ARTICLE | doi:10.20944/preprints202204.0114.v1
Subject: Life Sciences, Microbiology Keywords: Cystic Fibrosis; elexacaftor-tezacaftor-ivacaftor; microbiology; airway colonization
Online: 13 April 2022 (04:06:36 CEST)
The use of modulator drugs that target the cystic fibrosis transmembrane conductance regulator (CFTR) is the final frontier in the treatment of Cystic Fibrosis (CF), a genetic multiorgan disease. F508del is the most common mutation causing defective formation and function of CFTR. Elexacaftor-tezacaftor-ivacaftor is the first triple combination of CFTR modulators. Herein we report on a one-year case-control study that involved 26 patients with at least one F508del mutation. Patients were assigned to two similar groups, with patients with the worse clinical condition receiving treatment with the triple combination therapy. The study aims to define the clinical and especially microbiological implications of treatment administration. The treatment provided significant clinical benefits in terms of respiratory, pancreatic and sweat function. After one year of therapy, airway infection rates decreased and pulmonary exacerbations were dramatically reduced. Finally, treated patients reported a surprising improvement in their quality of life. The use of triple combination therapy has become essential in most CF people carrying the F508del mutation. While the clinical and instrumental benefits of treatment are thoroughly known, further investigations are needed to properly define its microbiological respiratory implications and establish the real advantage of life-long treatment with elexacaftor-tezacaftor-ivacaftor.
ARTICLE | doi:10.20944/preprints202105.0634.v1
Subject: Medicine & Pharmacology, Allergology Keywords: silica; nanoparticles; ATP; purinergic receptor; airway; epithelial cell
Online: 26 May 2021 (11:45:50 CEST)
Because of their low cost and easy production silica nanoparticles (NPs) are amply used in multiple manufactures as anti-caking, densifying and hydrophobic agents. However, this has increased the exposure levels of the general population and has raised concerns about possible toxicity of this nanomaterial. NPs are known to affect the function of the airway epithelium, but the biochemical pathways targeted by these particles remain largely unknown. Here we investigated the effects of NPs on the responses of cultured human bronchial epithelial (16HBE) cells to the damage-associated molecular pattern ATP, using fluorometric measurements of intracellular Ca2+ concentration. Upon stimulation with extracellular ATP these cells displayed a concentration-dependent increase in intracellular Ca2+, which was mediated by release from intracellular stores. Silica NPs inhibited the Ca2+ responses to ATP within minutes of application and at low micromolar concentrations, which are significantly faster and more potent than those previously reported for the induction of cellular toxicity and pro-inflammatory responses. NPs-induced inhibition appeared to be independent from the increase in intracellular Ca2+ they produce, and via a non-competitive mechanism. These findings suggest that NPs reduce the ability of airway epithelial cells to mount ATP-dependent protective responses such as the increase in mucociliary clearance and cough.
ARTICLE | doi:10.20944/preprints202207.0454.v1
Subject: Medicine & Pharmacology, Dentistry Keywords: orthodontics; airway; clear aligners; 3D diagnostics; sleep apnea; CBCT
Online: 29 July 2022 (09:37:56 CEST)
This retrospective study evaluated changes in the pharyngeal portion of the upper airway in pa-tients with constricted and normal airway treated with clear aligners (Invisalign, Align). Additionally, the paper has assessed the change of tongue position in the oral cavity from lateral view. Evaluation was performed with specialized software (Invivo 6.0, Anatomage) on pre-treatment and posttreatment pairs of cone beam computed tomography imaging (CBCT) data. The level of airway constriction, volume, cross-section minimal area, and tongue profile were evaluated. Patients with malocclusion, with pair or initial and finishing CBCT and without sig-nificant weight change between the scans, treated with Invisalign clear aligners were distributed in two groups. Group A consisted of fifty-five patients with orthodontic malocclusion and con-stricted upper airway. Control group B consisted of thirty-one patients with orthodontic malocclusions without any airway constriction. In the group with airway constriction, there was a statistically significant increase in volume during therapy (p<0.001). The surface of the most con-stricted cross-section of airway did not change significantly after treatment in any of the groups. The airway constriction was most frequently localized at the level of 2nd cervical vertebra. The final tongue position was different from initial in 62.2% of all clear aligner treatments.
Subject: Medicine & Pharmacology, Anesthesiology Keywords: Covid-19; airway extubation; aerosols; laryngeal masks; occupational health
Online: 7 April 2020 (12:33:07 CEST)
We report smooth weaning from mechanical ventilation in a patient with COVID-19. The use of the supraglottic airway device can cause fewer coughs in weaning from mechanical ventilation. This procedure avoids the aerosol-generating procedure, tracheal extubation, and is beneficial in terms of occupational health for health care workers.
ARTICLE | doi:10.20944/preprints202211.0500.v1
Subject: Engineering, Mechanical Engineering Keywords: CFD-DEM; Particle-particle interaction; Upper airway; DE; Spring constant
Online: 28 November 2022 (07:29:49 CET)
The fluid flow field at the upper airways is highly complex due to the complex structure of the airway. The inhaled particle flow, the air streamline and the interaction of the continuum and discrete phase could significantly affect the transport behaviour of the inhaled particles. A range of analytical, mathematical and computational fluid dynamics (CFD) models analyzed the airflow and particle transport in different idealized and asymmetric airway models. A precise understanding of the continuum and discrete phase interaction in realistic human airways is missing, and this study aims to develop a CFD-DEM model for particle transport in realistic airways. This study uses the CFD model for the continuum phase and the discrete element method (DEM) for the discrete phase. A soft sphere approach is used for the interaction of the discrete phase. Proper validation is performed for particle transport efficiency. The CFD-DEM model analyzed the particle transport in an idealized and realistic airway model, and different methods are used to analyze the transport behaviour. During the particle-particle interaction, a stagnation point and a high-pressure zone are observed at the airway model's carinal angle. The numerical results report higher deposition efficiency (DE) for particle-particle interaction than without interaction. The flow field becomes highly complex with the spring constant values, and higher DE is found for high spring constant values. The spring dashpot friction-dshf method shows higher deposition at the upper part of the airways than other interaction methods. The findings of this study and more case-specific analysis would improve the knowledge of aerosol transport in airways and the health risk assessment of the patient.
ARTICLE | doi:10.20944/preprints202211.0172.v1
Subject: Medicine & Pharmacology, Anesthesiology Keywords: airway manikin; apnoeic oxygenation; denitrogenisation; desaturation; oxygen insufflation; test lung
Online: 9 November 2022 (09:05:27 CET)
Background. In a cannot ventilate cannot intubate situation, careful preoxygenation with high FiO2 allowing subsequent apneic oxygenation can be life-saving. The best position for an oxygen supply line within the human airway at which oxygen insufflation is more effective than standard preoxygenation with a face mask, or comparably effective as intratracheal insufflation, is unknown. Methods. In this experimental study, we compared effectiveness of preoxygenation by placing an oxygen cannula at the nose entrance, through the nose at the soft palatine, or at the base of tongue; as control we used ambient air. We connected a fully preoxygenated test lung on one side to an oximeter with a flow rate of 200ml/min simulating oxygen consumption of a normal adult, and on the other side to the trachea of an anatomically correctly shaped airway manikin over a 20 min observation period five times for each cannula placement in random order. Results. Oxygen percentage in the test lung dropped from 100% in all groups to 53±1% in the ambient air control group, to 87±2% in the nasal cannula group, to 96±2% in the soft palatine group, while it remained at 99±1% in the base of tongue group (p=0.003 for soft palatine vs base of tongue; and p<0.001 between all other groups). Conclusions. When simulating apneic oxygenation in a preoxygenated manikin, oxygen insufflation at the base of tongue kept oxygen percentage at baseline values of 99% demonstrating a complete block for ambient air flowing into the manikin’s airway. Oxygen insufflation at the soft palatine or insufflation via nasal cannula were less effective in regard of this effect.
ARTICLE | doi:10.20944/preprints202111.0195.v2
Subject: Medicine & Pharmacology, Other Keywords: airway model; DPI; inhalation; aerosol testing; drug delivery; porcine lung
Online: 22 December 2021 (12:09:20 CET)
Dry powder inhalers are used by a large number of patients worldwide to treat respiratory diseases. The objective of this work is to experimentally investigate changes in aerosol particle diameter and particle number concentration of pharmaceutical aerosols generated by five dry powder inhalers under realistic inhalation and exhalation conditions. The active respiratory system model (xPULM™) was used as a model of the human respiratory system and to simulate a patient undergoing inhalation therapy. A mechanical upper airway model was developed, manufactured and introduced as a part of the xPULM™ to represent the human upper respiratory tract with high fidelity. Integration of optical aerosol spectrometry technique into the setup allowed for evaluation of pharmaceutical aerosols. The results show that the upper airway model increases the resistance of the overall system and act as a filter for bigger particles (>3 µm). Furthermore, there is a significant difference (p < 0.05) in mean particle diameter between inhaled and exhaled particles with the majority of the particles depositing in the lung. The minimum deposition is reached for particle size of 0.5 µm. The mean particle number concentrations exhaled are 2.94% (BreezHaler®), 2.66% (Diskus®), 10.24% (Ellipta®) 2.13% (HandiHaler®) and 6.22% (Turbohaler®). In conclusion, the xPULM™ active respiratory system model is a viable option for studying interactions of pharmaceutical aerosols and the respiratory tract in terms of applicable deposition mechanisms. The model can support the reduction of animal experimentation in aerosol research and provide an alternative to experiments with human subjects.
ARTICLE | doi:10.20944/preprints202107.0356.v1
Subject: Biology, Anatomy & Morphology Keywords: airway cell exosomes; viral infection; microglia; mitochondria; reactive oxygen species
Online: 15 July 2021 (11:12:49 CEST)
Viral infections induce exosomes containing viral material and inflammatory factors. During respiratory tract infection, exosomes can easily cross the blood-brain barrier and transmit the inflammatory signal to the brain; however, such a hypothesis has no experimental evidence. The study investigated whether exosomes from virus mimetic poly (I:C)-primed airway cells enter the brain and interact with brain immune cells microglia. Airway cells were isolated from Wistar rats and BALB/c mice; microglial cell cultures - from Wistar rats. Exosomes from poly (I:C)-stimulated airway cell culture medium were isolated by precipitation, visualised by transmission electron microscopy, and evaluated by nanoparticle analyser; exosomal markers CD81 and CD9 were determined by ELISA. For in vitro and in vivo tracking, exosomes were loaded with Alexa Fluor 555-labelled RNA. Intracellular reactive oxygen species (ROS) were evaluated by DCFDA fluo-rescence and mitochondrial superoxide - by MitoSOX. The exosomes from poly (I:C)-primed airway cells entered the brain within an hour after intranasal introduction, were internalised by microglia, and induced intracellular and intramitochondrial ROS production. There was no ROS increase in microglial cells was after treatment with exosomes from airway cells untreated with poly (I:C). The data indicate that virus-primed airway cell exosomes might enter the brain and induce the activation of microglial cells.
REVIEW | doi:10.20944/preprints202008.0260.v1
Subject: Medicine & Pharmacology, Pharmacology & Toxicology Keywords: COPD; muco-obstructive lung diseases; airway mucus hypersecretion; MUC5AC; cell differentiation
Online: 11 August 2020 (09:20:57 CEST)
Chronic obstructive pulmonary disease (COPD) is associated with high morbidity and mortality globally. Studies show that airway mucus hypersecretion strongly compromises lung function, leading to frequent hospitalization and mortality, highlighting an urgent need for effective COPD treatments. MUC5AC is known to contribute to severe muco-obstructive lung diseases, worsening COPD pathogenesis. Various pathways are implicated in the aberrant MUC5AC production and secretion MUC5AC. These include signaling pathways associated with mucus-secreting cell differentiation [ nuclear factor-κB (NF-кB)and IL-13-STAT6- SAM pointed domain containing E26 transformation-specific transcription factor (SPDEF), as well as epithelial sodium channel (ENaC) and cystic fibrosis transmembrane conductance regulator (CFTR)], and signaling pathways related to mucus transport and excretion-ciliary beat frequency (CBF). Various inhibitors of mucus hypersecretion are in clinical use but have had limited benefits against COPD. Thus, novel therapies targeting airway mucus hypersecretion should be developed for effective management of muco-obstructive lung disease. Here, we systematically review the mechanisms and pathogenesis of airway mucus hypersecretion, with emphasis on multi-target and multi-link intervention strategies for the elucidation of novel inhibitors of airway mucus hypersecretion.
REVIEW | doi:10.20944/preprints202212.0153.v1
Subject: Life Sciences, Cell & Developmental Biology Keywords: epithelial; smooth muscle; interaction; pulmonary disease; airway; asthma; COPD; bronchial re-modeling
Online: 8 December 2022 (09:46:26 CET)
Chronic pulmonary diseases such as asthma, COPD, and Idiopathic pulmonary fibrosis are significant causes of mortality and morbidity worldwide. Currently, there is no radical treatment for many chronic pulmonary diseases, and the treatment options focus on relieving the symptoms and improving lung function. Therefore, efficient therapeutic agents are highly needed. Bronchial epithelial cells and airway smooth muscle cells and their crosstalk play a significant role in the pathogenesis of these diseases. Thus, targeting the interactions of these two cell types could open the door to a new generation of effective therapeutic options. However, the studies on how these two cell types interact and how their crosstalk adds up to respiratory diseases are not well established. With the rise of modern research tools and technology, such as lab-on-chip, organoids, co-culture techniques, and advanced immunofluorescence imaging, a substantial degree of evidence about these cell interactions emerged. Hence, this contribution aims to review the growing evidence of bronchial epithelial cells and airway smooth muscle cells crosstalk under normal and pathophysiological conditions. The review first deliberates the effects of both healthy and stressed epithelial cells on airway smooth muscle cells, taking into account three themes; contraction, migration, and proliferation. Then, it discusses the impact of airway smooth muscle cells on the epithelium in inflammatory settings. Later, it examines the role of airway smooth muscle cells in the early development of bronchial epithelial cells and their recovery after injury.
REVIEW | doi:10.20944/preprints202007.0349.v1
Subject: Life Sciences, Molecular Biology Keywords: systematic review; extracellular vesicles; EVs; asthma; therapy; inflammation; respiratory disease; airway hyperresponsiveness; BALF
Online: 16 July 2020 (12:52:03 CEST)
Asthma is the most common chronic disease in children. It is characterized by difficulty in breathing and chronic airway inflammation associated with narrowing of the airways, and airway hyperresponsiveness. If left untreated, asthma can lead to respiratory distress and even death. A number of medications are available and prescribed to manage asthma. Yet despite that, only half of the asthmatic patients are able to control their condition. Extracellular vesicles (EVs) play an important role in transporting contents such as nucleic acids, proteins, and lipids to other cells. While EVs have been extensively studied as biomarkers of various pathological states, evidence indicates that they can play protective and therapeutic roles in mitigating diseases such as cancer, cardiovascular disease and asthma. Here we propose to conduct a systematic review that provides a detailed analysis of the therapeutic effect of EVs in mitigating the primary (inflammation, airway hyperresponsiveness) and secondary outcomes (airway remodelling, molecular indices of cellular signalling, and inflammatory mediators in serum) associated with asthma in preclinical studies.
REVIEW | doi:10.20944/preprints202108.0551.v1
Subject: Medicine & Pharmacology, Nutrition Keywords: Obstructive sleep apnoea; intermittent airway obstruction; sleep disorder; magnesium; micronutrient deficiency; metabolic risk factor
Online: 30 August 2021 (15:47:33 CEST)
Purpose: Obstructive sleep apnoea (OSA) affects patients’ quality of life and health. Magnesium (Mg) is an essential mineral and a potent antioxidant. Mg deficiency can worsen oxidative stress caused by sleep deprivation or disorders. The impact of OSA on serum Mg levels and its health consequences remain unclear. Methods: This study systematically reviewed clinical studies investigating the serum Mg levels of OSA patients and the potential relationships with other biomarkers.Results: Six articles were included for qualitative synthesis; five were used in quantitative analysis. Two out of four studies that compared OSA patients to healthy controls found them to have significantly lower serum Mg levels. Our meta-analysis with three studies shows that patients with OSA had significantly lower serum Mg with an effect size of -1.22 (95% CI: -2.24, -0.21). However, the mean serum Mg level of OSA patients (n=251) pooled from five studies (1.90 mg/dL, 95% CI: 1.77, 2.04) does not differ significantly from the normal range. OSA severity appears to affect serum Mg negatively. Serum Mg levels generally improve after treatment, coincide with the improvement of OSA severity. Low serum Mg levels correlate with worsening of cardiovascular risk biomarkers of C-reactive protein, ischaemia-modified albumin, and carotid intima-media thickness. The serum Mg levels also potentially correlate with biomarkers for lipid profile, glucose metabolism, calcium and heavy metals. Conclusions: Sleep deprivation appears to deplete Mg levels of OSA patients, making them at risk of Mg deficiency, which potentially increases systemic inflammation and the risk of cardiovascular and metabolic diseases.
REVIEW | doi:10.20944/preprints202210.0215.v2
Subject: Medicine & Pharmacology, Anesthesiology Keywords: Double lumen tube; Malposition; Thoracic surgery; Airway management; One-lung ventilation; Fiberoptic bronchoscopy; Bibliometric analysis
Online: 23 November 2022 (07:20:57 CET)
The thoracic surgery has increased drastically in recent years, especially in the light of the severe outbreak of 2019 novel coronavirus disease (COVID-19). Routine “passive” chest computed tomography (CT) screening of inpatients detects some pulmonary diseases requiring thoracic surgeries timely. As an essential device for thoracic anesthesia, the double-lumen tube (DLT) is particularly important for anesthesia and surgery. With the continuous upgrading of the DLTs and the widespread use of the fiberoptic bronchoscopy (FOB), the position of DLT in thoracic surgery is gradually becoming more stable and easier to observe or adjust. However, the DLT malposition still occurs during transferring patients from supine to lateral position in thoracic surgery, which leads to lung isolation failure and hypoxemia during one-lung ventilation (OLV). Recently some innovative DLTs or improved intervention methods have shown good results in reducing the incidence of DLT malposition. This review aims to summarize the recent studies of the incidence of left-sided DLT malposition, the reasons and effects of malposition, and summarize current methods for reducing DLT malposition and prospects for possible approaches. Meanwhile, we use bibliometric analysis to summarize the research trends and hot spots of the DLT research.
ARTICLE | doi:10.20944/preprints202112.0284.v1
Subject: Medicine & Pharmacology, Other Keywords: Retina; Retinal nerve fiber layer; Obstructive sleep apnea syndrome; Optical coherence tomography; OCT; CPAP; Upper airway surgery.
Online: 17 December 2021 (08:47:15 CET)
Retinal findings may change in patients with obstructive sleep apnea syndrome (OSAS). The present study aims to evaluate several retinal findings such as macula layer thickness, peripapillary retinal nerve fiber layer, and the optic nerve head in patients with OSAS using optical coherence tomography (OCT) and monitor the result of several types of treatment of OSAS with OCT. A prospective comparative study was designed. Patients were recruited at a Sleep Unit of a University Hospital and underwent comprehensive ophthalmological examinations. Following exclusion criteria, fifty-two patients with OSAS were finally included. Patients were examined by OCT twice: first, before treatment; secondly, after six months of treatment. In mild-moderate patients, where retinal swelling has been demonstrated, retinal thicknesses decreased [fovea (p=0.026), as well as inner ring macula (p=0.007), outer ring macula (p=0.015), and macular volume (p=0.015)]. In severe patients, where retinal atrophy had been observed, retinal thickness increased [fovea (p<0.001)]. No statistically significant differences in efficacy between treatments were demonstrated. In conclusion, OCT can evaluate the retina in patients with OSAS and help monitor results after treatment. In severe OSAS, retinal thickness increased six months after treatment.
ARTICLE | doi:10.20944/preprints202105.0522.v1
Subject: Life Sciences, Biochemistry Keywords: Cerium oxide NPs; acute and subchronic toxicity; in vitro; pulmonary and interstitial cell lines; human airway epithelial model; air-liquid interface; aerosolized NPs.
Online: 21 May 2021 (13:17:36 CEST)
Engineered nanomaterials (ENMs) are of significant relevance due to their unique properties, which have been exploited for widespread applications. Cerium oxide nanoparticles (CeO2-NPs) are one of most exploited ENM in the industry due to their excellent catalytic and multi-enzyme mimetic properties. Thus, toxicological effects of these ENMs should be further studied. Acute and subchronic toxicity of CeO2-NPs were assessed. First an in vitro multi-dose short-term (24h) toxicological assessment was performed in three different cell lines: A549 and Calu3, representing the lung tissue, and 3T3 as an interstitial tissue model. After that, a sub-chronic toxicity assessment (90 days) of these NPs was carried out on a realistic and well stablished reconstituted primary human airway epithelial model (MucilAir™), cultured at the Air-Liquid Interface (ALI), to study long-term effects of these particles. Results showed minor toxicity of CeO2-NPs in acute exposures. However, in subchronic exposures, cytotoxic and inflammatory responses were observed in the human airway epithelial model after 60 days of exposure to CeO2-NPs. These results suggest that acute toxicity approaches may underestimate the toxicological effect of some ENM, highlighting the need of subchronic toxicological studies in order to accurately assess the toxicity of ENM and their cumulative effects in the organism.