Nicolle Jasmin Domnik

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a disease of neonatal lung development that is linked to impaired pulmonary vascularization, dysregulated TGF-β (transforming growth factor-β) signaling, and the accumulation of senescent cells. Despite the established role of TGF-β signaling in promoting vascular remodeling and suppressing the senolytic activity of natural killer (NK) cells, the contribution of NK cell TGF-β signaling to postnatal lung patterning and the pathogenesis of BPD remains unclear. METHODS: Mice bearing an NK cell-selective deletion of the type-II TGF-β receptor ( Tgfbr2 ^{NK− /−} ) were analyzed for vascular and alveolar structure, lung NK cell infiltration, senescence markers, and lung function testing across neonatal and adult time points. Lung tissue from both neonatal mice and human infants with BPD was assessed by single-cell RNA sequencing. The effects of enhanced NK cell activity in a hyperoxia-induced model of BPD were examined in Tgfbr2 ^NK−/− neonates, as well as pharmacologically, using the TGF-β ligand trap/IL-15 superagonist, HCW9218. RESULTS: Neonatal Tgfbr2 ^NK−/− mice exhibited a baseline reduction in distal arteriolar density, impaired alveolarization, and sex-specific deficits in long-term lung function. Single-cell RNA sequencing identified excessive clearance of senescent endothelial cells by TGF-β-insensitive NK cells in the lungs of Tgfbr2 ^NK−/− neonates. This enhanced NK cell activity promoted a BPD-like phenotype in naïve Tgfbr2 ^NK−/− mice but protected these animals from impaired lung development under hyperoxia. Sequencing of lung tissue from human infants with BPD confirmed excessive TGF-β signaling and cytotoxic impairment in NK cells. Treatment with HCW9218 prevented senescent cell accumulation and rescued lung development in the hyperoxia mouse model. CONCLUSIONS: TGF-β is a tunable regulator of NK cell senolytic activity that is essential for normal postnatal lung development. Excessive NK cell TGF-β signaling contributes to impaired lung development with neonatal hyperoxia and may serve as a viable therapeutic target in human BPD.

Background: Exertional dyspnoea is largely explained by excessive or (mechanically) constrained ventilation. Although the severity of resting lung function impairment is commonly used to estimate whether self-reported activity-related dyspnoea can be attributed to these abnormalities, the optimal use of routine pulmonary function tests in this context remains unclear in tobacco-exposed subjects. Methods: Lung function and exercise testing data from 1105 males and females (523 “at-risk” smokers with FEV ₁ /FVC and FEV ₁ ≥−1.645 z-score and 582 patients with COPD, of whom 189 were non-obstructed with FEV ₁ <−1.645). The burden of exertional dyspnoea and its proximate mechanical-ventilatory determinants were determined across the whole exercise test. Severe-to-very severe dyspnoea plus “excessive” and/or “constrained” breathing indicated ventilation-related dyspnoea. Results: Ventilation-related dyspnoea was identified in ∼40% (433/1105) of subjects, who typically exhibited poorer exercise tolerance ( p 1 , only the transfer coefficient (K _CO ) independently predicted exercise intolerance and ventilation-related dyspnoea across cohorts; moreover, inspiratory capacity (IC) was independently associated with these negative outcomes in obstructed subjects with low FEV ₁ . The odds of ventilation-related dyspnoea increased markedly as these abnormal findings compounded. When FEV ₁ was controlled for, “excessive” breathing was predicted by a low K _CO (odds ratio [95% confidence interval]=3.68 [2.30–6.41]), whereas “constrained” breathing was predicted by a low IC (9.96 [4.53–21.92]) ( p CO ) and restraints to tidal expansion (low IC) provide independent information beyond FEV ₁ for estimating the burden of exertional dyspnoea attributable to ventilation in tobacco-exposed subjects with a highly variable pre-test likelihood of abnormality.

Background: Exertional dyspnoea remains a chief complaint of patients assessed by pulmonologists, yet current cardiopulmonary exercise testing (CPET) displays and interpretations are not geared to properly expose its key determinant: ventilatory demand-capacity imbalance. Methods: We analyzed cycle ergometer CPET data from 3 cohorts of smokers and ex-smokers at risk for, or at different stages of, COPD (N=1161; 471 females; FEV ₁ z-score from −5.53 to 3.06). Considering all test data points, a novel AI-based framework (Dynamic Assessment of Dyspnoea and Ventilation on Exercise, DyVe-X) quantified the severity of dyspnoea while simultaneously assessing the gradual erosion of mechanical-ventilatory reserves in subjects with varying pre-test likelihood of abnormality. Results: Categories of progressively worse mechanical-ventilatory abnormalities, as defined by DyVe-X, were closely associated with increasing dyspnoea burden and decreasing exercise capacity across cohorts ( p peak )- the current criterion for ventilatory limitation – showed reduced submaximal ventilatory and/or inspiratory reserves on DyVe-X; these patients were as dyspnoeic and functionally impaired as those with low BR _peak and abnormal DyVe-X. DyVe-X, but not BR _peak , predicted high dyspnoea and impaired exercise tolerance across the full range of resting functional abnormalities; the odds ratio of combined “constrained” and “excessive” breathing by DyVe-X, adjusted by BR _peak , for high dyspnoea burden and poor exercise tolerance were 26.5 [15.8–44.3) and 26.0 [16.6–40.7], respectively ( p <0.001). Conclusions: These novel paradigms for the display and interpretation of CPET in dyspnoeic patients are poised to empower clinicians to uncover the root causes of exertional breathlessness with potentially relevant therapeutic implications.

Rationale: Poor sleep quality is associated with poor health outcomes, while exercise is protective of health. However, understanding of the impact of poor sleep on exercise tolerance and capacity in community-dwelling adults is limited. Objectives: To explore associations between sleep quality and exercise in a community-dwelling adult population (age > 40 y). Methods: We analyzed a cross-sectional sample of adults from the CanCOLD study, a prospective cohort study conducted in adults > 40y containing demographic and cardiopulmonary exercise (CPET) outcomes. We used adjusted multiple linear regression to determine associations between Pittsburgh Sleep Quality Index (PSQI) and CPET variables at peak exercise. Logistic regression determined the odds of poor sleepers (PSQI > 5) compared to good sleepers (PSQI ≤ 5) having abnormally high dyspnea (>ULN) or abnormal physiologic CPET outcomes ( ULN). Measurements and Main Results: In 1072 analyzed individuals (425 poor sleepers; age 66.4 ± 9.7 years; 40.5% female), poor sleepers were more likely to experience abnormally high levels of dyspnea at peak CPET (dyspnea > ULN for work rate odds ratio [95% CI] 1.65 [1.21-2.24], for ⩒E 1.52 [1.07-2.17]), but no differences in the odds of having abnormal key physiologic variables at peak CPET (⩒O2peak, HR, O2 pulse normal). Dyspnea adjusted for ⩒E or ⩒O2 positively correlated, and percent-predicted work rate negatively correlated, with PSQI (ie, worse sleep; both P < .05), while most physiologic variables showed no correlation. Conclusions: Perceptual responses to exercise were impacted more by poor sleep quality than physiological outcomes. These data highlight the importance of adequate sleep quality to lessen the burden of uncomfortable activity-related sensations.

Background: Exertional dyspnoea largely represents the sensory translation of an ever-growing dynamic mismatch between ventilatory demand and capacity as exercise intensifies. This fundamental tenet, however, has not been formally incorporated into data display and clinical interpretation of incremental cardiopulmonary exercise testing (CPET). Objectives: To validate a novel framework ( Dy namic Assessment of Dy spnoea and Ve ntilation on E x ercise, DyVe-X) to quantify the severity of exertional dyspnoea while exposing its mechanical-ventilatory underpinnings across progressively higher exercise intensities in subjects showing varied pre-test likelihood of abnormality. Methods: Incremental CPET data from 3 large cohorts of tobacco-exposed subjects: smokers and ex-smokers at risk for, or at different stages of, COPD (N=1161). Based on recently published normative data, a homonymous software (DyVe-X 1.0.0 Kingston, ON, Canada) uses an AI-based algorithm to establish the burden of a) exertional dyspnoea versus work rate and ventilation, b) excessive breathing (low submaximal ventilatory reserve, high dyspnoea-work rate but preserved dyspnoea-ventilation), and c) constrained breathing (reduced inspiratory reserve, high dyspnoea-work rate and dyspnoea-ventilation). We hypothesize that categories of progressive mechanical-ventilatory abnormalities, based on DyVe-X, would exhibit progressively worse physiological and sensory CPET outcomes. Using the current key criterion to indicate ventilatory limitation to exercise (peak breathing reserve ≤15%) as the comparator, we anticipate a superior performance of DyVe-X in exposing dyspnoea-generating mechanical-ventilatory abnormalities across cohorts. Implications: This study may validate an original framework for investigating dyspnoea using CPET, characterized by continuous assessment of symptom intensity and time course, in light of the rate of dynamic depletion of mechanical-ventilatory reserves.

Background: Patients with advanced chronic obstructive pulmonary disease (COPD) often report that adopting a specific body posture improves their dyspnoea. Exploring the underlying mechanisms could enhance our understanding of the origin of this symptom and approaches towards its alleviation. Methods: Pulmonary function tests and detailed sensory-mechanical measurements, including gastroesophageal catheter-based crural diaphragm electromyography (surrogate for inspiratory neural drive) and respiratory manometry, were performed in 16 patients (9M; age: 66±7 years) with advanced COPD (FEV ₁ =36±16% predicted; residual volume/total lung capacity: 55±11%) while adopting their most favourable (MF) and least favourable (LF) postures. Results: The MF postures included sitting upright (56%), sitting with arms on knees in a forward-leaning position (25%), standing (13%), and lying with three pillows (6%). About two-thirds of patients choose the supine posture as the LF posture. There were no significant differences in minute ventilation and inspiratory capacity between MF and LF postures ( p >0.05). Compared to LF, MF postures were associated with a) increased dynamic lung compliance, b) lower transdiaphragmatic pressures, and c) reduced total work of breathing, leading to d) decreased inspiratory neural drive to the diaphragm and e) improved neuromechanical and neuroventilatory coupling (all p difficulty breathing in ” dyspnoea qualifier when assuming the MF posture correlated with corresponding improvements in neuromechanical (r=0.62, p=0.01) and neuroventilatory uncoupling (r=0.57, p=0.02). Conclusion: Healthcare professionals should evaluate the benefits of positional therapy for reducing dyspnoea in patients with COPD. Incorporating postural interventions into rehabilitation or using them at night may help lessen symptoms and improve quality of life.

Synthetic oral nicotine pouches (ONP) are an increasingly popular route for non-tobacco nicotine consumption. While there is a growing understanding of ONP use internationally, especially in countries where these products have been available longer, few studies address ONP use in Canada. This cross-sectional study sought to quantify and characterize current ONP use in Canadian post-secondary students. A Qualtrics-based web survey of Canadian post-secondary (university or college) students was conducted in September/October 2024. This collected demographics, participant ONP history, recent use, and other nicotine/non-nicotine substance use. The Penn State Nicotine Pouch Dependence Index (PSNPDI) was embedded within the broader survey to assess nicotine dependence. Descriptive analysis was performed for ever- and recent-ONP use prevalence, poly-use of ONP with other products/substances, and ONP use with key demographic or contextualizing factors. Of 452 post-secondary student respondents (22% male, 78% female; age: 20.2 ± 2.6y), 27% reported ever-use of ONPs, with a mean ± SD age at first use of 19.2 ± 3.0y and 12% of all respondents reporting ONP use in the last 30 days. 77% and 89% of ONP users reported ever-use of tobacco and e-cigarettes, respectively, versus 24% and 44% of non-ONP users (p < 0.001). Among ONP ever-users, 62.3% reported no (PSNPDI score 0–3), 29.5% reported low (PSNPDI score 4–8), and 8.2% reported medium (PSNPDI score 9–12) dependence. These data provide a first glimpse into ONP use in Canadian post-secondary students, against which to assess future use patterns.

Background Lung volumes and dyspnoea vary markedly at a given FEV₁ in COPD. We aim to investigate whether hyperinflation (high total lung capacity (TLC)) adds value to simpler inspiratory capacity (IC) in predicting mechanical-ventilatory impairment and exertional dyspnoea in these patients. Methods 345 patients with mild to very severe COPD (190 men) underwent incremental cycling with measurements of dyspnoea (0–10 Borg) and operating lung volumes. Resting volumes by body plethysmography were compared with the 2021 z-score-based Global Lung Initiative standards. A novel artificial intelligence (AI)-based algorithm quantified the burden of mechanical-ventilatory constraints and dyspnoea as ventilation increased. Results Four lung volumes phenotypes were identified: 168 patients with preserved IC and TLC, 51 with preserved IC and high TLC (hyperinflation), 52 with low IC but no hyperinflation, and 74 with low IC and hyperinflation. Patients with low IC and/or hyperinflation showed worse air trapping and lower transfer factor (p <0.05). Hyperinflated patients at a given IC presented with worse sensory and functional outcomes; similarly, patients showing low IC at a given TLC were more symptomatic and impaired (p <0.05). The highest and lowest odds ratios [95% confidence interval] for “very severe” mechanical-ventilatory constraints and dyspnoea according to the AI algorithm were found in hyperinflated patients with low IC (5.2 [4.7–7.5]) and non-hyperinflated patients with preserved IC (0.99 [0.71–1.16]), respectively. Conclusion By combining IC and TLC expressed as z scores, clinicians can identify physiological phenotypes relevant to dynamic lung mechanical abnormalities on exertion, activity-related dyspnoea, and exercise tolerance across the spectrum of COPD severity.

Background: Activity-related dyspnoea in moderate–severe COPD is centrally related to heightened wasted ventilation in the physiological dead space colliding with constraints to tidal expansion due to acute-on-chronic gas trapping. Both phenomena are ultimately related to small airway dysfunction. However, it remains unknown whether the positive effects of pharmacological deflation on exertional dyspnoea in COPD can be ascribed to improved small airway conductance, enhancing ventilation–perfusion matching and neuromechanical coupling. Main hypotheses: We postulate that inhaled bronchodilators will enhance small airway function at rest and during exercise, improving gas exchange efficiency, lung mechanics and exertional dyspnoea in hyperinflated patients with COPD. Methods: A double-blind, placebo-controlled study involving 25 symptomatic patients (modified Medical Research Council score ≥2) showing functional residual capacity >120% pred and/or >upper limit of normal will receive nebulised salbutamol sulphate (2.5 mg) plus ipratropium bromide (0.5 mg) or normal saline. On different days, patients will undergo a constant-load test at 75% peak to symptom limitation. Single- and multiple-breath N ₂ washout and impulse oscillometry (IOS) will assess resting small airway function. Key exercise measurements will include 1) alveolar and physiological dead space by volumetric capnography, 2) operating lung volumes, 3) oesophageal catheter-based respiratory manometry and inspiratory neural drive via diaphragm electromyography, 4) exercise IOS, and 5) exertional dyspnoea (0–10 Borg scale). Implications: Confirmation of the study's hypotheses will shed new light on the mechanisms of dyspnoea improvement after inhaled bronchodilators in patients with COPD. Moreover, it will provide a novel integrative platform for assessing the effects of therapeutic approaches targeting their small airways.

Background: High ventilation–CO₂output, signaling increased wasted ventilation in the physiological dead space (V_Dphys), has a dominant role in eliciting activity-related dyspnoea in subjects with COPD showing only mild airflow obstruction. Exposing the mechanisms driving wasted ventilation is key to advancing the field towards new therapeutic approaches to improve dyspnoea and exercise tolerance in this growing patient sub-population.Central hypothesis: Increased areas of high alveolar ventilation (V̇_A)/capillary perfusion (Q̇_c) due to impairedQ̇_cin nonemphysematous, non-air trapping areas of the lungs add to any underlying emphysema to increase wasted ventilation and exertional dyspnoea in mild COPD.Methods: 40 patients (20 women) showing post-bronchodilator forced expiratory volume in 1 s ≥70% predicted and 20 sex- and age-matched controls will perform constant load exercise tests in a flutter-kicking device in the physiology laboratory and, in another visit, a magnetic resonance imaging (MRI) facility. Volumetric capnography will be used to breath-by-breath quantify rest and exerciseV_Dphys. Free-breathing, noncontrast proton MRI (phase-resolved functional lung (PREFUL))V̇_A,Q̇_candV̇_A/Q̇_c,maps will be co-registered to emphysema and air trapping severity and distribution as established by computed tomography (parametric response mapping).Study implications: Confirmation of the study's main hypothesis will provide the first evidence that increased wasted ventilation in dyspnoeic patients with mild COPD is not a mere consequence of emphysematous destruction being also reflective of impaired perfusion across apparently preserved lung tissue. This will set the stage for subsequent interventional studies geared to address this potentially treatable disease trait.