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Abstract Background During pregnancy asthma may remain stable, improve or worsen. The factors underlying the deleterious effect of pregnancy on asthma remain unknown. Oxytocin is a neurohypophyseal protein that regulates a number of central and peripheral responses such as uterine contractions and milk ejection. Additional evidence suggests that oxytocin regulates inflammatory processes in other tissues given the ubiquitous expression of the oxytocin receptor. The purpose of this study was to define the role of oxytocin in modulating human airway smooth muscle (HASMCs) function in the presence and absence of IL-13 and TNFα, cytokines known to be important in asthma. Method Expression of oxytocin receptor in cultured HASMCs was performed by real time PCR and flow cytomery assays. Responses to oxytocin was assessed by fluorimetry to detect calcium signals while isolated tracheal rings and precision cut lung slices (PCLS) were used to measure contractile responses. Finally, ELISA was used to compare oxytocin levels in the bronchoalveloar lavage (BAL) samples from healthy subjects and those with asthma. Results PCR analysis demonstrates that OXTR is expressed in HASMCs under basal conditions and that both interleukin (IL)-13 and tumor necrosis factor (TNFα) stimulate a time-dependent increase in OXTR expression at 6 and 18 hr. Additionally, oxytocin increases cytosolic calcium levels in fura-2-loaded HASMCs that were enhanced in cells treated for 24 hr with IL-13. Interestingly, TNFα had little effect on oxytocin-induced calcium response despite increasing receptor expression. Using isolated murine tracheal rings and PCLS, oxytocin also promoted force generation and airway narrowing. Further, oxytocin levels are detectable in bronchoalveolar lavage (BAL) fluid derived from healthy subjects as well as from those with asthma. Conclusion Taken together, we show that cytokines modulate the expression of functional oxytocin receptors in HASMCs suggesting a potential role for inflammation-induced changes in oxytocin receptor signaling in the regulation of airway hyper-responsiveness in asthma.

Abstract Background Surfactant protein D (SP-D), an innate immune molecule, plays an important protective role during airway inflammation. Deficiency of this molecule induces emphysematous changes in murine lungs, but its significance in human COPD remains unclear. Methods We collected bronchoalveolar lavage fluid from 20 subjects with varying degrees of COPD (8 former smokers and 12 current smokers) and 15 asymptomatic healthy control subjects (5 never smokers, 3 remote former smokers, and 7 current smokers). All subjects underwent a complete medical history and pulmonary function testing. SP-D was measured by Enzyme-Linked ImmunoSorbent Assay. Statistical analysis was performed using nonparametric methods and multivariable linear regression for control of confounding. The effect of corticosteroid treatment on SP-D synthesis was studied in vitro using an established model of isolated type II alveolar epithelial cell culture. Results Among former smokers, those with COPD had significantly lower SP-D levels than healthy subjects (median 502 and 1067 ng/mL, respectively, p = 0.01). In a multivariable linear regression model controlling for age, sex, race, and pack-years of tobacco, COPD was independently associated with lower SP-D levels (model coefficient -539, p = 0.04) and inhaled corticosteroid use was independently associated with higher SP-D levels (398, p = 0.046). To support the hypothesis that corticosteroids increase SP-D production we used type II alveolar epithelial cells isolated from adult rat lungs. These cells responded to dexamethasone treatment by a significant increase of SP-D mRNA (p = 0.041) and protein (p = 0.037) production after 4 days of culture. Conclusion Among former smokers, COPD is associated with lower levels of SP-D and inhaled corticosteroid use is associated with higher levels of SP-D in the lung. Dexamethasone induced SP-D mRNA and protein expression in isolated epithelial cells in vitro. Given the importance of this molecule as a modulator of innate immunity and inflammation in the lung, low levels may play a role in the pathogenesis and/or progression of COPD. Further, we speculate that inhaled steroids may induce SP-D expression and that this mechanism may contribute to their beneficial effects in COPD. Larger, prospective studies are warranted to further elucidate the role of surfactant protein D in modulating pulmonary inflammation and COPD pathogenesis.

BackgroundSurfactant protein D (SP-D), an innate immune molecule, plays an important protective role during airway inflammation. Deficiency of this molecule induces emphysematous changes in murine lungs, but its significance in human COPD remains unclear.MethodsWe collected bronchoalveolar lavage fluid from 20 subjects with varying degrees of COPD (8 former smokers and 12 current smokers) and 15 asymptomatic healthy control subjects (5 never smokers, 3 remote former smokers, and 7 current smokers). All subjects underwent a complete medical history and pulmonary function testing. SP-D was measured by Enzyme-Linked ImmunoSorbent Assay. Statistical analysis was performed using nonparametric methods and multivariable linear regression for control of confounding. The effect of corticosteroid treatment on SP-D synthesis was studied in vitro using an established model of isolated type II alveolar epithelial cell culture.ResultsAmong former smokers, those with COPD had significantly lower SP-D levels than healthy subjects (median 502 and 1067 ng/mL, respectively, p = 0.01). In a multivariable linear regression model controlling for age, sex, race, and pack-years of tobacco, COPD was independently associated with lower SP-D levels (model coefficient -539, p = 0.04) and inhaled corticosteroid use was independently associated with higher SP-D levels (398, p = 0.046). To support the hypothesis that corticosteroids increase SP-D production we used type II alveolar epithelial cells isolated from adult rat lungs. These cells responded to dexamethasone treatment by a significant increase of SP-D mRNA (p = 0.041) and protein (p = 0.037) production after 4 days of culture.ConclusionAmong former smokers, COPD is associated with lower levels of SP-D and inhaled corticosteroid use is associated with higher levels of SP-D in the lung. Dexamethasone induced SP-D mRNA and protein expression in isolated epithelial cells in vitro. Given the importance of this molecule as a modulator of innate immunity and inflammation in the lung, low levels may play a role in the pathogenesis and/or progression of COPD. Further, we speculate that inhaled steroids may induce SP-D expression and that this mechanism may contribute to their beneficial effects in COPD. Larger, prospective studies are warranted to further elucidate the role of surfactant protein D in modulating pulmonary inflammation and COPD pathogenesis.

Objective: Frailty is a prevalent risk factor for adverse outcomes among patients with chronic lung disease. However, identifying frail patients who may benefit from interventions is challenging using standard data sources. We therefore sought to identify phrases in clinical notes in the electronic health record (EHR) that describe actionable frailty syndromes.Materials and Methods: We used an active learning strategy to select notes from the EHR and annotated each sentence for 4 actionable aspects of frailty: respiratory impairment, musculoskeletal problems, fall risk, and nutritional deficiencies. We compared the performance of regression, tree-based, and neural network models to predict the labels for each sentence. We evaluated performance with the scaled Brier score (SBS), where 1 is perfect and 0 is uninformative, and the positive predictive value (PPV).Results: We manually annotated 155 952 sentences from 326 patients. Elastic net regression had the best performance across all 4 frailty aspects (SBS 0.52, 95% confidence interval [CI] 0.49-0.54) followed by random forests (SBS 0.49, 95% CI 0.47-0.51), and multi-task neural networks (SBS 0.39, 95% CI 0.37-0.42). For the elastic net model, the PPV for identifying the presence of respiratory impairment was 54.8% (95% CI 53.3%-56.6%) at a sensitivity of 80%.Discussion: Classification models using EHR notes can effectively identify actionable aspects of frailty among patients living with chronic lung disease. Regression performed better than random forest and neural network models.Conclusions: NLP-based models offer promising support to population health management programs that seek to identify and refer community-dwelling patients with frailty for evidence-based interventions. [ABSTRACT FROM AUTHOR]

Background: Care management programs for chronic lung disease attempt to reduce hospitalizations, yet have not reliably achieved this goal. A key limitation of many programs is that they target patients with characteristics associated with hospitalization risk, but do not specifically modify the mechanisms that lead to hospitalization., Research Question: What are the common mechanisms underlying known patient-level risk characteristics leading to hospitalizations for acute exacerbations of chronic lung disease?, Study Design and Methods: We conducted a qualitative study of patients admitted to the University of Pennsylvania Health System with acute exacerbations of chronic lung disease between January and September 2019. We interviewed patients, their family caregivers, and their inpatient and outpatient clinicians about experiences leading up to the hospitalization. We analyzed the interview transcripts using triangulation and abductive analytic methods., Results: We conducted 69 interviews focused on the admission of 22 patients with a median age of 66 years (interquartile range, 60-70 years), of whom 16 patients (73%) were female and 14 patients (64%) were Black. We interviewed 22 patients, 14 caregivers, 19 inpatient clinicians, and 14 outpatient clinicians. We triangulated the available interview data for each patient admission and identified the underlying mechanisms of how several known patient characteristics associated with risk actually led to hospitalization. These mechanisms included limited capacity for home management of acute symptom changes, barriers to accessing care, chronic functional limitations, and comorbid behavioral health disorders. Importantly, many of the clinical, social, and behavioral mechanisms underlying hospitalizations were present for months or years before the symptoms that prompted inpatient care., Interpretation: Care management programs should be built to target specific clinical, social, and behavioral mechanisms that directly lead to hospitalization. Upstream interventions that reduce hospitalization risk are possible given that many contributory mechanisms are present for months or years before the onset of acute exacerbations.