Lung Airway Research Articles

Lung volume recruitment and airway clearance for children at home in France

BackgroundAirway clearance (ACT) and lung volume recruitment (LVR) techniques are used to manage bronchial secretions, increase cough efficiency and lung/chest wall recruitment, to prevent and treat respiratory tract infections. The aim of the study was to review the prescription of ACT/LVR techniques for home use in children in France. MethodsAll the centers of the national pediatric noninvasive ventilation (NIV) network were invited to fill in an anonymous questionnaire for every child aged ≤20 years who started a treatment with an ACT/LVR device between 2022 and 2023. The devices comprised mechanical in-exsufflation (MI-E), intermittent positive pressure breathing (IPPB), intrapulmonary percussive ventilation (IPV), and/or invasive mechanical ventilation (IMV)/NIV for ACT/LVR. ResultsOne hundred and thirty-nine patients were included by 13 centers. IPPB was started in 83 (60 %) patients, MI-E in 43 (31 %) and IPV in 30 (22 %). No patient used IMV/NIV for ACT/LVR. The devices were prescribed mainly by pediatric pulmonologists (103, 74 %). Mean age at initiation was 8.9 ± 5.6 (0.4–18.5) years old. The ACT/LVR devices were prescribed mainly in patients with neuromuscular disorders (n = 66, 47 %) and neurodisability (n = 37, 27 %). The main initiation criteria were cough assistance (81 %) and airway clearance (60 %) for MI-E, thoracic mobilization (63 %) and vital capacity (47 %) for IPPB, and airway clearance (73 %) and repeated respiratory exacerbations (57 %) for IPV. The parents were the main carers performing the treatment at home. ConclusionsIPPB was the most prescribed technique. Diseases and initiation criteria are heterogeneous, underlining the need for studies validating the indications and settings of these techniques.

A stepwise lung recruitment maneuver using I-gel can improve respiratory parameters: A prospective observational study.

I-gel has been used in various clinical situations. The study investigated alterations in respiratory parameters following a stepwise lung recruitment maneuver (LRM) using the i-gel. The research involved 60 patients classified as American Society of Anesthesiologists class I-II, aged 30 to 75 years, undergoing elective urologic surgery. Various respiratory parameters, including lung compliance, airway resistance, leak volume, airway pressure, and oxygen reserve index, were recorded at different time points: before LRM, immediately after LRM, and at 5, 15, and 30 minutes after LRM, as well as at the end of the surgery. The primary outcome was to assess an improvement in lung compliance. Dynamic lung compliance (mean ± SD) was significantly increased from 49.2 ± 1.8 to 70.15 ± 3.2 mL/cmH2O (P < .05) after LRM. Static lung compliance (mean ± SD) was increased considerably from 52.4 ± 1.7 to 65.0 ± 2.5 mL/cmH2O (P < .05) after the LRM. Both parameters maintained a statistically significant increased status for a certain period compared to baseline despite a decreased degree of increment. Airway resistance (mean ± SD) was significantly reduced after the LRM from 12.05 ± 0.56 to 10.41 ± 0.64 L/cmH2O/s (P < .05). Stepwise LRM using i-gel may improve lung compliance and airway resistance. Repeated procedures could lead to prolonged improvements in respiratory parameters.

Dysanapsis Genetic Risk Predicts Lung Function Across the Lifespan.

Rationale Dysanapsis refers to a mismatch between airway tree caliber and lung size arising early in life. Dysanapsis assessed by computed tomography (CT) is evident by early adulthood and associated with chronic obstructive pulmonary disease (COPD) risk later in life. Objective By examining the genetic factors associated with CT-assessed dysanapsis, we aimed to elucidate its molecular underpinnings and physiological significance across the lifespan. Methods We performed a genome-wide association study (GWAS) of CT-assessed dysanapsis in 11,951 adults, including individuals from two population-based and two COPD-enriched studies. We applied colocalization analysis to integrate GWAS and gene expression data from whole blood and lung. Genetic variants associated with dysanapsis were combined into a genetic risk score that was applied to examine association with lung function in children from a population-based birth cohort (n=1,278) and adults from the UK Biobank (n=369,157). Measurements and Main Results CT-assessed dysanapsis was associated with genetic variants from 21 independent signals in 19 gene regions, implicating HHIP, DSP, and NPNT as potential molecular targets based on colocalization of their expression. Higher dysanapsis genetic risk score was associated with obstructive spirometry among 5 year old children and among adults in the 5th, 6th and 7th decades of life. Conclusions CT-assessed dysanapsis is associated with variation in genes previously implicated in lung development and dysanapsis genetic risk is associated with obstructive lung function from early life through older adulthood. Dysanapsis may represent an endo-phenotype link between the genetic variations associated with lung function and COPD.

Large eddy simulation-based modeling of cold-air inhalation from nasal cavities to the distal lung: Insights for athlete health and performance

In cold environments, athletes are frequently susceptible to injuries from inhaling cold and dry air, posing significant health risks. Despite abundant prior research focusing on risk analysis and prevention, the existing body of literature has predominantly focused on heat transfer within lung airways while mainly overlooking the broader respiratory tract. This pioneering study introduces a comprehensive assessment of the entire respiratory system, spanning from the nasal and oral cavities to the larynx, then the trachea, and extending to the 13th generation of lung airways. Employing cutting-edge Computational Fluid Dynamics (CFD) techniques, the investigation operates Large Eddy Simulation (LES) integrated with an algebraic wall-modeled LES subgrid-scale model to simulate heat transfer within the human lung. This approach provides a detailed insight into the complex dynamics of respiratory thermoregulation in cold environments. By offering a comprehensive analysis of the temperature, heat flux, Nusselt number and static pressure profiles throughout the respiratory system, this study fundamentally advances our understanding of the physiological responses of the respiratory system to cold air exposure. These findings have paramount implications for athlete health and performance, shedding light on the complexities of cold-induced respiratory challenges. Moreover, this research lays a solid foundation for developing more effective preventive measures and strategies for optimizing athletic performance in cold weather conditions.

A comparative analysis of RNA-Seq and NanoString technologies in deciphering viral infection response in upper airway lung organoids.

In this study, we delved into the comparative analysis of gene expression data across RNA-Seq and NanoString platforms. While RNA-Seq covered 19,671 genes and NanoString targeted 773 genes associated with immune responses to viruses, our primary focus was on the 754 genes found in both platforms. Our experiment involved 16 different infection conditions, with samples derived from 3D airway organ-tissue equivalents subjected to three virus types, influenza A virus (IAV), human metapneumovirus (MPV), and parainfluenza virus 3 (PIV3). Post-infection measurements, after UV (inactive virus) and Non-UV (active virus) treatments, were recorded at 24-h and 72-h intervals. Including untreated and Mock-infected OTEs as control groups enabled differentiating changes induced by the virus from those arising due to procedural elements. Through a series of methodological approaches (including Spearman correlation, Distance correlation, Bland-Altman analysis, Generalized Linear Models Huber regression, the Magnitude-Altitude Score (MAS) algorithm and Gene Ontology analysis) the study meticulously contrasted RNA-Seq and NanoString datasets. The Magnitude-Altitude Score algorithm, which integrates both the amplitude of gene expression changes (magnitude) and their statistical relevance (altitude), offers a comprehensive tool for prioritizing genes based on their differential expression profiles in specific viral infection conditions. We observed a strong congruence between the platforms, especially in identifying key antiviral defense genes. Both platforms consistently highlighted genes including ISG15, MX1, RSAD2, and members of the OAS family (OAS1, OAS2, OAS3). The IFIT proteins (IFIT1, IFIT2, IFIT3) were emphasized for their crucial role in counteracting viral replication by both platforms. Additionally, CXCL10 and CXCL11 were pinpointed, shedding light on the organ tissue equivalent's innate immune response to viral infections. While both platforms provided invaluable insights into the genetic landscape of organoids under viral infection, the NanoString platform often presented a more detailed picture in situations where RNA-Seq signals were more subtle. The combined data from both platforms emphasize their joint value in advancing our understanding of viral impacts on lung organoids.

Defective mesenchymal Bmpr1a-mediated BMP signaling causes congenital pulmonary cysts.

Abnormal lung development can cause congenital pulmonary cysts, the mechanisms of which remain largely unknown. Although the cystic lesions are believed to result directly from disrupted airway epithelial cell growth, the extent to which developmental defects in lung mesenchymal cells contribute to abnormal airway epithelial cell growth and subsequent cystic lesions has not been thoroughly examined. In the present study using genetic mouse models, we dissected the roles of bone morphogenetic protein (BMP) receptor 1a (Bmpr1a)-mediated BMP signaling in lung mesenchyme during prenatal lung development and discovered that abrogation of mesenchymal Bmpr1a disrupted normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions. Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were found in the cystic airways of the mesenchymal Bmpr1a knockout lungs. In addition, ectopic mesenchymal expression of BMP ligands and airway epithelial perturbation of the Sox2-Sox9 proximal-distal axis were detected in the mesenchymal Bmpr1a knockout lungs. However, deletion of Smad1/5, two major BMP signaling downstream effectors, from the lung mesenchyme did not phenocopy the cystic abnormalities observed in the mesenchymal Bmpr1a knockout lungs, suggesting that a Smad-independent mechanism contributes to prenatal pulmonary cystic lesions. These findings reveal for the first time the role of mesenchymal BMP signaling in lung development and a potential pathogenic mechanism underlying congenital pulmonary cysts.

Defective mesenchymal Bmpr1a-mediated BMP signaling causes congenital pulmonary cysts

Abnormal lung development can cause congenital pulmonary cysts, the mechanisms of which remain largely unknown. Although the cystic lesions are believed to result directly from disrupted airway epithelial cell growth, the extent to which developmental defects in lung mesenchymal cells contribute to abnormal airway epithelial cell growth and subsequent cystic lesions has not been thoroughly examined. In the present study using genetic mouse models, we dissected the roles of bone morphogenetic protein (BMP) receptor 1a (Bmpr1a)-mediated BMP signaling in lung mesenchyme during prenatal lung development and discovered that abrogation of mesenchymal Bmpr1a disrupted normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions. Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were found in the cystic airways of the mesenchymal Bmpr1a knockout lungs. In addition, ectopic mesenchymal expression of BMP ligands and airway epithelial perturbation of the Sox2-Sox9 proximal-distal axis were detected in the mesenchymal Bmpr1a knockout lungs. However, deletion of Smad1/5, two major BMP signaling downstream effectors, from the lung mesenchyme did not phenocopy the cystic abnormalities observed in the mesenchymal Bmpr1a knockout lungs, suggesting that a Smad-independent mechanism contributes to prenatal pulmonary cystic lesions. These findings reveal for the first time the role of mesenchymal BMP signaling in lung development and a potential pathogenic mechanism underlying congenital pulmonary cysts.

Pulmonary Fibrosis Ferret Model Demonstrates Sustained Fibrosis, Restrictive Physiology, and Aberrant Repair.

The role of MUC5B mucin expression in IPF pathogenesis is unknown. Bleomycin-exposed rodent models do not exhibit sustained fibrosis or airway remodeling. Unlike mice, ferrets have human-like distribution of MUC5B expressing cell types and natively express the risk-conferring variant that induces high MUC5B expression in humans. We hypothesized that ferrets would consequently exhibit aberrant repair to propagate fibrosis similar to human IPF. Bleomycin (5U/kg) or saline-control was micro-sprayed intratracheally then wild-type ferrets were evaluated through 22 wks. Clinical phenotype was assessed with lung function. Fibrosis was assessed with µCT imaging and comparative histology with Ashcroft scoring. Airway remodeling was assessed with histology and quantitative immunofluorescence. Bleomycin ferrets exhibited sustained restrictive physiology including decreased inspiratory capacity, decreased compliance, and shifted Pressure-Volume loops through 22 wks. Volumetric µCT analysis revealed increased opacification of the lung bleomycin-ferrets. Histology showed extensive fibrotic injury that matured over time and MUC5B-positive cystic structures in the distal lung suggestive of honeycombing. Bleomycin ferrets had increased proportion of small airways that were double-positive for CCSP and alpha-tubulin compared to controls, indicating an aberrant 'proximalization' repair phenotype. Notably, this aberrant repair was associated with extent of fibrotic injury at the airway level. Bleomycin-exposed ferrets exhibit sustained fibrosis through 22 wks and have pathologic features of IPF not found in rodents. Ferrets exhibited proximalization of the distal airways and other pathologic features characteristic of human IPF. MUC5B expression through native cell types may play a key role in promoting airway remodeling and lung injury in IPF.

Environmental exposures, the oral-lung axis and respiratory health: The airway microbiome goes on stage for the personalized management of human lung function.

The human respiratory system is constantly exposed to environmental stimuli, sometimes including toxicants, which can trigger dysregulated lung immune responses that lead to respiratory symptoms, impaired lung function and airway diseases. Evidence supports that the microbiome in the lungs has an indispensable role in respiratory health and disease, acting as a local gatekeeper that mediates the interaction between the environmental cues and respiratory health. Moreover, the microbiome in the lungs is intimately intertwined with the oral microbiome through the oral-lung axis. Here, we discuss the intricate three-way relationship between (i) cigarette smoking, which has strong effects on the microbial community structure of the lung; (ii) microbiome dysbiosis and disease in the oral cavity; and (iii) microbiome dysbiosis in the lung and its causal role in patients suffering chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide. We highlight exciting outcomes arising from recently established interactions in the airway between environmental exposures, microbiome, metabolites-functional attributes and the host, as well as how these associations have the potential to predict the respiratory health status of the host through an airway microbiome health index. For completion, we argue that incorporating (synthetic) microbial community ecology in our contemporary understanding of lung disease presents challenges and also rises novel opportunities to exploit the oral-lung axis and its microbiome towards innovative airway disease diagnostics, prognostics, patient stratification and microbiota-targeted clinical interventions in the context of current therapies.

Metabolomics analysis of bronchoalveolar lavage fluid predicts unique features of the lower airway in pediatric cystic fibrosis

BackgroundProgressive, obstructive lung disease resulting from chronic infection and inflammation is the leading cause of morbidity and mortality in persons with cystic fibrosis (PWCF). Metabolomics and next -generation sequencing (NGS) of airway secretions can allow for better understanding of cystic fibrosis (CF) pathophysiology. In this study, global metabolomic profiling on bronchoalveolar lavage fluid (BALF) obtained from pediatric PWCF and disease controls (DCs) was performed and compared to lower airway microbiota, inflammation, and lung function. MethodsBALF was collected from children undergoing flexible bronchoscopies for clinical indications. Metabolomic profiling was performed using a platform developed by Metabolon Inc. Total bacterial load (TBL) was measured using quantitative polymerase chain reaction (qPCR), and bacterial communities were characterized using 16S ribosomal RNA (rRNA) sequencing. Random Forest Analysis (RFA), principal component analysis (PCA), and hierarchical clustering analysis (HCA) were performed. ResultsOne hundred ninety-five BALF samples were analyzed, 142 (73 %) from PWCF. Most metabolites (425/665) and summed categories (7/9) were significantly increased in PWCF. PCA of the metabolomic data revealed CF BALF exhibited more dispersed clustering compared to DC BALF. Higher metabolite concentrations correlated with increased inflammation, increased abundance of Staphylococcus, and decreased lung function. ConclusionsThe lower airway metabolome of PWCF was defined by a complex expansion of metabolomic activity. These findings could be attributed to heightened inflammation in PWCF and aspects of the CF airway polymicrobial ecology. CF-specific metabolomic features are associated with the unique underlying biology of the CF airway.

Fecal microbiome extract downregulates the expression of key proteins at the interface between airway remodelling and lung cancer pathogenesis in vitro

Lung cancer (LC) is the leading cause of cancer-related mortality, and it is caused by many factors including cigarette smoking. Despite numerous treatment strategies for LC, its five-year survival is still poor (<20 %), attributable to treatment resistance and lack of early diagnosis and intervention. Importantly, LC incidence is higher in patients affected by chronic respiratory diseases (CRDs) such as asthma and chronic obstructive pulmonary disorder (COPD), and LC shares with other CRDs common pathophysiological features including chronic inflammation, oxidative stress, cellular senescence, and airway remodelling. Remodelling is a complex process resulting from the aberrant activation of tissue repair secondary to chronic inflammation, oxidative stress, and tissue damage observed in the airways of CRD patients, and it is characterized by irreversible airway structural and functional alterations, concomitantly with tissue fibrosis, epithelial-to-mesenchymal transition (EMT), excessive collagen deposition, and thickening of the basement membrane. Many processes involved in remodelling, particularly EMT, are also fundamental for LC pathogenesis, highlighting a potential connection between CRDs and LC. This provides rationale for the development of novel treatment strategies aimed at targeting components of the remodelling pathways. In this study, we tested the in vitro therapeutic activity of rat fecal microbiome extract (FME) on A549 human lung adenocarcinoma cells. We show that treatment with FME significantly downregulates the expression of six proteins whose function is at the forefront between airway remodelling and LC development: Snail, SPARC, MUC-1, Osteopontin, MMP-2, and HIF-1α. The results of this study, if confirmed by further investigations, provide proof-of-concept for a novel approach in the treatment of LC, focused on tackling the airway remodelling mechanisms underlying the increased susceptibility to develop LC observed in CRD patients.

Orally administered yeast-derived β-glucan alleviates mast cell-dependent airway hyperresponsiveness and inflammation in a murine model of asthma.

Particulate β-glucans (WGP) are natural compounds with regulatory roles in various biological processes, including tumorigenesis and inflammatory diseases such as allergic asthma. However, their impact on mast cells (MCs), contributors to airway hyperresponsiveness (AHR) and inflammation in asthma mice, remains unknown. C57BL/6 mice underwent repeated OVA sensitization without alum, followed by Ovalbumin (OVA) challenge. Mice received daily oral administration of WGP (OAW) at doses of 50 or 150 mg/kg before sensitization and challenge. We assessed airway function, lung histopathology, and pulmonary inflammatory cell composition in the airways, as well as proinflammatory cytokines and chemokines in the bronchoalveolar lavage fluid (BALF). The 150 mg/kg OAW treatment mitigated OVA-induced AHR and airway inflammation, evidenced by reduced airway reactivity to aerosolized methacholine (Mch), diminished inflammatory cell infiltration, and goblet cell hyperplasia in lung tissues. Additionally, OAW hindered the recruitment of inflammatory cells, including MCs and eosinophils, in lung tissues and BALF. OAW treatment attenuated proinflammatory tumor necrosis factor (TNF)-α and IL-6 levels in BALF. Notably, OAW significantly downregulated the expression of chemokines CCL3, CCL5, CCL20, CCL22, CXCL9, and CXCL10 in BALF. These results highlight OAW's robust anti-inflammatory properties, suggesting potential benefits in treating MC-dependent AHR and allergic inflammation by influencing inflammatory cell infiltration and regulating proinflammatory cytokines and chemokines in the airways.

Inflammatory imbalance in tracheal aspirate of very preterm newborns is associated with airway obstruction and lung function deficiencies at school age: a cohort study

ObjectiveA low expression of club cell secretory protein (CC16) and high levels of proinflammatory cytokines at preterm birth are associated with airway inflammation and more severe neonatal lung disease. The...

Bronchoscopic Evaluations in Preterm Infants with Moderate to Severe Bronchopulmonary Dysplasia

Purpose: Bronchopulmonary dysplasia (BPD) is a chronic lung disease that primarily affects premature infants receiving mechanical ventilation and oxygen therapy. Severe BPD leads to long-term respiratory complications, including lung tissue damage, vascular abnormalities, and airway diseases. This study aimed to investigate bronchoscopy findings and characteristics in patients with moderate-to-severe BPD, and to investigate BPD-associated airway diseases.Methods: A retrospective study of preterm infants diagnosed with moderate-to-severe BPD who underwent bronchoscopic evaluation in the neonatal intensive care unit at Seoul National University Bundang Hospital between 2004 and December 2022 was conducted.Results: Nineteen patients with a mean gestational age of 28.0±1.6 weeks and mean birth weight of 960.5±271.0 g were included in the study. Among these 19 patients, 18 were diagnosed with severe BPD. Tracheobronchomalacia, laryngomalacia, and subglottic stenosis were observed in 63.2%, 52.6%, and 36.8% of patients, respectively. Tracheostomy was performed in nine of the 19 patients (47.4%); five were discharged without requiring tracheostomy following surgical or medical interventions.Conclusion: Tracheobronchomalacia, laryngomalacia, and subglottic stenosis were common in patients with moderate or severe BPD who underwent bronchoscopic evaluations, of which 50% required tracheostomy. Our study findings provide valuable insights into the pathophysiology of BPD-associated airway diseases and may inform future clinical management strategies for patients with BPD.

Pregnancy-Related Disorders and Intrauterine Impaired Lung Development

Various pregnancy-related disorders are known to affect fetal lung development negatively. During pregnancy, chronic nutrition and/or oxygen limitation is known to impede lung maturation and induce airway and lung abnormalities. Structural abnormalities and reduced lung function may be evident immediately after birth, persist, or develop with age. The expansion of the fetal lung, fetal breath movements, fetal lung growth, alveolarization, blood-air barrier, extracellular matrix (ECM), airways, surfactant system, and lung immune function are all affected by nutritional limitations during pregnancy. Gestational hypoxia disrupts fetal lung development, which manifests as morphological and functional pulmonary abnormalities. Additionally, intrauterine growth restriction (IUGR), preeclampsia (PE), exposure to air pollution, and smoking are known to interfere with embryonic lung development. Birth defects, such as bronchopulmonary dysplasia, as well as chronic obstructive pulmonary disease (COPD), can be caused by abnormalities in pregnancy. Adequate nutrition, avoidance of smoking, and watchful monitoring and intervention during pregnancy should be promoted to prevent chronic lung disease of the newborn, child, and adult.

Environmental pollutants particulate matter (PM2.5, PM10), Carbon Monoxide (CO), Nitrogen dioxide (NO2), Sulfur dioxide (SO2), and Ozone (O3) impact on lung functions

ObjectivesEnvironmental pollution has been an emerging global public health problem worldwide. This study aimed to investigate the impact of air pollutants particulate matter PM2.5, PM10, Carbon Monoxide (CO), Nitrogen Dioxide (NO2), Sulfur Dioxide (SO2), and Ozone (O3) on lung functions. MethodsIn this matched case-control, cross-sectional study, two schools were selected located in two different areas, school # 1 was located near a traffic-polluted area, and school # 2 was in an area away from the traffic-polluted area. Of a total of 300 students, 150 (75 boys and 75 girls) students from school # 1 and 150 students (75 boys and 75 girls) were from school # 2 located away from a traffic-polluted area. The mean age of students was 13.53 ± 1.20 years. The students in both schools were enrolled in the study on their voluntary involvement, and health status, matched by age, height, weight, gender, nationality, regional, socioeconomic, and cultural background, and the admission criteria of their schools. The environmental pollutants particulate matter “PM2.5, PM10, CO, NO2, SO2, and O3” were recorded. The level of air pollutants in school # 1 was 35.00 ± 0.65, significantly higher compared to school # 2 (29.95 ± 0.32). The pulmonary function test (PFT) parameters were performed on an electronic Spirometer. The parameters included “Forced Vital Capacity (FVC); Forced Expiratory Volume in the first second (FEV1); Forced Expiratory Ratio (FEV1/FVC %); Forced Expiratory Flow 25 % (FEF 25 %); Forced Expiratory Flow 50 % (FEF 50 %); Forced Expiratory Flow 75 % (FEF 75 %) and Peak Expiratory Flow Rate (PEFR) were recorded”. ResultsThe results revealed that the mean values for FEF-50 % (3.31 ± 1.18); FEF-75 % (1.66 ± 0.80) and PEFR (5.02 ± 1.79) were significantly decreased among students studying in school situated in a motor vehicle polluted area compared to those studying in school positioned away from the motor vehicle polluted area FEF-50 % (5.85 ± 6.21) (p = 0.001); and FEF-75 % (4.49 ± 6.87) (p = 0.001), and PEFR (8.14 ± 15.08) (p = 0.012). However, the groups had no significant difference between FVC, FEV1, FEV1/FVC Ratio (%), and FEF-25 %. The findings further demonstrated that the pattern of lung function impairment was peripheral airway lung involvement amongst the students in schools placed in environmentally contaminated areas. ConclusionsEnvironmental pollution significantly impaired lung function parameters FEF-50%, FEF-75% and PEFR, with peripheral airway lung involvement among students who studied in a school situated in motor vehicle-polluted areas. The results highlight the importance of the implementation of effective mitigation strategies and promoting sustainable and environmentally friendly transportation options to combat environmental pollution.

Orphan response regulator NnaR is critical for nitrate and nitrite assimilation in Mycobacterium abscessus.

Mycobacterium abscessus (Mab) is an opportunistic pathogen afflicting individuals with underlying lung disease such as Cystic Fibrosis (CF) or immunodeficiencies. Current treatment strategies for Mab infections are limited by its inherent antibiotic resistance and limited drug access to Mab in its in vivo niches resulting in poor cure rates of 30-50%. Mab's ability to survive within macrophages, granulomas and the mucus laden airways of the CF lung requires adaptation via transcriptional remodeling to counteract stresses like hypoxia, increased levels of nitrate, nitrite, and reactive nitrogen intermediates. Mycobacterium tuberculosis (Mtb) is known to coordinate hypoxic adaptation via induction of respiratory nitrate assimilation through the nitrate reductase narGHJI. Mab, on the other hand, does not encode a respiratory nitrate reductase. In addition, our recent study of the transcriptional responses of Mab to hypoxia revealed marked down-regulation of a locus containing putative nitrate assimilation genes, including the orphan response regulator nnaR (nitrate/nitrite assimilation regulator). These putative nitrate assimilation genes, narK3 (nitrate/nitrite transporter), nirBD (nitrite reductase), nnaR, and sirB (ferrochelatase) are arranged contiguously while nasN (assimilatory nitrate reductase identified in this work) is encoded in a different locus. Absence of a respiratory nitrate reductase in Mab and down-regulation of nitrogen metabolism genes in hypoxia suggest interplay between hypoxia adaptation and nitrate assimilation are distinct from what was previously documented in Mtb. The mechanisms used by Mab to fine-tune the transcriptional regulation of nitrogen metabolism in the context of stresses e.g. hypoxia, particularly the role of NnaR, remain poorly understood. To evaluate the role of NnaR in nitrate metabolism we constructed a Mab nnaR knockout strain (MabΔnnaR ) and complement (MabΔnnaR+C ) to investigate transcriptional regulation and phenotypes. qRT-PCR revealed NnaR is necessary for regulating nitrate and nitrite reductases along with a putative nitrate transporter. Loss of NnaR compromised the ability of Mab to assimilate nitrate or nitrite as sole nitrogen sources highlighting its necessity. This work provides the first insights into the role of Mab NnaR setting a foundation for future work investigating NnaR's contribution to pathogenesis.

Effect of different lung recruitment strategies and airway device on oscillatory mechanics in children under general anaesthesia.

Atelectasis has been reported in 68 to 100% of children undergoing general anaesthesia, a phenomenon that persists into the recovery period. Children receiving recruitment manoeuvres have less atelectasis and fewer episodes of oxygen desaturation during emergence. The optimal type of recruitment manoeuvre is unclear and may be influenced by the airway device chosen. We aimed to investigate the different effects on lung mechanics as assessed by the forced oscillation technique (FOT) utilising different recruitment strategies: repeated inflations vs. one sustained inflation and different airway devices, a supraglottic airway device vs. a cuffed tracheal tube. Pragmatic enrolment with randomisation to the recruitment strategy. We conducted this single-centre trial between February 2020 and March 2022. Seventy healthy patients (53 boys) aged between 2 and 16 years undergoing general anaesthesia were included. Forced oscillations (5 Hz) were superimposed on the ventilator waveform using a customised system connected to the anaesthesia machine. Pressure and flow were measured at the inlet of the airway device and used to compute respiratory system resistance and reactance. Measurements were taken before and after recruitment, and again at the end of surgery. The primary endpoint measured is the change in respiratory reactance. Statistical analysis (linear model with recruitment strategy and airway device as factors) did not show any significant difference in resistance and reactance between before and after recruitment. Baseline reactance was the strongest predictor for a change in reactance after recruitment: prerecruitment Xrs decreased by mean (standard error) of 0.25 (0.068) cmH 2 O s l -1 per 1 cmH 2 O -1 s l -1 increase in baseline Xrs ( P < 0.001). After correcting for baseline reactance, the change in reactance after recruitment was significantly lower for sustained inflation compared with repeated inflation by mean (standard error) 0.25 (0.101) cmH 2 O ( P = 0.0166). Although there was no significant difference between airway devices, this study demonstrated more effective recruitment via repeated inflations than sustained inflation in anaesthetised children. Australian New Zealand Clinical Trials Registry: ACTRN12619001434189.

Statin administration or blocking PCSK9 alleviates airway hyperresponsiveness and lung fibrosis in high-fat diet-induced obese mice

BackgroundObesity is associated with airway hyperresponsiveness and lung fibrosis, which may reduce the effectiveness of standard asthma treatment in individuals suffering from both conditions. Statins and proprotein convertase subtilisin/kexin-9 inhibitors not only reduce serum cholesterol, free fatty acids but also diminish renin-angiotensin system activity and exhibit anti-inflammatory effects. These mechanisms may play a role in mitigating lung pathologies associated with obesity.MethodsMale C57BL/6 mice were induced to develop obesity through high-fat diet for 16 weeks. Conditional TGF-β1 transgenic mice were fed a normal diet. These mice were given either atorvastatin or proprotein convertase subtilisin/kexin-9 inhibitor (alirocumab), and the impact on airway hyperresponsiveness and lung pathologies was assessed.ResultsHigh-fat diet-induced obesity enhanced airway hyperresponsiveness, lung fibrosis, macrophages in bronchoalveolar lavage fluid, and pro-inflammatory mediators in the lung. These lipid-lowering agents attenuated airway hyperresponsiveness, macrophages in BALF, lung fibrosis, serum leptin, free fatty acids, TGF-β1, IL-1β, IL-6, and IL-17a in the lung. Furthermore, the increased RAS, NLRP3 inflammasome, and cholecystokinin in lung tissue of obese mice were reduced with statin or alirocumab. These agents also suppressed the pro-inflammatory immune responses and lung fibrosis in TGF-β1 over-expressed transgenic mice with normal diet.ConclusionsLipid-lowering treatment has the potential to alleviate obesity-induced airway hyperresponsiveness and lung fibrosis by inhibiting the NLRP3 inflammasome, RAS and cholecystokinin activity.Graphical abstract

A quasi-realistic computational model development and flow field study of the human upper and central airways.

The impact of drug delivery and particulate matter exposure on the human respiratory tract is influenced by various anatomical and physiological factors, particularly the structure of the respiratory tract and its fluid dynamics. This study employs computational fluid dynamics (CFD) to investigate airflow in two 3D models of the human air conducting zone. The first model uses a combination of CT-scan images and geometrical data from human cadaver to extract the upper and central airways down to the ninth generation, while the second model develops the lung airways from the first Carina to the end of the ninth generation using Kitaoka's deterministic algorithm. The study examines the differences in geometrical characteristics, airflow rates, velocity, Reynolds number, and pressure drops of both models in the inhalation and exhalation phases for different lobes and generations of the airways. From trachea to the ninth generation, the average air flowrates and Reynolds numbers exponentially decay in both models during inhalation and exhalation. The steady drop is the case for the average air velocity in Kitaoka's model, while that experiences a maximum in the 3rd or 4th generation in the quasi-realistic model. Besides, it is shown that the flow field remains laminar in the upper and central airways up to the total flow rate of 15l/min. The results of this work can contribute to the understanding of flow behavior in upper respiratory tract.