SOD2 expression levels. Sirt3 overexpression partially ameliorated HN2-induced cell injury. Meanwhile, vitamin D3 treatment partially attenuated HN2-induced apoptosis and improved the mitochondrial functions upon HN2 intervention. In addition, HN2 exposure decreased VDR expression, thus inhibiting the Nrf2 phosphorylation and Sirt3 activation. Inhibition of Nrf2 or Sirt3 could decrease the protective effects of vitamin D3 and enhance mitochondrial ROS production via modulating mitochondrial redox balance. In conclusion, impaired VDR/Nrf2/Sirt3 axis contributed to NM-induced apoptosis, while vitamin D3 supplementation provides protective effects via the activation of VDR and the improvement of mitochondrial functions. This study provides novel mechanism and strategy for NM exposure-induced pulmonary injuries.

Asthma-inducing potential of 28 substances in spray cleaning products-Assessed by quantitative structure activity relationship (QSAR) testing and literature review.

Exposure to spray cleaning products constitutes a potential risk for asthma induction. We set out to review whether substances in such products are potential inducers of asthma. We identified 101 spray cleaning products for professional use. Twenty-eight of their chemical substances were selected. We based the selection on (a) positive prediction for respiratory sensitisation in humans based on quantitative structure activity relationship (QSAR) in the Danish (Q)SAR Database, (b) positive QSAR prediction for severe skin irritation in rabbits and (c) knowledge on the substances' physico-chemical characteristics and toxicity. Combining the findings in the literature and QSAR predictions, we could group substances into four classes: (1) some indication in humans for asthma induction: chloramine, benzalkonium chloride; (2) some indication in animals for asthma induction: ethylenediaminetetraacetic acid (EDTA), citric acid; (3) equivocal data: hypochlorite; (4) few or lacking data: nitriloacetic acid, monoethanolamine, 2-(2-aminoethoxy)ethanol, 2-diethylaminoethanol, alkyldimethylamin oxide, 1-aminopropan-2-ol, methylisothiazolinone, benzisothiazolinone and chlormethylisothiazolinone; three specific sulphonates and sulfamic acid, salicylic acid and its analogue sodium benzoate, propane-1,2-diol, glycerol, propylidynetrimethanol, lactic acid, disodium malate, morpholine, bronopol and benzyl alcohol. In conclusion, we identified an asthma induction potential for some of the substances. In addition, we identified major knowledge gaps for most substances. Thus, more data are needed to feed into a strategy of safe-by-design, where substances with potential for induction of asthma are avoided in future (spray) cleaning products. Moreover, we suggest that QSAR predictions can serve to prioritise substances that need further testing in various areas of toxicology.

Gastrointestinal tissue as a "new" target of pollution exposure.

Airborne pollution has become a leading cause of global death in industrialized cities and the exposure to environmental pollutants has been demonstrated to have adverse effects on human health. Among the pollutants, particulate matter (PM) is one of the most toxic and although its exposure has been more commonly correlated with respiratory diseases, gastrointestinal (GI) complications have also been reported as a consequence to PM exposure. Due to its composition, PM is able to exert on intestinal mucosa both direct damaging effects, (by reaching it either via direct ingestion of contaminated food and water or indirect inhalation and consequent macrophagic mucociliary clearance) and indirect ones via generation of systemic inflammation. The relationship between respiratory and GI conditions is well described by the lung-gut axis and more recently, has become even clearer during coronavirus disease 2019 (COVID-19) pandemic, when respiratory symptoms were associated with gastrointestinal conditions. This review aims at pointing out the mechanisms and the models used to evaluate PM induced GI tract damage.

Clinical Picture and Risk Factors of Severe Respiratory Symptoms in COVID-19 in Children.

Children with COVID-19 develop moderate symptoms in most cases. Thus, a proportion of children requires hospital admission. The study aimed to assess the history, clinical and laboratory parameters in children with COVID-19 concerning the severity of respiratory symptoms. The study included 332 children (median age 57 months) with COVID-19. History data, clinical findings, laboratory parameters, treatment, and outcome, were evaluated. Children were compared in the groups that varied in the severity of symptoms of respiratory tract involvement. Children who required oxygen therapy represented 8.73%, and intensive care 1.5% of the whole cohort. Comorbidities were present in 126 patients (37.95%). Factors increasing the risk of oxygen therapy included comorbidities (odds ratio (OR) = 92.39; 95% confidence interval (95% CI) = (4.19; 2036.90); p < 0.00001), dyspnea (OR = 45.81; 95% CI (4.05; 518.21); p < 0.00001), auscultation abnormalities (OR = 34.33; 95% CI (2.59; 454.64); p < 0.00001). Lactate dehydrogenase (LDH) > 280 IU/L and creatinine kinase > 192 IU/L were parameters with a good area under the curve (0.804-LDH) and a positive predictive value (42.9%-CK). The clinical course of COVID-19 was mild to moderate in most patients. Children with comorbidities, dyspnea, or abnormalities on auscultation are at risk of oxygen therapy. Laboratory parameters potentially useful in patients evaluated for the severe course are LDH > 200 IU/L and CK > 192 IU/L.

Laminar flow ventilation system to prevent airborne infection during exercise in the COVID-19 crisis: A single-center observational study.

Particulate generation occurs during exercise-induced exhalation, and research on this topic is scarce. Moreover, infection-control measures are inadequately implemented to avoid particulate generation. A laminar airflow ventilation system (LFVS) was developed to remove respiratory droplets released during treadmill exercise. This study aimed to investigate the relationship between the number of aerosols during training on a treadmill and exercise intensity and to elucidate the effect of the LFVS on aerosol removal during anaerobic exercise. In this single-center observational study, the exercise tests were performed on a treadmill at Running Science Lab in Japan on 20 healthy subjects (age: 29±12 years, men: 80%). The subjects had a broad spectrum of aerobic capacities and fitness levels, including athletes, and had no comorbidities. All of them received no medication. The exercise intensity was increased by 1-km/h increments until the heart rate reached 85% of the expected maximum rate and then maintained for 10 min. The first 10 subjects were analyzed to examine whether exercise increased the concentration of airborne particulates in the exhaled air. For the remaining 10 subjects, the LFVS was activated during constant-load exercise to compare the number of respiratory droplets before and after LFVS use. During exercise, a steady amount of particulates before the lactate threshold (LT) was followed by a significant and gradual increase in respiratory droplets after the LT, particularly during anaerobic exercise. Furthermore, respiratory droplets ≥0.3 µm significantly decreased after using LFVS (2120800±759700 vs. 560 ± 170, p<0.001). The amount of respiratory droplets significantly increased after LT. The LFVS enabled a significant decrease in respiratory droplets during anaerobic exercise in healthy subjects. This study's findings will aid in exercising safely during this pandemic.

Exosomes in chronic respiratory diseases.

Exosomes are nano-sized vesicles released by almost all cell types, with a central role as mediators of intercellular communication. In addition to physiological conditions, these extracellular vesicles seem to play a pivotal role in inflammatory processes. This assumption offers the opportunity to study exosomes as promising biomarkers and therapeutic tools for chronic respiratory disorders. Indeed, although it is well-known that at the basis of conditions like asthma, chronic obstructive pulmonary disease, alpha-1 antitrypsin deficiency and idiopathic pulmonary fibrosis there is a dysregulated inflammatory process, an unequivocal correlation between different phenotypes and their pathophysiological mechanisms has not been established yet. In this review, we report and discuss some of the most significant studies on exosomes from body fluids of subjects affected by airway diseases. Furthermore, the most widespread techniques for exosome isolation and characterization are described. Further studies are needed to answer the unresolved questions about the functional link between exosomes and chronic respiratory diseases.

Evaluation of Effects of Ractopamine on Cardiovascular, Respiratory, and Locomotory Physiology in Animal Model Zebrafish Larvae.

Ractopamine (RAC) is a beta-adrenoceptor agonist that is used to promote lean and increased food conversion efficiency in livestock. This compound has been considered to be causing behavioral and physiological alterations in livestock like pig. Few studies have addressed the potential non-target effect of RAC in aquatic animals. In this study, we aimed to explore the potential physiological response after acute RAC exposure in zebrafish by evaluating multiple endpoints like locomotor activity, oxygen consumption, and cardiovascular performance. Zebrafish larvae were subjected to waterborne RAC exposure at 0.1, 1, 2, 4, or 8 ppm for 24 h, and the corresponding cardiovascular, respiratory, and locomotion activities were monitored and quantified. In addition, we also performed in silico molecular docking for RAC with 10 zebrafish endogenous ß-adrenergic receptors to elucidate the potential acting mechanism of RAC. Results show RAC administration can significantly boost locomotor activity, cardiac performance, oxygen consumption, and blood flow rate, but without affecting the cardiac rhythm regularity in zebrafish embryos. Based on structure-based flexible molecular docking, RAC display similar binding affinity to all ten subtypes of endogenous ß-adrenergic receptors, from adra1aa to adra2db, which are equivalent to the human one. This result suggests RAC might act as high potency and broad spectrum ß-adrenergic receptors agonist on boosting the locomotor activity, cardiac performance, and oxygen consumption in zebrafish. To validate our results, we co-incubated a well-known ß-blocker of propranolol (PROP) with RAC. PROP exposure tends to minimize the locomotor hyperactivity, high oxygen consumption, and cardiac rate in zebrafish larvae. In silico structure-based molecular simulation and binding affinity tests show PROP has an overall lower binding affinity than RAC. Taken together, our studies provide solid in vivo evidence to support that RAC plays crucial roles on modulating cardiovascular, respiratory, and locomotory physiology in zebrafish for the first time. In addition, the versatile functions of RAC as ß-agonist possibly mediated via receptor competition with PROP as ß-antagonist.

Lung cancer dynamics using fractional order impedance modeling on a mimicked lung tumor setup.

Introduction: As pulmonary dysfunctions are prospective factors for developing cancer, efforts are needed to solve the limitations regarding applications in lung cancer. Fractional order respiratory impedance models can be indicative of lung cancer dynamics and tissue heterogeneity. Objective: The purpose of this study is to investigate how the existence of a tumorous tissue in the lung modifies the parameters of the proposed models. The first use of a prototype forced oscillations technique (FOT) device in a mimicked lung tumor setup is investigated by comparing and interpreting the experimental findings. Methods: The fractional order model parameters are determined for the mechanical properties of the healthy and tumorous lung. Two protocols have been performed for a mimicked lung tumor setup in a laboratory environment. A low frequency evaluation of respiratory impedance model and nonlinearity index were assessed using the forced oscillations technique. Results: The viscoelastic properties of the lung tissue change, results being mirrored in the respiratory impedance assessment via FOT. The results demonstrate significant differences among the mimicked healthy and tumor measurements, (p-values <0.05) for impedance values and also for heterogeneity index. However, there was no significant difference in lung function before and after immersing the mimicked lung in water or saline solution, denoting no structural changes. Conclusion: Simulation tests comparing the changes in impedance support the research hypothesis. The impedance frequency response is effective in non-invasive identification of respiratory tissue abnormalities in tumorous lung, analyzed with appropriate fractional models.

Study of the Expected Impact of Palm Pollen on Human Respiratory Tract Allergy.

<b>Background and Objective:</b> Date-Palm trees (<i>Phoenix dactylifera</i> L.) are the most abundant crop in Saudi Arabia. Date Palm Pollen (DPP) are considered an important allergens. The reasons for the increase in susceptibility to allergy are not clear. This investigation aimed to link the size, shape, moisture contents and biogenic contents of the collected pollens to susceptibility. <b>Materials and Methods:</b> Pollens were collected from three different regions in the Kingdom. Date palm pollen sizes were determined in wet and dry states by Microtrac. A microscope with a camera was used to image the forms of date palm pollens. The biogenic amines were determined after extraction using HPLC. Data were analyzed by one-way analysis of variance (ANOVA), using SPSS version 16.0. <b>Results:</b> There was a variation in the sizes of pollens from different regions ranging between 3.3-704 µm. Most pollen grains are spherical. The concentrations of six biogenic amines were detected in all samples but with different concentrations. They included B-phenyl ethylamine, Putrescine, Cadaverine, Histamine, Tyramine and Spermidine. <b>Conclusion:</b> The shape and size of the pollen grains studied were variable and will not facilitate deep penetration into the respiratory system but their biogenic contents were very high and suggested to cause allergy.

Multi-disciplinary management of patients with benign airway strictures: A review.

Histologically benign airway strictures are frequently misdiagnosed as asthma or COPD and may present with severe symptoms including respiratory failure. A clear understanding of pathophysiology and existing classification systems is needed to determine the appropriate treatment options and predict clinical course. Clinically significant airway strictures can involve the upper and central airways extending from the subglottis to the lobar airways. Optimal evaluation includes a proper history and physical examination, neck and chest computed tomography, pulmonary function testing, endoscopy and serology. Available treatments include medical therapy, endoscopic procedures and open surgery which are based on the stricture's extent, location, etiology, morphology, severity of airway narrowing and patient's functional status. The acuity of the process, patient's co-morbidities and operability at the time of evaluation determine the need for open surgical or endoscopic interventions. The optimal management of patients with benign airway strictures requires the availability, expertise and collaboration of otolaryngologists, thoracic surgeons and interventional pulmonologists. Multidisciplinary airway teams can facilitate accurate diagnosis, guide management and avoid unnecessary procedures that could potentially worsen the extent of the disease or clinical course. Implementation of a complex airway program including multidisciplinary clinics and conferences ensures that such collaboration leads to timely, patient-centered and evidence-based interventions. In this article we outline algorithms of care and illustrate therapeutic techniques based on published evidence.

Involvement of epithelia-derived exosomes in chronic respiratory diseases.

Exosomes are tiny membrane lipid bilayer vesicles (φ40-100 nm) formed by the fusion of multivesicular bodies with plasma membrane, which are released extracellular by exocytosis. As natural nanocarriers, exosomes contain a variety of signal substances of the mother cell: nucleic acids, proteins and lipids, etc., which always play a vital role in the transmission of signal molecules between different cells. Epithelial cells are the first-line defense system against various inhaled allergens causing chronic respiratory diseases (CRD), such as asthma and chronic obstructive pulmonary disease (COPD). It's noted that increasing literature shows the exosomes derived from epithelial cells are involved in the pathogenesis of CRD. Moreover, the correlations between exosome cargo and the disease phenotypes show a high potential of using exosomes as biomarkers of CRD. In this review, we mainly focus on the physiological functions of epithelial-derived exosomes and illustrate the involved mechanism of epithelial-derived exosomes in common CRD.

SARS-CoV-2 shedding dynamics across the respiratory tract, sex, and disease severity for adult and pediatric COVID-19.

Background: Previously, we conducted a systematic review and analyzed the respiratory kinetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Chen et al., 2021). How age, sex, and coronavirus disease 2019 (COVID-19) severity interplay to influence the shedding dynamics of SARS-CoV-2, however, remains poorly understood. Methods: We updated our systematic dataset, collected individual case characteristics, and conducted stratified analyses of SARS-CoV-2 shedding dynamics in the upper (URT) and lower respiratory tract (LRT) across COVID-19 severity, sex, and age groups (aged 0-17 years, 18-59 years, and 60 years or older). Results: The systematic dataset included 1266 adults and 136 children with COVID-19. Our analyses indicated that high, persistent LRT shedding of SARS-CoV-2 characterized severe COVID-19 in adults. Severe cases tended to show slightly higher URT shedding post-symptom onset, but similar rates of viral clearance, when compared to nonsevere infections. After stratifying for disease severity, sex and age (including child vs. adult) were not predictive of respiratory shedding. The estimated accuracy for using LRT shedding as a prognostic indicator for COVID-19 severity was up to 81%, whereas it was up to 65% for URT shedding. Conclusions: Virological factors, especially in the LRT, facilitate the pathogenesis of severe COVID-19. Disease severity, rather than sex or age, predicts SARS-CoV-2 kinetics. LRT viral load may prognosticate COVID-19 severity in patients before the timing of deterioration and should do so more accurately than URT viral load. Funding: Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery Grant, NSERC Senior Industrial Research Chair, and the Toronto COVID-19 Action Fund.

Physiological and pathophysiological roles of acidic mammalian chitinase (CHIA) in multiple organs.

Acidic mammalian chitinase (CHIA) belongs to the 18-glycosidase family and is expressed in epithelial cells and certain immune cells (such as neutrophils and macrophages) in various organs. Under physiological conditions, as a hydrolase, CHIA can degrade chitin-containing pathogens, participate in Type 2 helper T (Th2)-mediated inflammation, and enhance innate and adaptive immunity to pathogen invasion. Under pathological conditions, such as rhinitis, ocular conjunctivitis, asthma, chronic atrophic gastritis, type 2 diabetes, and pulmonary interstitial fibrosis, CHIA expression is significantly changed. In addition, studies have shown that CHIA has an anti-apoptotic effect, promotes epithelial cell proliferation and maintains organ integrity, and these effects are not related to chitinase degradation. CHIA can also be used as a biomolecular marker in diseases such as chronic atrophic gastritis, dry eye, and acute kidney damage caused by sepsis. Analysis of the authoritative TCGA database shows that CHIA expression in gastric adenocarcinoma, liver cancer, renal clear cell carcinoma and other tumors is significantly downregulated compared with that in normal tissues, but the specific mechanism is unclear. This review is based on all surveys conducted to date and summarizes the expression patterns and functional diversity of CHIA in various organs. Understanding the physiological and pathophysiological relevance of CHIA in multiple organs opens new possibilities for disease treatment.

Modular Breath Analyzer (MBA): Introduction of a Breath Analyzer Platform Based on an Innovative and Unique, Modular eNose Concept for Breath Diagnostics and Utilization of Calibration Transfer Methods in Breath Analysis Studies.

Exhaled breath analysis for early disease detection may provide a convenient method for painless and non-invasive diagnosis. In this work, a novel, compact and easy-to-use breath analyzer platform with a modular sensing chamber and direct breath sampling unit is presented. The developed analyzer system comprises a compact, low volume, temperature-controlled sensing chamber in three modules that can host any type of resistive gas sensor arrays. Furthermore, in this study three modular breath analyzers are explicitly tested for reproducibility in a real-life breath analysis experiment with several calibration transfer (CT) techniques using transfer samples from the experiment. The experiment consists of classifying breath samples from 15 subjects before and after eating a specific meal using three instruments. We investigate the possibility to transfer calibration models across instruments using transfer samples from the experiment under study, since representative samples of human breath at some conditions are difficult to simulate in a laboratory. For example, exhaled breath from subjects suffering from a disease for which the biomarkers are mostly unknown. Results show that many transfer samples of all the classes under study (in our case meal/no meal) are needed, although some CT methods present reasonably good results with only one class.