Browsing by Author "Tepper, Robert S."
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Item Additional Thoughts on Intrinsic Dysanapsis(American Thoracic Society, 2024) Tepper, Robert S.; Morgan, Wayne J.; Taussig, Lynn M.; Pediatrics, School of MedicineItem An IL-9-pulmonary macrophage axis defines the allergic lung inflammatory environment(American Association for the Advancement of Science, 2022) Fu, Yongyao; Wang, Jocelyn; Zhou, Baohua; Pajulas, Abigail; Gao, Hongyu; Ramdas, Baskar; Koh, Byunghee; Ulrich, Benjamin J.; Yang, Shuangshuang; Kapur, Reuben; Renauld, Jean-Christophe; Paczesny, Sophie; Liu, Yunlong; Tighe, Robert M.; Licona-Limón, Paula; Flavell, Richard A.; Takatsuka, Shogo; Kitamura, Daisuke; Tepper, Robert S.; Sun, Jie; Kaplan, Mark H.; Microbiology and Immunology, School of MedicineDespite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9-responsive cell repertoire is still not well defined. Here, we found that IL-9 mediates proallergic activities in the lungs by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c+ and CD11c- interstitial macrophage populations. Interstitial macrophages were required for IL-9-dependent allergic responses. Mechanistically, IL-9 affected the function of lung macrophages by inducing Arg1 activity. Compared with Arg1-deficient lung macrophages, Arg1-expressing macrophages expressed greater amounts of CCL5. Adoptive transfer of Arg1+ lung macrophages but not Arg1- lung macrophages promoted allergic inflammation that Il9r-/- mice were protected against. In parallel, the elevated expression of IL-9, IL-9R, Arg1, and CCL5 was correlated with disease in patients with asthma. Thus, our study uncovers an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation.Item Antenatal corticosteriods decrease forced vital capacity in infants born fullterm(Wiley, 2020-10) Bandyopadhyay, Anuja; Slaven, James E.; Evrard, Cindy; Tiller, Christina; Haas, David M.; Tepper, Robert S.; Pediatrics, School of MedicineAntenatal corticosteroids (ACS) administration to pregnant women for threatened preterm labor is standard obstetric care to reduce neonatal respiratory distress syndrome and the associated respiratory morbidity. While ACS stimulates surfactant production in the fetal lung, the effects of ACS upon the subsequent growth and development of the lung are unclear. Follow-up studies outside of the neonatal period have been primarily limited to spirometry, and most subjects evaluated were born prematurely. To our knowledge, no study has assessed both airway and parenchymal function in infants or adults following ACS exposure. We hypothesized that ACS impairs lung growth and performed infant pulmonary function testing, which included spirometry, alveolar volume (VA ) and lung diffusion (DL ). As a pilot study, we limited our assessment to infants whose mothers received ACS for threatened preterm labor, but then proceeded to full term delivery. This approach evaluated a more homogenous population and eliminated the confounding effects of preterm birth. We evaluated 36 full-term infants between 4 to 12 months of age; 17 infants had ACS exposure and 19 infants had no ACS exposure. Infants exposed to ACS had a significantly lower forced vital capacity compared with non-ACS exposed infants (250 vs 313 mL; P = .0075). FEV0.5 tended to be lower for the ACS exposed group (205 vs 237 mL; P = .075). VA and DL did not differ between the two groups. These findings suggest that ACS may impair subsequent growth of the lung parenchyma.Item Are Newborn Outcomes Different for Term Babies Who Were Exposed to Antenatal Corticosteroids?(Elsevier, 2021) McKinzie, Alexandra H.; Yang, Ziyi; Teal, Evgenia; Daggy, Joanne K.; Tepper, Robert S.; Quinney, Sarah K.; Rhoads, Eli; Haneline, Laura S.; Haas, David M.; Obstetrics and Gynecology, School of MedicineBackground: Antenatal corticosteroids improve newborn outcomes for preterm infants. However, predicting which women presenting for threatened preterm labor will have preterm infants is inaccurate, and many women receive antenatal corticosteroids but then go on to deliver at term. Objective: This study aimed to compare the short-term outcomes of infants born at term to women who received betamethasone for threatened preterm labor with infants who were not exposed to betamethasone in utero. Study design: We performed a retrospective cohort study of infants born at or after 37 weeks' gestational age to mothers diagnosed as having threatened preterm labor during pregnancy. The primary neonatal outcomes of interest included transient tachypnea of the newborn, neonatal intensive care unit admission, and small for gestational age and were evaluated for their association with betamethasone exposure while adjusting for covariates using multiple logistic regression. Results: Of 5330 women, 1459 women (27.5%) received betamethasone at a mean gestational age of 32.2±3.3 weeks. The mean age of women was 27±5.9 years and the mean gestational age at delivery was 38.9±1.1 weeks. Women receiving betamethasone had higher rates of maternal comorbidities (P<.001 for diabetes mellitus, asthma, and hypertensive disorder) and were more likely to self-identify as White (P=.022). Betamethasone-exposed neonates had increased rates of transient tachypnea of the newborn, neonatal intensive care unit admission, small for gestational age, hyperbilirubinemia, and hypoglycemia (all, P<.05). Controlling for maternal characteristics and gestational age at delivery, betamethasone exposure was not associated with a diagnosis of transient tachypnea of the newborn (adjusted odds ratio, 1.10; 95% confidence interval, 0.80-1.51), although it was associated with more neonatal intensive care unit admissions (adjusted odds ratio, 1.49; 95% confidence interval, 1.19-1.86) and higher odds of the baby being small for gestational age (adjusted odds ratio, 1.78; 95% confidence interval, 1.48-2.14). Conclusion: Compared with women evaluated for preterm labor who did not receive betamethasone, women receiving betamethasone had infants with higher rates of neonatal intensive care unit admission and small for gestational age. Although the benefits of betamethasone to infants born preterm are clear, there may be negative impacts for infants delivered at term.Item Are Newborn Outcomes Different for Term Babies Who Were Exposed to Antenatal Corticosteroids?(American Journal of Obstetrics and Gynecology, 2021-05-03) McKinzie, Alexandra; Yang, Ziyi; Teal, Evgenia; Daggy, Joanne K.; Tepper, Robert S.; Quinney, Sarah K.; Rhoads, Eli; Haneline, Laura S.; Haas, David M.; Obstetrics and Gynecology, School of MedicineBackground Antenatal corticosteroids improve newborn outcomes for preterm infants. However, predicting which women presenting for threatened preterm labor will have preterm infants is inaccurate and many women receive antenatal corticosteroids but then go on to deliver at term. Objective The purpose of this study was to compare the short-term outcomes of infants born at term to women who received betamethasone (BMZ) for threatened preterm labor to infants who were not exposed to BMZ in utero. Study Design We performed a retrospective cohort study of infants born at or after 37 weeks’ gestational age (GA) to mothers diagnosed with threatened preterm labor during pregnancy. The primary neonatal outcomes of interest included transient tachypnea of the newborn (TTN), neonatal intensive care unit (NICU) admission, and small for gestational age (SGA), and were evaluated for their association with BMZ exposure while adjusting for covariates using multiple logistic regression. Results Of 5330 women, 1459 (27.5%) women received BMZ at a mean GA of 32.2±3.3 weeks. The mean age of women was 27±5.9 years-old and the mean GA at delivery was 38.9±1.1 weeks. Women receiving BMZ had higher rates of maternal comorbidities (P<0.001 for diabetes, asthma, and hypertensive disorder) and were more likely to self-identify as white (P=0.022). BMZ-exposed neonates had increased rates of TTN, NICU admission, SGA, hyperbilirubinemia, and hypoglycemia (all P-values <0.05). Controlling for maternal characteristics and GA at delivery, BMZ exposure was not significantly associated with diagnosis of TTN (aOR 1.10, 95% CI 0.80-1.51), though it was associated with more NICU admissions (aOR 1.49, 95% CI 1.19-1.86) and higher odds of the baby being small for gestational age (SGA, aOR 1.78, 95%CI 1.48 to 2.14). Conclusions Compared to women evaluated for preterm labor that did not receive BMZ, women receiving BMZ had infants with higher rates of NICU admission and SGA. While the benefits of BMZ to infants born preterm are clear, there may be negative impacts for infants delivered at term.Item Chinstraps are Needed for Neonatal Nasal CPAP: Reflections from a Non-Human Primate Model(Wiley, 2020-05) MacDonald, Kelvin D.; Davies, Michael; Lam, Ryan; Lund, Kelli; Park, Byung; Spindel, Eliot R.; Tepper, Robert S.; McEvoy, Cindy T.; Pediatrics, School of MedicineItem Correction: Improvements in lung function following vitamin C supplementation to pregnant smokers are associated with buccal DNA methylation at 5 years of age(Springer Nature, 2024-04-25) Shorey‑Kendrick, Lyndsey E.; McEvoy, Cindy T.; Milner, Kristin; Harris, Julia; Brownsberger, Julie; Tepper, Robert S.; Park, Byung; Gao, Lina; Vu, Annette; Morris, Cynthia D.; Spindel, Eliot R.; Pediatrics, School of MedicineCorrection to: Clinical Epigenetics (2024) 16:35 10.1186/s13148-024-01644-8 Following publication of the original article [1], the authors noticed that the NCBI Gene Expression Omnibus (GEO) accession series has been incorrectly listed as GSE253158 within the “Availability of data and materials section”. The correct GEO series for this work is GSE252169.Item Cumulative Effects of Neonatal Hyperoxia on Murine Alveolar Structure and Function(Wiley, 2017-05) Cox, Angela M.; Gao, Yong; Perl, Anne-Karina T.; Tepper, Robert S.; Ahlfeld, Shawn K.; Pediatrics, School of MedicineBackground Bronchopulmonary dysplasia (BPD) results from alveolar simplification and abnormal development of alveolar and capillary structure. Survivors of BPD display persistent deficits in airflow and membrane and vascular components of alveolar gas diffusion. Despite being the defining feature of BPD, various neonatal hyperoxia models of BPD have not routinely assessed pulmonary gas diffusion. Methods To simulate the most commonly-utilized neonatal hyperoxia models, we exposed neonatal mice to room air or ≥90% hyperoxia during key stages of distal lung development: through the first 4 (saccular), 7 (early alveolar), or 14 (bulk alveolar) postnatal days, followed by a period of recovery in room air until 8 weeks of age when alveolar septation is essentially complete. We systematically assessed and correlated the effects of neonatal hyperoxia on the degree of alveolar–capillary structural and functional impairment. We hypothesized that the degree of alveolar–capillary simplification would correlate strongly with worsening diffusion impairment. Results Neonatal hyperoxia exposure, of any duration, resulted in alveolar simplification and impaired pulmonary gas diffusion. Mean Linear Intercept increased in proportion to the length of hyperoxia exposure while alveolar and total lung volume increased markedly only with prolonged exposure. Surprisingly, despite having a similar effect on alveolar surface area, only prolonged hyperoxia for 14 days resulted in reduced pulmonary microvascular volume. Estimates of alveolar and capillary structure, in general, correlated poorly with assessment of gas diffusion. Conclusion Our results help define the physiological and structural consequences of commonly-employed neonatal hyperoxia models of BPD and informtheir clinical utility.Item Decision tree-based rules outperform risk scores for childhood asthma prognosis(Wiley, 2021) Owora, Arthur H.; Tepper, Robert S.; Ramsey, Clare D.; Becker, Allan B.; Pediatrics, School of MedicineBackground: There are no widely accepted prognostic tools for childhood asthma; this is in part due to the multifactorial and time-dependent nature of mechanisms and risk factors that contribute to asthma development. Our study objective was to develop and evaluate the prognostic performance of conditional inference decision tree-based rules using the Pediatric Asthma Risk Score (PARS) predictors as an alternative to the existing logistic regression-based risk score for childhood asthma prediction at 7 years in a high-risk population. Methods: The Canadian Asthma Primary Prevention Study data were used to develop, compare, and contrast the prognostic performance (area under the curve [AUC], sensitivity, and specificity) of conditional inference tree-based decision rules to the pediatric asthma risk score for the prediction of childhood asthma at 7 years. Results: Conditional inference decision tree-based rules have higher prognostic performance (AUC: 0.85; 95% CI: 0.81, 0.88; sensitivity = 47%; specificity = 93%) than the pediatric asthma risk score at an optimal cutoff of ≥6 (AUC: 0.71; 95% CI: 0.67, 0.76; sensitivity = 60%; specificity = 74%). Moreover, the pediatric asthma risk score is not linearly related to asthma risk, and at any given pediatric asthma risk score value, different combinations of its pediatric asthma risk score clinical variables differentially predict asthma risk. Conclusion: Conditional inference tree-based decision rules could be a useful childhood asthma prognostic tool, providing an alternative way to identify unique subgroups of at-risk children, and insights into associations and effect mechanisms that are suggestive of appropriate tailored preventive interventions. However, the feasibility and effectiveness of such decision rules in clinical practice is warranted.Item Decreased vascular reactivity associated with increased IL-8 in 6-month-old infants of mothers with pre-eclampsia(Springer Nature, 2024) Kua, Kok Lim; Rhoads, Eli; Slaven, James E.; Edwards, Shanique; Haas, David M.; Ren, Clement L.; Tiller, Christina; Bjerregaard, Jeffrey; Haneline, Laura S.; Tepper, Robert S.; Pediatrics, School of MedicineBackground: Offspring born to mothers with pre-eclampsia (Pre-E) suffer higher risks of adult cardiovascular diseases, suggesting that exposure to an antiangiogenic environment in-utero has a lasting impact on the development of endothelial function. The goal of this study is to test the hypothesis that in-utero exposure to Pre-E results in alterations of angiogenic factors/cytokines that negatively impact vascular development during infancy. Methods: Infants born from mothers with and without Pre-E were recruited and followed up at 6 months. Plasma cytokines, blood pressure, microvessel density, and vascular reactivity were assessed. Results: 6-month-old infants born to mothers with Pre-E had unchanged blood pressure (p = 0.86) and microvessel density (p = 0.57). Vascular reactivity was decreased in infants born to mothers with Pre-E compared to infants born to healthy mothers (p = 0.0345). Interleukin 8 (IL-8) (p = 0.03) and Angiopoeitin-2 (Ang-2) (p = 0.04) were increased in infants born to mothers with Pre-E. We observed that higher IL-8 was associated with lower vascular reactivity (rho = -0.14, p < 0.0001). Conclusion: At 6 months of age, infants born to mothers with Pre-E had impaired vascular reactivity and higher IL-8 and Ang-2, but similar blood pressure and microvessel density compared to infants born to non-Pre-E mothers. Impact statement: Changes in cord blood antiangiogenic factors are documented in infants of mothers with pre-eclampsia and may contribute to offspring risks of adult cardiovascular disease. How these factors evolve during early infancy and their correlation with offspring vascular development have not been studied. This study found that 6-month-old infants born to mothers with pre-eclampsia had decreased vascular reactivity, which was correlated with higher IL-8. These findings underscore the lasting impact of maternal pre-eclampsia on offspring vascular development and highlight the need for long-term follow-up in children born to mothers with pre-eclampsia.