Role Of Airways Research Articles

Airway inflammation due to SARS-CoV-2

Although there has been a large number of studies focusing on the role of airways in coronavirus disease 2019 (COVID-19), the relationship still remains unclear. With the disruption of the defense mechanism of the airways, including the intact mucus barrier, ciliary activity, and normal cough reflex, sticky and difficult-to-remove sputum becomes the main problem and the cough becomes the main symptom. Although interferons are considered the main elements of the defense against the virus, the pathogenesis of COVID-19 is complex and cannot be elucidated with only elevated interferon levels; there is more. The progression of the disease is mainly determined by the type and the levels of interferons and the affected part of the respiratory system. The airways have an important role in the pathogenesis of COVID-19, as the microorganism uses the airways as a gateway to the body, being the first element of defense against the virus, the importance of its relationship with the immune system, and its importance in the treatment.

To Detect and Reject, Parallel Roles for Taste and Immunity.

Purpose of ReviewFrom single cells to entire organisms, biological entities are in constant communication with their surroundings, deciding what to ‘allow’ in, and what to reject. In very different ways, the immune and taste systems both fulfill this function, with growing evidence suggesting a relationship between the two, through shared signaling pathways, receptors, and feedback loops. The purpose of this review was to explore recent reports on taste and immunity in model animals and in humans to explore our understanding of the interplay between these systems.Recent FindingsAcute infections in the upper airway, as with SARS-CoV-2, are associated with a proinflammatory state, and blunted taste perception. Further, recent findings highlight taste receptors working as immune sentinels throughout the body. Work in humans and mice also points to inflammation from obesity impacting taste, altering taste bud abundance and composition.SummaryThere is accumulating evidence that taste cells, and particularly their receptors, play a role in airway and gut immunity, responsive to invading organisms. Inflammation itself may further act on taste buds and other taste receptor expressing cells throughout the body as a form of homeostatic control.

Organic Cation Transporters (OCTs) in EpiAirway™, A Cellular Model of Normal Human Bronchial Epithelium.

Organic cation transporters (OCTs) and novel organic cation transporters (OCTNs) are responsible for drug delivery in the intestine and kidney; in the lung, OCTs mediate inhaled drugs’ transport, although their physiological role in airways remains poorly understood. The studies addressing OCTs/OCTNs in human airways were mostly performed in immortal or transformed cell lines; here, we studied OCTs in EpiAirway™, a recently developed in vitro model of normal bronchial epithelium. Calu-3 monolayers were used for comparison. The activity of OCTs was evaluated by measuring the uptake of 1-methyl-4-phenylpyridinium (MPP+) at the apical and basolateral side of monolayers and protein expression through Western Blot analysis. OCTs and OCTNs expression, along with that of Amino acid Transporter B0,+ (ATB0,+)transporter, was determined by measuring the number of mRNA molecules through quantitative Polymerase Chain Reaction (qPCR). The interaction of the transporters with bronchodilators was also assessed. Results highlight significant differences between Calu-3 cells and EpiAirway™, since, in the latter, OCTs are active only on the basolateral membrane where they interact with the bronchodilator ipratropium. No activity of OCTs is detectable at the apical side; there, the most abundant carrier is, instead, SLC6A14/ATB0,+, that can thus be potentially listed among organic cation transporters responsible for drug delivery in the lung.

Airway Epithelial Cell Peroxisome Proliferator-Activated Receptor γ Regulates Inflammation and Mucin Expression in Allergic Airway Disease.

Airway epithelial cells (AECs) orchestrate inflammatory responses to airborne irritants that enter the respiratory system. A viscous mucus layer produced by goblet cells in the airway epithelium also contributes to a physiological defense mechanism through the physical and chemical barriers it provides. Dysregulation or impairment in these functions has been implicated as a cause of the chronic inflammation and tissue remodeling that constitute major pathological features of asthma. In particular, mucus hypersecretion leading to airway obstruction and impaired pulmonary function is associated with morbidity and mortality in asthma patients. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor involved in a variety of cellular processes. Accumulating evidence indicates that PPARγ agonists antagonize exaggerated inflammatory responses, yet PPARγ's precise role in airway remodeling/mucus hypersecretion has yet to be defined. In this study, we created an AEC-specific PPARγ (AEC-PPARγ) deletion to investigate PPARγ's functions in a murine model of allergic airway disease. AEC-PPARγ deficiency exaggerated airway hyperresponsiveness, inflammation, cytokine expression, and tissue remodeling. We also found that PPARγ directly bound to a PPAR response element found in MUC5AC and repressed gene expression. Likewise, PPARγ regulated mucin and inflammatory factors in primary human bronchial epithelial cells. In light of the current standard therapies' limited and inadequate direct effect on airway mucus hypersecretion, our study showing AEC-PPARγ's role as a transcriptional repressor of MUC5AC highlights this receptor's potential as a pharmacological target for asthma.

Pneumocystis colonization in asthmatic patients not receiving oral corticosteroid therapy

Pneumocystis jirovecii can colonize patients with chronic obstructive pulmonary disease. To determine if colonization occurs in asthma patients, sputum samples from 10 patients with mild asthma, who were not receiving...

Vitamin D Deficiency Is Associated with Rapid Decline in Exercise Capacity in Male Patients with Chronic Obstructive Pulmonary Disease

Background: Vitamin D is suggested to play a role in airway and systemic inflammation in chronic obstructive pulmonary disease (COPD). Low serum 25-hydroxyvitamin D (25-OHD) levels have been suggested to be associated with lower lung function and poorer exercise capacity in COPD. Objectives: The main purpose of this study was to investigate the effects of vitamin D deficiency on the change in exercise capacity in male COPD patients. Methods: A total of 156 male subjects were selected from the Korean Obstructive Lung Disease cohort. Vitamin D deficiency was subdivided into three subgroups: mild, moderate, and severe deficiency groups. Rapid decline was defined as an annual rate of change in exercise capacity ≥17 m. Exercise capacity was assessed by 6-minute walk distance (6MWD). Results: Significant differences were observed in the serum levels of 25-OHD, the number of patients with vitamin D sufficiency, and moderate-to-severe deficiency between rapid decliners (n = 40) and non-rapid decliners (n = 116). No differences were found between the groups for age, smoking status, lung function, and 6MWD. Multivariate analysis showed that vitamin D deficiency was independently related to rapid decline in exercise capacity (p = 0.028). A statistically significant difference was observed among the subgroups of vitamin D deficiency in terms of the change in exercise capacity (p < 0.001). The annual decline in exercise capacity was prominent in the severe deficiency group (23.1 m/year). Conclusion: This study shows that vitamin D deficiency is associated with rapid decline in exercise capacity in male patients with COPD.

The Role of Airway and Endobronchial Ultrasound in Perioperative Medicine.

Recent years have witnessed an increased use of ultrasound in evaluation of the airway and the lower parts of the respiratory system. Ultrasound examination is fast and reliable and can be performed at the bedside and does not carry the risk of exposure to ionizing radiation. Apart from use in diagnostics it may also provide safe guidance for invasive and semi-invasive procedures. Ultrasound examination of the oral cavity structures, epiglottis, vocal cords, and subglottic space may help in the prediction of difficult intubation. Preoperative ultrasound may diagnose vocal cord palsy or deviation or stenosis of the trachea. Ultrasonography can also be used for confirmation of endotracheal tube, double-lumen tube, or laryngeal mask placement. This can be achieved by direct examination of the tube inside the trachea or by indirect methods evaluating lung movements. Postoperative airway ultrasound may reveal laryngeal pathology or subglottic oedema. Conventional ultrasound is a reliable real-time navigational tool for emergency cricothyrotomy or percutaneous dilational tracheostomy. Endobronchial ultrasound is a combination of bronchoscopy and ultrasonography and is used for preoperative examination of lung cancer and solitary pulmonary nodules. The method is also useful for real-time navigated biopsies of such pathological structures.

Deficiency of urokinase plasminogen activator suppresses epithelial sodium channels in tracheal epithelial cells

Epithelial sodium channels (ENaC) govern transepithelial salt and fluid transport in tracheal, bronchi, and lungs. Fibrinolytic proteases play a crucial role in airway and lung injury and repair. We hypothesized that urokinase‐like plasminogen activator (uPA) regulates respiratory ENaC activity in primary mouse tracheal epithelial cells. The short‐circuit currents in confluent monolayer cells were compared between wild type and uPA null mice. Knockout of uPA led to depressed ENaC activity in both intact and permeabilized cells significantly. A significant decrease in Na+/K+‐ATPase activity was observed as well. Application of uPA and plasmin partially restored ENaC activity and increased cleavage of alpha ENaC proteins in confluent monolayers. ERK1/2 but not Akt phosphorylation was augmented in uPA−/− cells and lungs. Taken together, uPA may regulate ENaC activity via multifaceted mechanisms, including proteolytic cleavage of α ENaC proteins, reduction in vectorial Na+ driving force, and upregulation of ERK1/2 phosphorylation.Supported by NIH HL87017 and HL95435

The clinical application of Shikani in airway management

Background Shikani Optical Stylet (SOS) is a novel fiberoptic intubation device.It features both fiberoptic bronchoscope and lightwand,and it can be used for tracheal intubation and difficult airway management. Objective To review the application of SOS in the clinical setting and describe the characteristics of the technique for tracheal intubation. Content Summarizing the structural characteristics,operational technique,clinical application and clinical determination of SOS,especially reminding us of its limitations. Trend SOS will play a pivotal role in airway management.However,it is not a universal instrument to cope with all difficult airways,and clinical physicians should make decisions in accordance with specific conditions. Key words: Airway management; Shikani Optical Stylet; Difficult airway; Tracheal intubation

Neutralization of IL‐13Ra1 receptor on Human CD4+ CD45RO+ Memory T cells Stimulates Release of IL‐17

Interleukin 13 (IL‐13) has been shown to play a role in airway hyper‐responsiveness and immune cell‐mediated cytokine release in models of allergic airway inflammation. Additionally, neutralization of IL‐13 has been shown to improve lung function in a placebo‐controlled trial of adult asthmatics. Previous studies have shown that Th17 cells express a functional IL‐13 receptor and that IL‐13 attenuates IL‐17A, a cytokine involved in airway inflammation. The existence of a parallel IL‐13/IL‐17 axis in memory T cells, a source of inflammatory cytokines able to respond quickly to extrinsic insult and effect the tissue micro environment, has not been explored. In this study, human CD4+/CD45RO+/CCR7‐ effector memory T cells (TEM) were isolated from human blood and characterized by flow cytometry. Subsequently, cells were activated with anti‐CD3 and anti‐CD28 in the presence or absence of anti IL‐13Ra1 (20ng/ml) and anti IL‐4 (20ng/ml). Blockade of IL‐13Ra1 stimulated release of IL‐17A (8 fold) compared to unstimulated cells on day 5 post‐stimulation. Addition of an IL‐4Ra neutralizing antibody in combination with anti‐IL‐13Ra1 further increased IL‐17‐A expression compared to anti IL‐13Ra1 inhibition alone. These results suggest that increased IL‐17A production as a consequence of IL‐13 neutralization occurs in effector memory T‐cells.

Inflammatory cytokines in allergy and rhinosinusitis

Cytokines are involved in initiating and perpetuating the host immune response to allergens and also modulating the mucosal cellular milieu characteristic of chronic rhinosinusitis. This paper reviews the current state of knowledge regarding the most relevant cytokines in allergy and rhinosinusitis and highlights recent findings in the literature. Chronic rhinosinusitis with nasal polyps is characterized by a type 2 T helper cell cytokine polarization, whereas chronic rhinosinusitis without nasal polyps has a type 1 T helper cell cytokine expression pattern. Targeted therapies against specific cytokines such as interleukin-5 have shown promise in treating allergic diseases. Genetic polymorphisms in cytokines and their receptors have been shown to confer susceptibility to asthma and allergy. Transforming growth factor-beta has been found to have proinflammatory and anti-inflammatory effects in the nose and paranasal sinuses and appears to have a role in airway remodeling. Cytokines drive the immune system's response to allergen exposure and participate in sinonasal mucosal inflammatory conditions. Although the roles of individual cytokines in atopic disease and rhinosinusitis are becoming clearer, future studies will need to build on our knowledge of cytokine functions by focusing on therapeutic approaches to quieting the immune system and dampening the inflammatory cascade.

Role of the coagulation system in allergic inflammation in the upper airways

Thrombin has been detected and demonstrated to play a role in the airways of patients with bronchial asthma, but its role in the upper airways including during allergic rhinitis is unknown. This study was conducted to explore whether thrombin is presence in the upper airways and, if so, whether it affects mucin secretion. Fifteen patients with allergic rhinitis were enrolled in the clinical study; primary nasal septum epithelial cells and normal bronchial epithelial cells were used for in vitro evaluation, and rats as animal models. Significant concentrations of thrombin were found in nasal secretion after allergic provocation in allergic patients, and thrombin and its agonistic receptor peptide induced significant secretion of mucin in primary nasal cells and normal bronchial epithelial cells as compared to non-stimulated cells. Increased mucosubstance secretion in septum epithelial cells was also induced after nasal instillation of thrombin in rats. Further, the anticoagulant, activated protein C, significantly inhibited thrombin-induced mucin secretion from septum epithelial cells in rats. The results of this study suggest that activation of the coagulation system occurs during the allergic response and that thrombin plays a crucial role in the regulation of mucin production in the upper airways.

The IL-17F signaling pathway is involved in the induction of IFN-γ–inducible protein 10 in bronchial epithelial cells

IL-17F is involved in airway inflammation, but its biologic activity and signaling pathway remain incompletely defined. Interferon-gamma-inducible protein 10 (IP-10) is widely expressed and plays a role in airway inflammatory diseases. We sought to investigate the functional linkage between IL-17F and IP-10 expression in bronchial epithelial cells. Bronchial epithelial cells were cultured in the presence or absence of IL-17F, and/or a T(H)1 cytokine, T(H)2 cytokines, proinflammatory cytokines, various kinase inhibitors, or a Raf1 dominant-negative mutant to analyze the expression of IP-10. Moreover, the involvement of p90 ribosomal S6 kinase (p90RSK) and cyclic AMP response element-binding protein (CREB) in IL-17F-induced IP-10 expression were investigated. IL-17F induces the gene and protein expression of IP-10. The addition of IFN-gamma, IL-1beta, and TNF-alpha augmented IL-17F-induced IP-10 expression. The mitogen-activated protein kinase kinase (MEK) inhibitors PD98059, U0126, and Raf1 kinase inhibitor I significantly inhibited its production. In contrast, a p38 inhibitor, a JNK inhibitor, protein kinase C inhibitors, and a phosphatidylinositol 3-kinase inhibitor, showed no inhibitory effect. Furthermore, overexpression of a Raf1 dominant-negative mutant inhibited its expression. Of interest, IL-17F phosphorylated p90RSK and CREB, and transfection of the cells with a short interfering RNA for p90RSK or CREB inhibited its expression, suggesting p90RSK and CREB as novel signaling molecules of IL-17F. IL-17F is a potent inducer of IP-10 in bronchial epithelial cells through the activation of the Raf1-MEK1/2-extracellular signal-regulated kinase 1/2-p90RSK-CREB pathway, supporting its regulatory role in airway inflammation. The IL-17F-IP-10 axis might be a novel and critical therapeutic target for airway inflammatory diseases.

The Glidescope® system: a clinical assessment of performance

The Glidescope is a new videolaryngoscope. It has a digital camera incorporated in the blade which displays a view of the vocal cords on a monitor. This allows the placement of a tracheal tube to be visualised. We describe its performance in 50 patients who required orotracheal intubation for elective surgery. Two investigators performed 25 intubations each. Intubation with the Glidescope was successful in 47 of the 50 cases. The three failures occurred early in the series and were attributed to the initial learning curve. The success rate after the first eight patients in each series was 100%. The median (IQR [range]) time to intubation was 40 (30-55 [15-105]) s. The Glidescope provided a grade I view of the glottis in 44 cases and a grade II view in six cases. The view of the larynx was improved in almost half (23) of the cases. The Glidescope improved the view by one grade in 22 and by two grades in one patient. We conclude that the Glidescope is an effective device for tracheal intubation and provides an improved view of the larynx. Further clinical studies are necessary to evaluate its role in airways that are difficult to manage.

Nosocomial Pneumonia in the Intensive Care Unit: Controversies and Dilemmas

Nosocomial pneumonia (NP), and its most serious form, ventilator-associated pneumonia (VAP), is a major cause of morbidity and mortality in the ICU. Numerous controversies exist, from diagnostic criteria to prevention and treatment, including the issues of attributable mortality of VAP, differences in the approach to early and late VAP, and the best diagnostic methods. Initial, accurate therapy is one of the most important factors determining outcome in VAP. Antibiotic monotherapy versus combination therapy is not clearly defined, as clinicians struggle with the dual risk of inadequate therapy negatively affecting outcome and overtreatment promoting antibiotic resistance. The role of airway and gastrointestinal colonization and innovative preventive strategies such as noninvasive ventilation, antibiotic rotation, and aerosolized antibiotics are discussed. No uniform standards exist for the approach to VAP. The authors highlight the major controversies and dilemmas in the clinical approach to VAP, with recommendations for the bedside management of these patients.

Neutrophilic airway inflammation and IL-17.

Neutrophilic airway inflammation and IL-17.

Recent developments in diisocyanate asthma

Despite recent advances in our understanding of diisocyanate-induced asthma, this disease remains a perplexing phenomenon. Studies reported in the past year have focused on: (i) diisocyanate antigens; (ii) the role of airway and skin epithelium; (iii) human immune responses to exposure; (iv) neurogenic pathways; and (v) genetic factors that may confer susceptibility. These studies support the hypothesis that diisocyanate asthma results from the host immune response to these chemicals, and may represent a mixed T helper type 1/2 response. A better understanding of the pathogenesis of diisocyanate asthma should facilitate the development of better diagnostic tests and strategies for disease surveillance and intervention.

Recent developments in diisocyanate asthma

Despite recent advances in our understanding of diisocyanate-induced asthma, this disease remains a perplexing phenomenon. Studies reported in the past year have focused on: (i) diisocyanate antigens; (ii) the role of airway and skin epithelium; (iii) human immune responses to exposure; (iv) neurogenic pathways; and (v) genetic factors that may confer susceptibility. These studies support the hypothesis that diisocyanate asthma results from the host immune response to these chemicals, and may represent a mixed T helper type 1/2 response. A better understanding of the pathogenesis of diisocyanate asthma should facilitate the development of better diagnostic tests and strategies for disease surveillance and intervention.

Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients.

Antibacterial peptides and proteins are an integral part of the epithelial defense barrier that provides immediate protection against bacterial invasion. In humans, alpha-defensins are mainly bactericidal effectors in circulating granulocytes, beta-defensin-1 is synthesized in epithelial cells, and LL-37 is produced in granulocytes but is also induced in skin epithelia during inflammation. To investigate the importance of these defense effectors in disease, we analyzed bronchoalveolar lavage fluid (BALF) for bactericidal activity. Antibacterial activity was found in BALF material from healthy individuals and sarcoidosis patients, with enhanced activity in BALF from the patients. The activity was present as several antibacterial components, of which we have so far characterized LL-37, lysozyme, alpha-defensins, and antileukoprotease. In addition, the antibacterial peptide LL-37 was located in alveolar macrophages, bronchial epithelial cells, and bronchial glands, suggesting that it has a defensive role in airway mucosa. In conclusion, the airway epithelium is protected by a complex antibacterial defense system. This is activated in sarcoidosis, and may explain why these patients seldom develop severe respiratory tract infections.

Evaluation of the mechanism of decreased airway responsiveness in lambs.

In this study we investigated three possible mechanisms for the decreased airway responsiveness (AR) found in young lambs. To evaluate aerosol delivery, 6 adult sheep (9 mo-3 yr old) and 12 lambs (4-8 wk old) were challenged with aerosol (aH) and intravenous histamine (ivH). Awake animals were intubated and studied in a plethysmograph, which measured dynamic compliance (Cdyn), resistance of the lung, and functional residual capacity. AR to histamine was measured by administration of increasing concentrations of histamine until a significant change in lung mechanics occurred or until the maximum dose of histamine was given. In all six adult sheep, the response to both aH and iVH was a decrease in Cdyn. In two lambs Cdyn was decreased with both aH and ivH, in five lambs with neither, in three lambs with aH only, and in two lambs with ivH only. To examine the role of beta-adrenergic activity in determining AR, six adult sheep and six lambs received ivH and on a separate day ivH with propranolol pretreatment (p + ivH). The median effective dose of histamine that caused a reduction in Cdyn to 65% of normal saline control (ED65Cdyn) for the adult sheep given ivH was 3.60 (range 0.23-4.85) and 0.70 (range 0.49-8.0) micrograms.kg-1.min-1 for p + ivH (P = NS). The median ED65Cdyn for the six lambs was 8.0 micrograms.kg-1.min-1 for both ivH alone and p + ivH. To evaluate the role of airway smooth muscle (SM), AR to aH was quantitated in six adult sheep and six lambs, and then an open-lung biopsy was performed.(ABSTRACT TRUNCATED AT 250 WORDS)