Increased Airway Obstruction Research Articles

NADH Intraperitoneal Injection Prevents Lung Inflammation in a BALB/C Mice Model of Cigarette Smoke-Induced Chronic Obstructive Pulmonary Disease.

Cigarette smoke is one of the main factors in Chronic Obstructive Pulmonary Disease (COPD), a respiratory syndrome marked by persistent respiratory symptoms and increasing airway obstruction. Perturbed NAD+/NADH levels may play a role in various diseases, including lung disorders like COPD. In our study, we investigated the preventive effect of NADH supplementation in an experimental model of COPD induced by cigarette smoke extract (CSE). N = 64 mice randomly distributed in eight groups were injected with NADH (two doses of 100 mg/kg or 200 mg/kg) or dexamethasone (2 mg/kg) before being exposed to CSE for up to 9 weeks. Additionally, NADH supplementation preserved lung antioxidant defenses by preventing the functional loss of key enzymes such as superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase, and the expression levels of glutathione (GSH) (n = 4, p < 0.001). It also reduced oxidative damage markers, such as malondialdehyde (MDA) and nitrites (n = 4, p < 0.001). A marked increase in tissue myeloperoxidase activity was assessed (MPO), confirming neutrophils implication in the inflammatory process. The latter was significantly ameliorated in the NADH-treated groups (p < 0.001). Finally, NADH prevented the CSE-induced secretion of cytokines such as Tumor Necrosis Factor alpha (TNF-α), IL-17, and IFN-y (n = 4, p < 0.001). Our study shows, for the first time, the clinical potential of NADH supplementation in preventing key features of COPD via its unique anti-inflammatory and antioxidant properties.

Interaction effect of chronic cough and ageing on increased risk of exacerbation in patients with asthma: a prospective cohort study in a real-world setting.

Older adults with asthma have the greatest burden and worst outcomes, and there is increasing evidence that chronic cough (CC) is associated with asthma severity and poor prognosis. However, the clinical characteristics of older adult patients with both asthma and CC remain largely unknown. Participants with stable asthma underwent two cough assessments within 3 months to define the presence of CC. Patients were divided into four groups based on CC and age (cut-off ≥60 years). Multidimensional assessment was performed at baseline, followed by a 12-month follow-up to investigate asthma exacerbations. Logistic regression models were used to explore the interaction effect of CC and age on asthma control and exacerbations. In total, 310 adult patients were prospectively recruited and divided into four groups: older CC group (n=46), older non-CC group (n=20), younger CC group (n=112) and younger non-CC group (n=132). Compared with the younger non-CC group, the older CC group had worse asthma control and quality of life and increased airflow obstruction. The older CC group showed an increase in moderate-to-severe exacerbations during the 12-month follow-up. There was a significant interaction effect of CC and ageing on the increased moderate-to-severe exacerbations (adjusted risk ratio 2.36, 95% CI 1.47-3.30). Older asthma patients with CC have worse clinical outcomes, including worse asthma control and quality of life, increased airway obstruction and more frequent moderate-to-severe exacerbations, which can be partly explained by the interaction between CC and ageing.

Hyperextended head position during mask ventilation in neonates may be associated with increased airway obstruction.

Hyperextended head position during mask ventilation in neonates may be associated with increased airway obstruction.

0988 Vagal Nerve Stimulation and OSA

Abstract Introduction We present a case of obstructive sleep apnea (OSA) worsened by implantation of a vagal nerve stimulator (VNS). A 22-year-old M with PMH of autism and refractory epilepsy s/p VNS implantation was diagnosed with moderate OSA. His parents noted that his sleep-disordered breathing worsened after VNS implantation. He was started on APAP 4-12 cm H2O. Review of adherence data revealed an elevated residual apnea-hypopnea index (AHI) despite nightly usage. PAP titration study was obtained with improvement of AHI on 16 cm H2O. Despite consequent use of determined pressure settings, residual AHI remained elevated. In consultation with the patient’s neurologist, VNS settings were gradually down titrated. Residual AHI improved and remained low as CPAP settings were subsequently weaned. Report of case(s) The vagus nerve is part of the parasympathetic nervous system. Afferent fibers project to cortical regions involved in seizure activity. Vagal nerve activation leads to desynchrony, thereby decreasing seizure activity.3 VNS, an adjunctive non-pharmacologic treatment of refractory epilepsy, consists of a generator with multiple adjustable settings and a lead connected to the left vagus nerve.1 VNS activation, in conjuction with medical therapy, can lead to decreased seizures. However, VNS may cause complications such as vocal cord dysfunction, laryngeal spasm, and dyspnea.2 In this case, VNS was noted to cause OSA due to increased airway obstruction, though the pathophysiological mechanism behind this has not been clearly delineated. 3 Conclusion Based on current evidence of precipitation or worsening OSA with VNS activation, screening and diagnostic testing for OSA in patients under evaluation for VNS placement should be considered. A multidisciplinary approach between Sleep Medicine and Neurology in conjunction with patient goals can lead to a balanced optimization of both epilepsy and OSA management via adjustments of VNS settings, anti-epileptics, and CPAP. Support (if any) 1. VNS therapy epilepsy. Epilepsy Foundation. https://www.epilepsy.com/sites/default/files/atoms/files/516VNS_VNS_FINAL.pdf. December 20, 2022. 2. Ebben MR, Sethi NK, Conte M, Pollak CP, Labar D. Vagus nerve stimulation, sleep apnea, and CPAP titration. J ClinSleepMed. 2008 Oct 15;4(5):471-3. PMID: 18853706. 3. Parhizgar F, Nugent K, Raj R. Obstructive sleep apnea and respiratory complications associated with vagus nerve stimulators. J ClinSleepMed. 2011 Aug 15;7(4):401-7. doi: 10.5664/JCSM.1204. PMID: 21897779.

Increasing airway obstruction through life following bronchopulmonary dysplasia: a meta-analysis.

Few studies exist investigating lung function trajectories of those born preterm; however growing evidence suggests some individuals experience increasing airway obstruction throughout life. Here we use the studies identified in a recent systematic review to provide the first meta-analysis investigating the impact of preterm birth on airway obstruction measured by the forced expiratory volume in 1 s (FEV1) to forced vital capacity (FVC) ratio. Cohorts were included for analysis if they reported FEV1/FVC in survivors of preterm birth (<37 weeks' gestation) and control populations born at term. Meta-analysis was performed using a random effect model, expressed as standardised mean difference (SMD). Meta-regression was conducted using age and birth year as moderators. 55 cohorts were eligible, 35 of which defined groups with bronchopulmonary dysplasia (BPD). Compared to control populations born at term, lower values of FEV1/FVC were seen in all individuals born preterm (SMD -0.56), with greater differences seen in those with BPD (SMD -0.87) than those without BPD (SMD -0.45). Meta-regression identified age as a significant predictor of FEV1/FVC in those with BPD with the FEV1/FVC ratio moving -0.04 sds away from the term control population for every year of increased age. Survivors of preterm birth have significantly increased airway obstruction compared to those born at term with larger differences in those with BPD. Increased age is associated with a decline in FEV1/FVC values suggesting increased airway obstruction over the life course.

Application of Ultrasonic Piezoelectric Technology for Rhinoplasty.

Application of Ultrasonic Piezoelectric Technology for Rhinoplasty.

The affection of plasma exosomes on airway obstruction and endothelial function in OSA patients.

This study aimed to investigate the effects on airway obstruction and endothelial function by extracting and analyzing plasma exosomes with OSA patients. For this purpose, the clinical data and imaging data of 60 patients with OSA were retrospectively analyzed, who were admitted to the Central Hospital from Apr．2018 to Jul．2021．By using an electron microscope for the observation of exosomes, the degree of airway obstruction was compared by pulmonary function instrument, and HE staining was performed to analyze them. The results showed that the diameter of exosome particles was concentrated at 80.5 ~ 158.6 nm, the diameter of OSA exosomes was concentrated at about 121.9 nm, and the diameter of exosomes in the control group was concentrated at about 145.0 nm. Compared with the patients in the control group, the level of miRNA-33b-3p in the control group was significantly different (P < 0.05). The content of exosomal miRNA-33b-3p in OSA patients decreased significantly, and the corresponding airway obstruction increased. The results of HE staining showed that there were obvious atherosclerotic plaques in the arterial endothelium of the OSA group, and the atherosclerotic plaques were significantly reduced after miRNA-33b-3p injection (P < 0.05). In general, OSA patients can regulate airway obstruction and endothelial cell function by controlling the expression of Plasma exosomes and miRNA-33b-3p, resulting in increased airway obstruction and endothelial cell atherosclerosis.

A fogágybetegség és a krónikus obstruktív tüdőbetegség kapcsolatának jelentősége

A fogágybetegség és a krónikus obstruktív tüdőbetegség (COPD) is a leggyakrabban megjelenő krónikus betegségekcsoportjába tartozik. A fogelvesztéssel járó előrehaladott fogágybetegség a világ 6. leggyakrabban előforduló krónikusbetegsége, mely kb. 743 millió embert érint, míg a COPD világszerte évente átlagosan 3 millió emberéletet követel (ez5,3%-a az összes haláloknak világszerte) és 2016 óta a világ 3. vezető halálokává vált. Egy norvég tanulmány szerinta nagyon súlyos COPD-ben szenvedő, tüdőtranszplantáció előtt álló betegek esetén a parodontitisz prevalenciája megközelítia 44%-ot, szemben a nem COPD-s kontrollcsoport 7,3%-os gyakoriságával. A két betegség összefüggése jelenlegdirekt módon nem bizonyított, ám egyre több tanulmány támasztja alá a két betegség közti kapcsolat lehetőségét.Tanulmányunkban összegezni szeretnénk a jelenleg elérhető szakirodalmi adatokat és ez által betekintést nyújtania két betegség kölcsönhatásába és feltételezett patomechanizmusába. Szükség lenne olyan klinikai vizsgálatokra, melyekbennagy esetszámmal vizsgálnak parodontálisan érintett COPD-s betegeket, így megerősítve vagy cáfolva azta feltevést, miszerint a fogágybetegek parodontális terápiája hozzájárulhat-e a COPD-ben szenvedő betegek életminőségénekjavításához.

Chronic infection with Chlamydia pneumoniae in asthma: a type-2 low infection related phenotype

BackgroundChlamydia pneumoniae and Mycoplasma pneumoniae have been implicated in the pathogenesis of asthma and are responsible for chronic inflammation when host immune system fails to eradicate the bacteria.MethodWe performed a prospective study on 410 patients who underwent a visit at the asthma clinic of CHU of Liege between June 2016 and June 2018 with serology testing for C. pneumoniae and M. pneumoniae.Results65% of our asthmatic population had serum IgA and/or IgG towards C. pneumoniae, while only 12.6% had IgM and/or IgG against M. pneumoniae. Compared to seronegative asthmatics, asthmatics with IgA+ and IgG+ against C. pneumoniae were more often male and older with a higher proportion of patients with smoking history. They received higher doses of inhaled corticosteroids (ICS) and displayed lower FEV1/FVC ratio, higher RV/TLC ratio and lower conductance. They had higher levels of fibrinogen, though in the normal range and had lower sputum eosinophil counts. Patients with IgA− and IgG+ against C. pneumoniae were older and had higher blood monocyte counts and alpha-1-antitrypsin levels as compared to seronegative patients. Patients with IgM and/or IgG towards M. pneumoniae were more often males than seronegative asthmatics. In a subpopulation of 14 neutrophilic asthmatics with Chlamydia pneumoniae IgA + /IgG + treated with macrolides, we found a significant decrease in blood neutrophils and normalization of sputum neutrophil count but no effect on asthma quality of life and exacerbations.ConclusionPositive Chlamydia serologic test is more common than positive Mycoplasma serology. Asthmatics with IgA and IgG against C. pneumoniae have more severe disease with increased airway obstruction, higher doses of ICS, more signs of air trapping and less type-2 inflammation.

Effects of Obesity and Asthma on Lung Function and Airway Dysanapsis in Adults and Children

Obesity increases the risk of developing asthma in children and adults. Obesity is associated with different effects on lung function in children and adults. In adults, obesity has been associated with reduced lung function resulting from a relatively small effect on forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC), with the FEV1/FVC ratio remaining unchanged or mildly increased (restrictive pattern). In contrast, in children, obesity is associated with normal or higher FEV1 and FVC but a lower FEV1/FVC ratio (obstructive pattern). This anomaly has recently been associated with a phenomenon known as dysanapsis which results from a disproportionate growth between lung parenchyma size and airway calibre. The mechanisms that promote disproportionate lung parenchyma growth compared with airways in obese children remain to be elucidated. Obesity and dysanapsis in asthma patients might contribute to asthma morbidity by increasing airway obstruction, airway hyper-reactivity and airway inflammation. Obesity and dysanapsis in asthma patients are associated with increased medication use, more emergency department visits, hospitalizations and systemic corticosteroid burst than patients with normal weight. Dysanapsis may explain the reduced response to asthma medications in obese children. Weight loss results in a significant improvement in lung function, airway reactivity and asthma control. Whether these improvements are associated with the changes in the dysanaptic alteration is as yet unclear.

Chronic Rhinosinusitis with Nasal Polyps and Asthma

Patients with chronic rhinosinusitis with nasal polyps (CRSwNP) characterized by a type 2 immune signature often have severe and recurrent disease. Lower airway conditions such as asthma are common comorbidities and share similar pathophysiology. CRSwNP with asthma is characterized by tissue eosinophilia and high local IgE levels. Clinically, CRSwNP with comorbid asthma is associated with more severe sinonasal symptoms and worse quality of life, and it is more difficult to treat both medically and surgically. Asthma in the presence of nasal polyposis is also more difficult to control, being more exacerbation prone, with increased airway obstruction and more extensive eosinophilic inflammation. Aspirin/nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (AERD) is a recognized phenotype of CRSwNP with comorbid asthma. Patients with CRSwNP with comorbid AERD are among those with the most severe and difficult-to-treat disease, and tend to have severe NP. The shared pathophysiology of the upper and lower airways has important implications for both the diagnosis and management of respiratory comorbidities. However, in clinical practice, the nose and lungs are often treated as separate entities. The underlying systemic inflammatory link between CRSwNP and asthma provides a compelling rationale for systemic treatment with novel biologics targeting shared underlying type 2 inflammatory pathways.

Increase in Airway Obstruction between 1993 and 2012 in Switzerland. An Observational Study

Rationale: Most studies determining the prevalence of airway obstruction are limited to short time periods.Objectives: Because temporal trends of obstruction in populations are largely unknown, we determined the prevalence of airway obstruction over 20 years in yearly general population samples in Switzerland between 1993 and 2012.Methods: We analyzed data of 85,789 participants aged 35 years and older who provided spirometric measurements as part of the LuftiBus lung function campaign. We linked data from the 2003-2012 period to the Swiss National Cohort to adjust for annual population differences. Spirometry was performed without bronchodilation, according to American Thoracic Society guidelines. We used Global Lung Initiative (GLI) and Hankinson reference equations to identify obstruction.Results: Obstruction prevalence increased between 1993 and 2012 from 6.1% (95% confidence interval [CI], 5.5 to 6.7) to 15.6% (95% CI, 13.8 to 17.3) based on GLI estimates and from 5.3% (95% CI, 4.7 to 5.9) to 15.4% (95% CI, 13.6 to 17.1) based on Hankinson estimates. When adjusted for participant demographics, air pollutant and occupational exposures, altitude, and season, the prevalence ratios of obstruction were 1.54 (95% CI, 1.22 to 1.93) and 1.65 (95% CI, 1.33 to 2.04) for GLI- and Hankinson-defined airway obstruction, respectively, for 2012 compared with 2003.Conclusions: Though prebronchodilator measurements likely overestimate the prevalence of airway obstruction in absolute terms compared with post-bronchodilator measurements, we found an increase in airway obstruction prevalence. Even with adjustment for several well-known risk factors for obstruction to make the populations across the years more comparable, we still saw a statistically significant increase in prevalence over this time period.

Air Pollution Exposure and Lung Function Until Age 16 Years: The PIAMA Birth Cohort Study

Evidence for the effects of air pollution exposure on lung function growth into adolescence is scarce. Therefore, the purpose of this study was to investigate the associations of air pollution exposure from birth with lung function growth from ages 8 to 16 and lung function at age 16. Potential confounders (sex and asthma diagnosis) were also explored.The study was performed within the Dutch population-based Prevention and Incidence of Asthma and Mite Allergy birth cohort. From the 3963 pregnant women initially enrolled, 915 children (mean age: 16.3 years) had sufficient longitudinal data for this study.Both longitudinal (n = 915) and cross-sectional (n = 721) analyses were conducted. Researchers estimated residential concentrations of nitrogen dioxide, “soot,” and particulate matter (PMx, where x is the 50% cutoff aerodynamic diameter in μm) with diameters of <2.5 μm (PM2.5), <10 μm (PM10), and 2.5 to 10 μm (PMcoarse) during the preschool, primary school, and secondary school time windows by land use regression models. Associations with (growth in) forced expiratory volume in 1 second (FEV1) and forced vital capacity were analyzed by linear (mixed effects) regression.Greater air pollution exposure was associated with reduced FEV1 growth (eg, adjusted difference: −0.26% [95% confidence interval: −0.49 to −0.03%] per interquartile range increase in secondary school PM2.5) and lower FEV1 (adjusted difference: −2.36% [95% confidence interval: −3.76 to −0.94%]) but was not adversely associated with forced vital capacity. Associations with FEV1 were stronger in boys than girls and were not modified by asthma status.Greater air pollution exposure may lead to increased airway obstruction but not reduced lung volume in adolescence.This study supports previous longitudinal studies that have reported an association between air pollution exposure and reduced lung function growth. The association between lower FEV1 and PM2.5 exposure during the secondary school time window suggests that exposure during this time frame is critical. This study was limited by a lack of racial diversity, which could create differing results because of epigenetic changes. Future longitudinal studies should address this issue.

Children with Asthma Have Fixed Airway Obstruction through Childhood Unaffected by Exacerbations

Children with asthma may have a disease course with or without exacerbations, but the relationship between exacerbations and lung function development is poorly understood. To compare lung function trajectories from birth till adolescence in asthmatic children with and without exacerbations. Children with asthma from the Copenhagen Prospective Studies on Asthma in Childhood2000 (COPSAC2000) birth cohort had lung function and bronchial reactivity assessed repeatedly from 1 month to 13 years. Exacerbations were diagnosed at the COPSAC clinic defined as symptoms requiring hospitalization, oral or high-dose inhaled corticosteroid treatment. Mixed models were applied to analyze lung function trajectories. Children with asthma with exacerbations (N= 50) had a trajectory of increased, fixed airway obstruction compared with children without exacerbations (N= 47): z-score difference in airway resistance (sRawz) (95% confidence interval [CI]):+0.34 (+0.03;+0.66), P= .03, and maximal mid-expiratory flow (MMEFz):-0.41 (-0.69;-0.13), P= .004, but no differences in forced expiratory volume (FEVz):-0.14 (-0.41;+0.13), P= .29, or bronchial reactivity to methacholine (PDz):+0.08 (-0.26;+0.42), P= .65. This did not change comparing lung function trajectories before and after exacerbations: z-score difference (95% CI) sRawz:-0.04 (-0.35; 0.27), P= .80; MMEFz: 0.01 (-0.02; 0.04), P= .55; FEVz: 0.02 (-0.02; 0.05), P= .42; and PDz:-0.01 (-0.06; 0.05), P= .88. Children with asthma with exacerbations compared with children with asthma without exacerbations are characterized by increased airway obstruction since infancy through childhood. The airway obstruction is a fixed trajectory without progression due to exacerbations, suggesting that exacerbations are a consequence rather than a cause of diminished airway caliber in childhood.

P3508A novel mouse model of sleep-disordered breathing is associated with contractile dysfunction and CaMKII overexpression

Abstract Background Patients with sleep-disordered breathing (SDB) develop arrhythmias and contractile dysfunction, but the mechanisms are poorly understood, possibly due to the lack of mouse models that mimic airway obstruction in spontaneously sleeping mice. Interestingly, New Zealand obese mice have been shown to develop airway obstruction with inspiratory flow limitation resulting in apneas, but these mice also develop diabetes. Purpose We developed a novel mouse model of increased airway obstruction in spontaneously sleeping lean mice and investigated the impact on sleep-related apneas and contractile function. Methods and results Male C57BL6 mice at 8–12 weeks of age were subjected to polytetrafluoroethylene (PTFE) injection (100 μl) into the tongue. This resulted in an increased tongue volume and reduced pharyngeal luminal diameter. Conscious mice behave normal and there was no difference in body weight between PTFE injected mice and untreated littermates (control). Whole body plethysmography was used to monitor spontaneous breathing for 8h in a quiet environment. Interestingly, compared to control, mice with PTFE injection showed a significantly increased frequency of apneas (lasting &gt;1s, fig. A, * indicated P&lt;0.05, t-test). Echocardiographic analysis revealed that ejection fraction was significantly reduced in PTFE-treated mice 8 weeks after surgery (vs. control, fig. B). In accordance, the developed force of isolated papillary muscles from hearts of PTFE mice was significantly reduced compared to control (fig. C). Ca/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the development of heart failure. Intriguingly, compared to control, CaMKII expression was significantly increased in ventricular heart homogenates of PTFE-treated mice (fig. D). Moreover, the magnitude of CaMKII overexpression correlated significantly with the frequency of apneas (fig. E). Papillary muscle post-pause contractions can be used as measure of diastolic sarcoplasmic reticulum (SR) Ca leak, which is known to be enhanced by CaMKII. Compared to control, post-pause contraction amplitude was significantly smaller in PTFE-treated mice, indicating an increased SR Ca leak (fig. F). Figure 1 Conclusion PTFE injection in mice results in an increased frequency of spontaneous apneas. PTFE-treated mice develop mild contractile dysfunction, which is accompanied by CaMKII overexpression. This novel mouse model offers great opportunities for investigation of sleep-related breathing disorders. Acknowledgement/Funding This study was supported by the Medical Faculty of the University of Regensburg (ReForM programme).

Dexmedetomidine versus propofol at different sedation depths during drug‐induced sleep endoscopy: A randomized trial

The aim of this study was to compare the effect of dexmedetomidine and propofol on airway dynamics, cardiorespiratory system, and emergence following drug-induced sleep endoscopy (DISE). Prospective, randomized, single-blinded study. Sixty patients age 18 to 65 years in American Society of Anesthesiologists physical status groups 1 and 2 scheduled to undergo DISE were randomly allocated to either Group P (N = 30; receiving propofol infusion at 50-150 μg/kg/min) or Group D (N = 30; receiving dexmedetomidine bolus of 1 μg/kg followed by infusion at 0.5-1.0 μg/kg/hr). DISE was done at light sleep and deep sleep. Airway obstruction at tongue base was recorded as primary outcome. Airway obstruction at velum, oropharyngeal lateral wall, and epiglottis level during light and deep sedation, hemodynamic and respiratory parameters, time to attain sufficient sedation, time for emergence from sedation, and any adverse events during DISE with the two study drugs were recorded as secondary outcomes. There was a greater degree of obstruction at the tongue base level (P = 0.001) and Oropharynx level (P = 0.017) in Group P compared with Group D during deep sedation. Increase in airway obstruction from light to deep sleep was seen with propofol at the oropharynx (P = 0.0185) and tongue base (P = 0.0108) levels. Two patients (6.6%) in Group D and 10 patients (33.3%) in Group P showed oxygen saturation below the minimum oxygen saturation recorded during polysomnography. Time to open eyes to call after stopping sedation was significantly less in Group P (P = 0.005). Dexmedetomidine shows a lesser degree of airway collapse and higher oxygen saturation levels at greater sedation depth during DISE. Propofol has a faster onset and emergence from sedation. 1b Laryngoscope, 130:257-262, 2020.

3123 TGFbeta, Early Cytokine Dysregulation, and Airway Smooth Muscle Dysfunction in Cystic Fibrosis

OBJECTIVES/SPECIFIC AIMS: This study aims to first describe the unique cytokine profile and TGFbeta levels of young children with CF, then understand the pathologic effects of TGFbeta on lung function in a CF animal model. These powerful translational studies linking observations in clinical disease with a transgenic mouse model allow us a unique opportunity to investigate the role of TGFbeta in early CF lung disease. METHODS/STUDY POPULATION: Cytokine levels (TGFbeta, TNFalpha, IL-8, IL-6, HNE, and IL-1beta) in bronchoalveolar lavage fluid (BALF) from CF patients (n = 15) and non-CF control patients (n = 21) under 6 years old were determined by ELISA and Luminex assay. Tracheotomized patients without significant underlying lung disease were chosen as non-CF inflamed control patients, as they had similar levels of neutrophilic inflammation and infection as CF patients. The percentage of BAL neutrophils (% PMNs) in each sample was assessed. The relationships between cytokines were analyzed using linear regression and principal components analysis. In animal studies, CF and non-CF mice (n = 4-5 per group) were treated with intratracheal adenoviral TGFbeta1 vector, an empty vector control, or PBS. After one week, animals were collected; lung function, response to the bronchoconstrictor methacholine, and rescue with albuterol were measured utilizing a FlexiVent machine. Lungs were collected for histology. Immunohistochemistry for alpha-SMA was performed and pictures of all cross-sectional airways were obtained. Burden of ASM was assessed by dividing the square root of alpha-SMA stained airway smooth muscle by the basement membrane perimeter length of each airway. RESULTS/ANTICIPATED RESULTS: Patient characteristics of CF and non-CF inflamed control patients were similar in terms of age (3.6 yrs vs 3.3 yrs respectively, p = 0.49), positive BAL culture (13% vs 14%, p = 0.94), and % PMNs (65% vs 56%, p = 0.64). Despite these similarities, TGFbeta levels were 2-fold higher in CF versus non-CF BAL (p = 0.034). Analysis of BAL cytokines from both patient groups showed that three principal components describe 86% of total variance across the cytokine variables. These components represent different contributions from the cytokines, with TGFbeta, IL6, and % PMNs comprising one component of similarly regulated inflammatory markers. These components can distinguish CF versus non-CF patients with 77% accuracy (area under the curve: 0.77). TGFbeta concentrations were uniquely associated with increased IL-6 in CF samples (r = 0.74; p = 0.0015) but did not demonstrate association with other cytokines. After TGFbeta exposure, CF mice demonstrated greater abnormalities in airway resistance than non-CF mice, with heightened response to methacholine. Importantly, this increase in airway obstruction in CF mice was reversible with albuterol treatment, indicating airway smooth muscle dysfunction as a principal driver of lung function abnormalities. Furthermore, TGFbeta induced an increased ASM burden on lung histology in both CF and non-CF mice (p&lt;0.05). IL-6 levels in the BAL of CF mice showed greater increases after TGFbeta treatment compared to non-CF mice (p&lt;0.05). Empty vector control treatment did not cause lung pathology. DISCUSSION/SIGNIFICANCE OF IMPACT: Young children with CF have a unique pattern of pulmonary inflammation compared to inflamed non-CF control patients. In CF, TGFbeta pulmonary levels are uniquely associated with IL-6, a driver of ASM dysfunction in other pulmonary diseases. We followed up this clinical observation study by investigating the effect of TGFbeta on pulmonary disease in a mouse model. CF mice demonstrate increased pulmonary IL-6, airway obstruction, and ASM dysfunction after TGFbeta exposure. This study provides evidence that TGFbeta is associated with a distinct cytokine pattern that may promote ASM dysfunction in early CF lung disease. Understanding the mechanism of early CF pathophysiology will be critical in developing targeted therapeutics that can prevent early lung damage.

An airway epithelial IL-17A response signature identifies a steroid-unresponsive COPD patient subgroup.

BACKGROUND. Chronic obstructive pulmonary disease (COPD) is a heterogeneous smoking-related disease characterized by airway obstruction and inflammation. This inflammation may persist even after smoking cessation and responds variably to corticosteroids. Personalizing treatment to biologically similar “molecular phenotypes” may improve therapeutic efficacy in COPD. IL-17A is involved in neutrophilic inflammation and corticosteroid resistance, and thus may be particularly important in a COPD molecular phenotype.METHODS. We generated a gene expression signature of IL-17A response in bronchial airway epithelial brushings from smokers with and without COPD (n = 238), and validated it using data from 2 randomized trials of IL-17 blockade in psoriasis. This IL-17 signature was related to clinical and pathologic characteristics in 2 additional human studies of COPD: (a) SPIROMICS (n = 47), which included former and current smokers with COPD, and (b) GLUCOLD (n = 79), in which COPD participants were randomized to placebo or corticosteroids.RESULTS. The IL-17 signature was associated with an inflammatory profile characteristic of an IL-17 response, including increased airway neutrophils and macrophages. In SPIROMICS the signature was associated with increased airway obstruction and functional small airways disease on quantitative chest CT. In GLUCOLD the signature was associated with decreased response to corticosteroids, irrespective of airway eosinophilic or type 2 inflammation.CONCLUSION. These data suggest that a gene signature of IL-17 airway epithelial response distinguishes a biologically, radiographically, and clinically distinct COPD subgroup that may benefit from personalized therapy.TRIAL REGISTRATION. ClinicalTrials.gov NCT01969344.FUNDING. Primary support from the NIH, grants K23HL123778, K12HL11999, U19AI077439, DK072517, U01HL137880, K24HL137013 and R01HL121774 and contracts HHSN268200900013C, HHSN268200900014C, HHSN268200900015C, HHSN268200900016C, HHSN268200900017C, HHSN268200900018C, HHSN268200900019C and HHSN268200900020C.

Deep vs. Awake Extubation and LMA Removal in Terms of Airway Complications in Pediatric Patients Undergoing Anesthesia: A Systemic Review and Meta-Analysis.

The purpose of this study was to compare the incidence of airway complications between extubation under deep anesthesia (deep extubation) and extubation when fully awake (awake extubation) in pediatric patients after general anesthesia. A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA) statement standards. The review protocol was registered with the International Prospective Register of Systematic Reviews (registration number: CRD 42018090172). Electronic databases were searched, without discrimination of publication year and language, to identify all randomized controlled trials investigating airway complications following deep or awake extubation after general anesthesia. The Cochrane tool was used to assess the risk of bias of trials. Randomized trials investigating airway complications of deep extubation compared with awake extubation after general anesthesia with an endotracheal tube and laryngeal mask airway (LMA) were sought. Overall airway complications, airway obstruction, cough, desaturation, laryngospasm and breath holding were analyzed using random-effect modelling. The odds ratio was used for these incidence variables. Seventeen randomized trials were identified, and a total of 1881 pediatric patients were enrolled. The analyses indicated deep extubation reduces the risk of overall airway complications (odds ratio (OR) 0.56, 95% confidence interval (CI) 0.33–0.96, p = 0.04), cough (OR 0.30, 95% CI 0.12–0.72, p = 0.007) and desaturation (OR 0.49, 95% CI 0.25–0.95, p = 0.04) in children after general anesthesia. However, deep extubation increased the risk of airway obstruction compared with awake extubation (OR 3.38 CI 1.69–6.73, p = 0.0005). No difference was observed in the incidence of laryngospasm and breath-holding between the two groups regardless of airway device. The result of this analysis indicates that deep extubation may decrease the risk of overall airway complications including cough and desaturation but may increase airway obstruction compared with awake extubation in pediatric patients after general anesthesia. Therefore, deep extubation may be recommended in pediatric patients to minimize overall airway complications except airway obstruction and the clinicians may choose the method of extubation according to the risk of airway complications of pediatric patients.

Air pollution exposure and lung function until age 16 years: the PIAMA birth cohort study.

Evidence for the effects of air pollution exposure on lung function growth into adolescence is scarce. We investigated associations of air pollution exposure with lung function and lung function growth until age 16.We conducted both longitudinal (n=915) and cross-sectional (n=721) analyses of associations of air pollution exposure with forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) growth from ages eight to 16 and FEV1 and FVC at age 16. We estimated residential concentrations of nitrogen dioxide (NO2), "soot" and particulate matter (PMx, where x is the 50% cut-off aerodynamic diameter in µm) with diameters of <2.5 µm (PM2.5), <10 µm (PM10) and 2.5-10 µm (PMcoarse) during the preschool, primary school and secondary school time windows by land use regression models. Associations with (growth in) FEV1 and FVC were analysed by linear (mixed effects) regression.Higher air pollution exposure was associated with reduced FEV1 growth (e.g. adjusted difference -0.26% (95% CI -0.49 to -0.03%) per interquartile range increase in secondary school PM2.5) and lower FEV1 (adjusted difference -2.36% (95% CI -3.76 to -0.94%)), but was not adversely associated with FVC. Associations with FEV1 were stronger in boys than girls and were not modified by asthma status.Higher air pollution exposure may lead to increased airway obstruction, but not reduced lung volume in adolescence.