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Preschool children with recurrent wheezing are a heterogeneous population with many underlying biological pathways that contribute to clinical presentations. Although the morbidity of recurrent wheezing in preschool children is significant, biological studies in this population remain quite limited. To address this gap, this study performed untargeted plasma metabolomic analyses in 68 preschool children with recurrent wheezing to identify metabolomic endotypes of wheezing. K-means cluster analysis was performed on metabolomic dataset including a total of 1382 named and unnamed metabolites. We identified three metabolomic clusters which differed in symptom severity, exacerbation occurrence, and variables associated with social disadvantage. Metabolites that distinguished the clusters included those involved in fatty acid metabolism, fatty acids (long chain monounsaturated fatty acids, long chain polyunsaturated fatty acids, and long chain saturated fatty acids), lysophospholipids, phosphatidylcholines, and phosphatidylethanolamines. Pathway analyses identified pathways of interest in each cluster, including steroid metabolism, histidine metabolism, sphingomyelins, and sphingosines, among others. This study highlights the biologic complexity of recurrent wheezing in preschool children and offers novel metabolites and pathways that may be amenable to future study and intervention.
Subject(s)
Metabolomics , Respiratory Sounds , Humans , Child, Preschool , Male , Female , Metabolomics/methods , Recurrence , Cluster Analysis , MetabolomeABSTRACT
Purpose: This study aimed to determine the prevalence and correlates of uncontrolled asthma among children with current asthma in four US states. We also determined the rates and correlates of asthma-related hospitalization, urgent care center (UCC), or emergency department (ED) visits. Participants and Methods: We analyzed the 2019 Behavioral Risk Factor Surveillance Survey (BRFSS) Asthma Call-back Survey (ACBS) datasets. Asthma control status was classified as well-controlled or uncontrolled asthma based on day- and night-time asthma symptoms, activity limitation or use of rescue medications. Multivariable logistic regression models were used to identify the correlates of uncontrolled asthma and asthma-related hospitalization or UCC/ED visits. Results: Among 249 children with current asthma, 55.1% had uncontrolled asthma while 40% reported asthma-related hospitalization or UCC/ED visits in the past year. Non-Hispanic ethnicity, ages of 0-9 and 15-17 years, household income <$25,000, and not having a flu vaccination had higher odds of uncontrolled asthma. Conversely, asthma self-management education and households with two children compared to one were positively associated with uncontrolled asthma. For healthcare utilization, male and non-Hispanic children, along with those from households earning <$25,000 exhibited higher odds of asthma-related hospitalization and UCC/ED visits. Conclusion: Uncontrolled asthma and asthma-related visits to UCC/ED and hospitalization are common among children with current asthma. These outcomes are influenced by low household income and male sex, among other factors which call for multi-faceted interventions by healthcare providers and policymakers. Targeted strategies to effectively manage asthma and reduce the need for emergency healthcare services are recommended.
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BACKGROUND: Epidemiologic studies have revealed associations between traffic-related pollutants such as diesel particulate matter (PM) and asthma outcomes in children, but the inflammatory features associated with diesel PM exposure in children with asthma are not understood. OBJECTIVE: To evaluate symptoms, exacerbations, and lung function measures in children with uncontrolled asthma and their associations with residential proximity to major roadways and to determine associations between diesel PM exposure and systemic inflammatory cytokines, circulating markers of T-cell activation and exhaustion, and metabolomic features using biomarker studies. METHODS: Children 5 to 17 years of age with physician-diagnosed, uncontrolled asthma despite treatment with an asthma controller medication completed a research visit involving questionnaires, lung function testing, and venipuncture for biomarker studies. Geocoding was performed to quantify residential proximity to major roadways and pollutant exposure. RESULTS: A total of 447 children with uncontrolled asthma were enrolled. Children living closer to highly trafficked roadways were more disadvantaged and had more exposure to diesel PM, more exacerbations prompting an emergency department visit, and lower lung function measures. Children with the highest diesel PM exposure, compared with children with the lowest diesel PM exposure, also had blunted cytokine secretion and evidence of T-cell exhaustion, including disturbances in several metabolites associated with glutathione formation and oxidative stress. CONCLUSION: Traffic-related diesel PM exposure in children with poorly controlled asthma is associated with poorer clinical outcomes and unique patterns of inflammation and oxidative stress. These findings argue for continued mitigation efforts to improve traffic-related air quality and health equity in children with asthma.
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Dysregulated neutrophil recruitment drives many pulmonary diseases, but most preclinical screening methods are unsuited to evaluate pulmonary neutrophilia, limiting progress towards therapeutics. Namely, high throughput therapeutic screening systems typically exclude critical neutrophilic pathophysiology, including blood-to-lung recruitment, dysfunctional activation, and resulting impacts on the air-blood barrier. To meet the conflicting demands of physiological complexity and high throughput, we developed an assay of 96-well Leukocyte recruitment in an Air-Blood Barrier Array (L-ABBA-96) that enables in vivo -like neutrophil recruitment compatible with downstream phenotyping by automated flow cytometry. We modeled acute respiratory distress syndrome (ARDS) with neutrophil recruitment to 20 ng/mL epithelial-side interleukin 8 (IL-8) and found a dose dependent reduction in recruitment with physiologic doses of baricitinib, a JAK1/2 inhibitor recently FDA-approved for severe COVID-19 ARDS. Additionally, neutrophil recruitment to patient-derived cystic fibrosis sputum supernatant induced disease-mimetic recruitment and activation of healthy donor neutrophils and upregulated endothelial e-selectin. Compared to 24-well assays, the L-ABBA-96 reduces required patient sample volumes by 25 times per well and quadruples throughput per plate. Compared to microfluidic assays, the L-ABBA-96 recruits two orders of magnitude more neutrophils per well, enabling downstream flow cytometry and other standard biochemical assays. This novel pairing of high-throughput in vitro modeling of organ-level lung function with parallel high-throughput leukocyte phenotyping substantially advances opportunities for pathophysiological studies, personalized medicine, and drug testing applications.
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Asthma exacerbations are a leading cause of pediatric hospitalizations despite multiple efforts to educate patients and families on disease course and medication management. Asthma education in the pediatric emergency department (ED) is challenging, and although the use of written action plans has been associated with reduction in hospitalizations and ED visits, written tools may not be useful for individuals with low health literacy. Moreover, asthmatic children should participate in their asthma education. In this prospective randomized study of 53 families presenting to a pediatric ED with a child experiencing an asthma exacerbation, education on asthma was presented via an interactive mobile-based video-game versus a standard-of-care asthma education video (SAV). Median age was 10 years; 64% were males. Many patients had moderate-to-severe asthma, with 57% experiencing ≥ 2 asthma-related ED visits in the last year, 58% requiring hospitalization and 32% reporting a critical care admission. In this cohort, the mobile-based video-game was found to be a feasible, acceptable educational tool; 86% of parents and 96% of children liked the game, while 96% of parents and 76% of children preferred playing the game over watching a SAV. Despite a history of persistent asthma, only 34% of children used an inhaled corticosteroid while 70% required rescue inhaler use in the prior week. Basic asthma knowledge was sub-optimal with only 60% of parents and 43% of children correctly recognizing symptoms that should prompt immediate medical care. This reflects a major gap in asthma knowledge that coexists with parental misconceptions regarding optimal asthma management.
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Background: The innate mechanisms associated with viral exacerbations in preschool children with recurrent wheezing are not understood. Objective: We sought to assess differential gene expression in blood neutrophils from preschool children with recurrent wheezing, stratified by aeroallergen sensitization, at baseline and after exposure to polyinosinic:polycytidylic acid (poly(I:C)) and also to examine whether poly(I:C)-stimulated blood neutrophils influenced airway epithelial gene expression. Methods: Blood neutrophils were purified and cultured overnight with poly(I:C) and underwent next-generation sequencing with Reactome pathway analysis. Primary human small airway epithelial cells were treated with poly(I:C)-treated neutrophil culture supernatants and were analyzed for type 1 interferon gene expression with a targeted array. Symptoms and exacerbations were assessed in participants over 12 months. Results: A total of 436 genes were differently expressed in neutrophils from children with versus without aeroallergen sensitization at baseline, with significant downregulation of type 1 interferons. These type 1 interferons were significantly upregulated in sensitized children after poly(I:C) stimulation. Confirmatory experiments demonstrated similar upregulation of type 1 interferons in IL-4-treated neutrophils stimulated with poly(I:C). Poly(I:C)-treated neutrophil supernatants from children with aeroallergen sensitization also induced a type 1 interferon response in epithelial cells. Children with aeroallergen sensitization also had higher symptom scores during exacerbations, and these symptom differences persisted for 3 days after prednisolone treatment. Conclusions: Type 1 interferon responses are dysregulated in preschool children with aeroallergen sensitization, which is in turn associated with exacerbation severity. Given the importance of type 1 interferon signaling in viral resolution, additional studies of neutrophil type 1 interferon responses are needed in this population.
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BACKGROUND: People living with cystic fibrosis (CF) experience a high symptom burden. Due to the changing landscape of CF in the era of modulator therapy, we sought to examine the epidemiology of symptoms and their association with quality of life, to help CF clinicians improve symptom screening in clinic. METHODS: Using baseline data from a trial of specialist palliative care in adults with CF, we examined symptom prevalence, distress, and association with quality of life (measured with the Functional Assessment of Chronic Illness Therapy Total Score). RESULTS: Among 262 participants, median age was 33, and 78% were on modulator therapy. The most common symptoms were lack of energy (n = 194, 74%) and cough (190, 73%), whereas the most distressing were difficulty sleeping (range 0-4, mean 2.19, SD 1.15) and pain (mean 2.04, SD 1.1). The symptoms that impaired quality of life the most were extrapulmonary: lack of energy (average quality of life score -29.8, 95% CI -36.8 to -22.8), feeling sad (-29.8, 95% CI -35.6 to -23.9) and worrying (-28.7, 95% CI -34.9 to -22.5). CONCLUSIONS: The symptoms that were associated with the lowest quality of life were extrapulmonary. CF clinicians may consider screening for common symptoms that affect quality of life the most (lack of energy, worrying, difficulty sleeping, feeling irritable, pain, and shortness of breath). These symptoms may identify people living with CF who are most at risk for a decreased quality of life and may benefit from additional support.
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BACKGROUND: Inhaled air pollutants are environmental determinants of health with negative impacts on human health. Air pollution has been linked to the incidence and progression of disease, with its effects unequally distributed across the population. Children compared to adults are a highly vulnerable group and suffer disproportionately from systemic environmental inequities exacerbated by social determinants. OBJECTIVE: To explore air pollution cluster patterns among 6- to 19-year-olds from the 2015-2016 National Health and Nutrition Examination Survey (NHANES) and examine chemical cluster associations with social vulnerability. METHODS: NHANES data was extracted for 697 children and adolescents. Social vulnerability characteristics from questionnaires were assembled to construct a modified social vulnerability index (SVI). Thirty-four air pollutant exposure chemicals were measured in urine and available from the laboratory sub-sample A data. K-means clustering classified the sample into three groups: low, medium, and high chemical exposure groups. Logistic regression was used to examine associations between high chemical group membership and SVI after adjusting for age, biological sex, and BMI. Complex survey analysis was conducted using SAS v9.4 to reflect population effects. RESULTS: Air pollution clusters revealed significant differences in mean concentrations between groups for 31 analytes with minimal distinction in mixture profiles. SVI scores differed significantly between the three groups (P = .002), and with each point increase in their SVI, the odds of a child being assigned to the highest-chemical exposure group increased by 11.55% (95% CI: 1.02-1.31), after adjustment. CONCLUSION: Unsupervised clustering of environmental sub-sample specimens from NHANES provides an innovative, multi-pollutant model that can be used to explore exposure patterns in this population. Utilizing the modified SVI allows for the identification of children that may be highly susceptible to air pollution. It is imperative to interpret the research findings in light of historical structural and discriminatory inequalities to develop beneficial and sustainable solutions.
Subject(s)
Air Pollutants , Environmental Exposure , Nutrition Surveys , Humans , Adolescent , Child , Female , Male , Air Pollutants/analysis , Air Pollutants/urine , Cluster Analysis , Young Adult , Environmental Exposure/analysis , Social Vulnerability , Air Pollution/analysisABSTRACT
BACKGROUND: Environmental justice mandates that no person suffers disproportionately from environmental exposures. The Environmental Justice Index (EJI) provides an estimate of the environmental burden for each census tract but has not yet been used in asthma populations. OBJECTIVE: We hypothesized that children from census tracts with high environmental injustice determined by the EJI would have a greater burden of asthma exacerbations, poorer asthma control, and poorer lung function over 12 months. METHODS: Children aged 6 to 18 years with asthma (N = 575) from metropolitan Atlanta, Georgia, completed a baseline research visit. Participant addresses were geocoded to obtain the EJI Social-Environmental Ranking for each participant's census tract, which was divided into tertiles. Medical records were reviewed for 12 months for asthma exacerbations. A subset of participants completed a second research visit involving spirometry and questionnaires. RESULTS: Census tracts with the greatest environmental injustice had more racial and ethnic minorities, lower socioeconomic status, more hazardous exposures (particularly to airborne pollutants), and greater proximity to railroads and heavily trafficked roadways. Children with asthma residing in high injustice census tracts had a longer duration of asthma, greater historical asthma-related health care utilization, poorer asthma symptom control and quality of life, and more impaired lung function. By 12 months, children from high injustice census tracts also had more asthma exacerbations with a shorter time to exacerbation and persistently more symptoms, poorer asthma control, and reduced lung function. CONCLUSIONS: Disparities in environmental justice are present in metropolitan Atlanta that may contribute to asthma outcomes in children. These findings require an additional study and action to improve health equity.
Subject(s)
Asthma , Environmental Exposure , Humans , Asthma/epidemiology , Child , Georgia/epidemiology , Female , Male , Adolescent , Environmental Exposure/adverse effects , Social JusticeABSTRACT
BACKGROUND: Effective asthma self-management requires that children recognize their asthma symptoms when they occur. However, some children have altered symptom perception, which impairs their ability to respond to their asthma symptoms in a timely manner. OBJECTIVE: To characterize the prevalence and features of altered symptom perception in children aged 5 to 18 years. We hypothesized that children with altered symptom perception would have more features of uncontrolled asthma, more health inequity, and poorer longitudinal asthma outcomes over 12 months. METHODS: Children (N = 371) completed an outpatient research visit for clinical characterization. Altered symptom perception was defined by discordance between child responses on the 6-item Asthma Control Questionnaire and medical provider-elicited symptoms. Electronic medical records were reviewed for 12 months for the occurrence of an asthma exacerbation treated with systemic corticosteroids and an asthma exacerbation prompting an emergency department visit. RESULTS: Approximately 15% of children had altered symptom perception and their asthma features were similar to those of children with uncontrolled asthma. Children with altered symptom perception were uniquely distinguished by non-White race and more severe prior exacerbations. These children also resided in ZIP codes with the poorest childhood opportunity (ie, poorest education, health and environmental features, and socioeconomic features). Outcomes of children with altered symptom perception were equally disparate with approximately 2-fold higher odds of a future exacerbation and approximately 3-fold higher odds of an emergency department visit for asthma. CONCLUSIONS: Altered symptom perception is present in a small but significant number of children with asthma and is related to poorer childhood opportunity and other health inequities that require additional intervention.
Subject(s)
Asthma , Humans , Child , Asthma/drug therapy , Asthma/epidemiology , Adrenal Cortex Hormones/therapeutic use , Emergency Room Visits , Health Behavior , PerceptionABSTRACT
PURPOSE: People living with cystic fibrosis (CF) experience impaired quality of life, but the extent to which pulmonary function is associated with quality of life in CF remains unclear METHODS: Using baseline data from a trial of specialist palliative care in adults with CF, we examined the association between pulmonary obstruction and quality of life (measured with the Functional Assessment of Chronic Illness Therapy Total Score). RESULTS: Among 262 participants, median age was 33, and 78% were on modulator therapy. The median quality of life score was higher in those with mild obstruction (135, IQR 110-156) compared to moderate (125, IQR 109-146) and severe obstruction (120, IQR 106-136). In an unadjusted model, we observed a non-significant trend toward lower quality of life with increased obstruction-compared to participants with mild obstruction, those with moderate obstruction had quality of life score 7.46 points lower (95% CI -15.03 to 0.10) and those with severe obstruction had a score 9.98 points lower (95% CI -21.76 to 1.80). However, this association was no longer statistically significant in the adjusted model, which may reflect confounding due to sex, age, BMI, and modulator therapy. Comorbidities (depression and anxiety) and social determinants of health (financial insecurity and education) were also associated with quality of life. CONCLUSION: Advancing our understanding of patient-centered markers of quality of life, rather than focusing on pulmonary function alone, may help identify novel interventions to improve quality of life in this patient population.
Subject(s)
Cystic Fibrosis , Adult , Humans , Anxiety/epidemiology , Anxiety/etiology , Anxiety Disorders , Cystic Fibrosis/complications , Cystic Fibrosis/therapy , Lung , Quality of Life , Clinical Trials as TopicABSTRACT
BACKGROUND: Preschool children with recurrent wheezing are heterogeneous, with differing responses to respiratory viral infections. Although neutrophils are crucial for host defense, their function has not been studied in this population. OBJECTIVE: We performed functional immunophenotyping on isolated blood neutrophils from 52 preschool children with recurrent wheezing (aeroallergen sensitization, n = 16; no sensitization, n = 36). METHODS: Blood neutrophils were purified and cultured overnight with polyinosinic:polycytidylic acid [poly(I:C)] as a viral analog stimulus. Neutrophils underwent next-generation sequencing with Reactome pathway analysis and were analyzed for cytokine secretion, apoptosis, myeloperoxidase, and extracellular DNA release. CD14+ monocytes were also exposed to neutrophil culture supernatant and analyzed for markers of M1 and M2 activation. RESULTS: A total of 495 genes, related largely to the innate immune system and neutrophil degranulation, were differently expressed in children with versus without aeroallergen sensitization. Functional experiments identified more neutrophil degranulation and extracellular trap formation (ie, more myeloperoxidase and extracellular DNA) and less neutrophil proinflammatory cytokine secretion in children with aeroallergen sensitization. Neutrophils also shifted CD14+ monocytes to a more anti-inflammatory (ie, M2) phenotype in sensitized children and a more proinflammatory (ie, M1) phenotype in nonsensitized children. Although both groups experienced viral exacerbations, annualized exacerbation rates prompting unscheduled health care were also higher in children without aeroallergen sensitization after enrollment. CONCLUSIONS: Systemic neutrophil responses to viral infection differ by allergic phenotype and may be less effective in preschool children without allergic inflammation. Further studies of neutrophil function are needed in this population, which often has less favorable therapeutic responses to inhaled corticosteroids and other therapies directed at type 2-high inflammation.
Subject(s)
Neutrophils , Respiratory Sounds , Humans , Child, Preschool , Immunophenotyping , Allergens , Inflammation/metabolism , Cytokines/metabolism , DNA/metabolism , Peroxidase/metabolismABSTRACT
Rhinoviruses (RVs) can cause severe wheezing illnesses in young children and patients with asthma. Vaccine development has been hampered by the multitude of RV types with little information about cross-neutralization. We previously showed that neutralizing antibody (nAb) responses to RV-C are detected twofold to threefold more often than those to RV-A throughout childhood. Based on those findings, we hypothesized that RV-C infections are more likely to induce either cross-neutralizing or longer-lasting antibody responses compared with RV-A infections. We pooled RV diagnostic data from multiple studies of children with respiratory illnesses and compared the expected versus observed frequencies of sequential infections with RV-A or RV-C types using log-linear regression models. We tested longitudinally collected plasma samples from children to compare the duration of RV-A versus RV-C nAb responses. Our models identified limited reciprocal cross-neutralizing relationships for RV-A (A12-A75, A12-A78, A20-A78, and A75-A78) and only one for RV-C (C2-C40). Serologic analysis using reference mouse sera and banked human plasma samples confirmed that C40 infections induced nAb responses with modest heterotypic activity against RV-C2. Mixed-effects regression modeling of longitudinal human plasma samples collected from ages 2 to 18 years demonstrated that RV-A and RV-C illnesses induced nAb responses of similar duration. These results indicate that both RV-A and RV-C nAb responses have only modest cross-reactivity that is limited to genetically similar types. Contrary to our initial hypothesis, RV-C species may include even fewer cross-neutralizing types than RV-A, whereas the duration of nAb responses during childhood is similar between the two species. The modest heterotypic responses suggest that RV vaccines must have a broad representation of prevalent types.
Subject(s)
Asthma , Rhinovirus , Child , Humans , Animals , Mice , Child, Preschool , Antibody Formation , Antibodies, Neutralizing , Cross ReactionsABSTRACT
Background: Asthma exacerbations are highly prevalent in children, but only a few studies have examined the biologic mechanisms underlying exacerbations in this population. Objective: High-resolution metabolomics analyses were performed to understand the differences in metabolites in children with exacerbating asthma who were hospitalized in a pediatric intensive care unit for status asthmaticus. We hypothesized that compared with a similar population of stable outpatients with asthma, children with exacerbating asthma would have differing metabolite abundance patterns with distinct clustering profiles. Methods: A total of 98 children aged 6 through 17 years with exacerbating asthma (n = 69) and stable asthma (n = 29) underwent clinical characterization procedures and submitted plasma samples for metabolomic analyses. High-confidence metabolites were retained and utilized for pathway enrichment analyses to identify the most relevant metabolic pathways that discriminated between groups. Results: In all, 118 and 131 high-confidence metabolites were identified in positive and negative ionization mode, respectively. A total of 103 unique metabolites differed significantly between children with exacerbating asthma and children with stable asthma. In all, 8 significantly enriched pathways that were largely associated with alterations in arginine, phenylalanine, and glycine metabolism were identified. However, other metabolites and pathways of interest were also identified. Conclusion: Metabolomic analyses identified multiple perturbed metabolites and pathways that discriminated children with exacerbating asthma who were hospitalized for status asthmaticus. These results highlight the complex biology of inflammation in children with exacerbating asthma and argue for additional studies of the metabolic determinants of asthma exacerbations in children because many of the identified metabolites of interest may be amenable to targeted interventions.
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CD4+ T cells contribute to lung inflammation in acute respiratory distress syndrome. The CD4+ T-cell response in pediatric acute respiratory distress syndrome (PARDS) is unknown. OBJECTIVES: To identify differentially expressed genes and networks using a novel transcriptomic reporter assay with donor CD4+ T cells exposed to the airway fluid of intubated children with mild versus severe PARDS. DESIGN: In vitro pilot study. SETTING: Laboratory-based study using human airway fluid samples admitted to a 36-bed university-affiliated pediatric intensive care unit. PATIENTS/SUBJECTS: Seven children with severe PARDS, nine children with mild PARDS, and four intubated children without lung injury as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We performed bulk RNA sequencing using a transcriptomic reporter assay of CD4+ T cells exposed to airway fluid from intubated children to discover gene networks differentiating severe from mild PARDS. We found that innate immunity pathways, type I (α and ß), and type II (γ) interferon response and cytokine/chemokine signaling are downregulated in CD4+ T cells exposed to airway fluid from intubated children with severe PARDS compared with those with mild PARDS. CONCLUSIONS: We identified gene networks important to the PARDS airway immune response using bulk RNA sequencing from a novel CD4+ T-cell reporter assay that exposed CD4+ T cells to airway fluid from intubated children with severe and mild PARDS. These pathways will help drive mechanistic investigations into PARDS. Validation of our findings using this transcriptomic reporter assay strategy is needed.
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INTRODUCTION: Female cancer survivors who received gonadotoxic cancer treatment are at risk for profound diminished ovarian reserve and/or primary ovarian insufficiency with resulting infertility, which can be associated with distress and decreased quality of life.. Despite prioritizing future parenthood, many survivors are unsure of the impact of their treatment on their future fertility, and little is known about the perceived reproductive health needs and factors associated with receipt of a fertility status assessment (FSA). There is a lack of developmentally appropriate reproductive health decisional support interventions available for emerging adult cancer survivors. This study will explore the perceived reproductive health needs of emerging adult female survivors of childhood cancer and to identify decisional and contextual factors that influence pursuit of FSA using an explanatory sequential quantitative to qualitative mixed methods design. METHODS AND ANALYSIS: This study will enroll 325 female survivors (aged 18 to 29 years and >1-year post treatment; diagnosed with cancer < age 21 years) from four cancer centers in the United States. Sociodemographic and developmental factors, reproductive knowledge and values, decisional needs, and receipt of an FSA will be assessed through a web-based survey. Informed by survey findings, a subset of participants will be recruited for qualitative interviews to explore decisional factors associated with uptake of an FSA. Clinical data will be abstracted from the medical records. Multivariable logistic regression models will be developed to identify factors associated with FSA and qualitative descriptive analysis will be used to develop themes from the interviews. Quantitative and qualitative findings will be merged using a joint display to develop integrated study conclusions and direct future interventional research.
Subject(s)
Cancer Survivors , Neoplasms , Child , Adult , Female , Humans , Quality of Life , Neoplasms/complications , Neoplasms/therapy , Survivors , FertilityABSTRACT
Myeloperoxidase (MPO) is released by neutrophils in inflamed tissues. MPO oxidizes chloride, bromide, and thiocyanate to produce hypochlorous acid (HOCl), hypobromous acid (HOBr), and hypothiocyanous acid (HOSCN), respectively. These oxidants are toxic to pathogens, but may also react with host cells to elicit biological activity and potential toxicity. In cystic fibrosis (CF) and related diseases, increased neutrophil inflammation leads to increased airway MPO and airway epithelial cell (AEC) exposure to its oxidants. In this study, we investigated how equal dose-rate exposures of MPO-derived oxidants differentially impact the metabolome of human AECs (BEAS-2B cells). We utilized enzymatic oxidant production with rate-limiting glucose oxidase (GOX) coupled to MPO, and chloride, bromide (Br-), or thiocyanate (SCN-) as substrates. AECs exposed to GOX/MPO/SCN- (favoring HOSCN) were viable after 24 h, while exposure to GOX/MPO (favoring HOCl) or GOX/MPO/Br- (favoring HOBr) developed cytotoxicity after 6 h. Cell glutathione and peroxiredoxin-3 oxidation were insufficient to explain these differences. However, untargeted metabolomics revealed GOX/MPO and GOX/MPO/Br- diverged significantly from GOX/MPO/SCN- for dozens of metabolites. We noted methionine sulfoxide and dehydromethionine were significantly increased in GOX/MPO- or GOX/MPO/Br--treated cells, and analyzed them as potential biomarkers of lung damage in bronchoalveolar lavage fluid from 5-year-olds with CF (n = 27). Both metabolites were associated with increasing bronchiectasis, neutrophils, and MPO activity. This suggests MPO production of HOCl and/or HOBr may contribute to inflammatory lung damage in early CF. In summary, our in vitro model enabled unbiased identification of exposure-specific metabolite products which may serve as biomarkers of lung damage in vivo. Continued research with this exposure model may yield additional oxidant-specific biomarkers and reveal explicit mechanisms of oxidant byproduct formation and cellular redox signaling.