Dynamic Hippo pathway activity underlies mesenchymal differentiation during lung alveolar morphogenesis.

Alveologenesis, the final stage in lung development, substantially remodels the distal lung, expanding the alveolar surface area for efficient gas exchange. Secondary crest myofibroblasts (SCMF) exist transiently in the neonatal distal lung and are crucial for alveologenesis. However, the pathways that regulate SCMF function, proliferation and temporal identity remain poorly understood. To address this, we purified SCMFs from reporter mice, performed bulk RNA-seq and found dynamic changes in Hippo-signaling components during alveologenesis. We deleted the Hippo effectors Yap/Taz from Acta2-expressing cells at the onset of alveologenesis, causing a significant arrest in alveolar development. Using single cell RNA-seq, we identified a distinct cluster of cells in mutant lungs with altered expression of marker genes associated with proximal mesenchymal cell types, airway smooth muscle and alveolar duct myofibroblasts. In vitro studies confirmed that Yap/Taz regulates myofibroblast-associated gene signature and contractility. Together, our findings show that Yap/Taz is essential for maintaining functional myofibroblast identity during postnatal alveologenesis.

Parental Report of Indoor Air Pollution is Associated with Respiratory Morbidities In Bronchopulmonary Dysplasia.

OBJECTIVE: To determine the association between indoor air pollution and respiratory morbidities in children with bronchopulmonary dysplasia recruited from the multicenter Bronchopulmonary Dysplasia (BPD) Collaborative. STUDY DESIGN: A cross-sectional study was performed among participants less than 3 years old in the BPD Collaborative Outpatient Registry. Indoor air pollution was defined as any reported exposure to tobacco or marijuana smoke, electronic cigarette emissions, gas stoves, and/or wood stoves. Clinical data included acute care use and chronic respiratory symptoms in the past 4 weeks. RESULTS: A total of 1,011 subjects born at a mean gestational age of 26.4 ± 2.2 weeks were included. Most (66.6%) had severe BPD. Over 40% of subjects were exposed to at least one source of indoor air pollution. The odds of reporting an emergency department visit (OR 1.7 [1.18, 2.45], antibiotic use (OR 1.9 [1.12, 3.21]), or a systemic steroid course (OR 2.18 [1.24, 3.84]) were significantly higher in subjects reporting exposure to secondhand smoke (SHS) compared with those without SHS exposure. Subjects reporting exposure to air pollution (not including SHS) also had a significantly greater odds (OR 1.48 [1.08, 2.03]) of antibiotic use as well. Indoor air pollution exposure (including SHS) was not associated with chronic respiratory symptoms or rescue medication use. CONCLUSION: Exposure to indoor air pollution, especially SHS, was associated with acute respiratory morbidities, including ED visits, antibiotics for respiratory illnesses, and systemic steroid use.

Long-term outcomes of infants with severe BPD.

Preterm birth disrupts the normal sequence of lung development. Additionally, interventions that support gas exchange, including positive pressure ventilation and supplemental oxygen can further exacerbate lung injury, increasing the risk of developing bronchopulmonary dysplasia (BPD) in infants born preterm. Approximately 50,000 preterm infants each year in the United States develop BPD. Heterogeneous lung pathology involving the upper and lower respiratory tract can contribute to the BPD phenotype and can be age-dependent. These phenotypes include alveolar, upper airway, large airways, small airways, and vascular. Each of these phenotypes may improve, resolve, or persist at different ages, throughout childhood. The development of BPD endotypes can be influenced by gestational age and length and type of respiratory support. Although, long-term pulmonary outcomes of infants with severe BPD are variable, the presence of small airway disease is a common phenotype in school age and adolescent children. In this review we examine the more common respiratory endotypes found in infants and children with severe BPD and discuss the long-term prognosis for cardiovascular, neurological, and gastrointestinal morbidities in this patient population.

Long-term pulmonary outcomes in BPD throughout the life-course.

Respiratory disease is one of the most common complications of preterm birth. Survivors of prematurity have increased risks of morbidities and mortalities independent of prematurity, and frequently require multiple medications, home respiratory support, and subspecialty care to maintain health. Although advances in neonatal and pulmonary care have improved overall survival, earlier gestational age, lower birth weight, chorioamnionitis and late onset sepsis continue to be major factors in the development of bronchopulmonary dysplasia. These early life events associated with prematurity can have respiratory consequences that persist into adulthood. Furthermore, after initial hospital discharge, air pollution, respiratory tract infections and socioeconomic status may modify lung growth trajectories and influence respiratory outcomes in later life. Given that the incidence of respiratory disease associated with prematurity remains stable or increased, there is a need for pediatric and adult providers to be familiar with the natural history, manifestations, and common complications of disease.

Outpatient inhaled corticosteroid use in bronchopulmonary dysplasia.

RATIONALE: In the outpatient setting, inhaled corticosteroids (ICS) are frequently given to children with bronchopulmonary dysplasia (BPD) for treatment of respiratory and asthma-associated symptoms. In this study we sought to determine if correlations existed between ICS use and ICS initiation and patient characteristics and outpatient respiratory outcomes. METHODS: This study included children with the diagnosis of BPD (n = 661) who were seen in outpatient pulmonary clinics at the Children's Hospital of Philadelphia between 2016 and 2021. Chart review was used to determine patient demographics, use and timing of ICS initiation, asthma diagnosis, and acute care usage following initial hospital discharge. RESULTS: At the first pulmonary visit, 9.2% of children had been prescribed an ICS at NICU discharge, 13.9% had been prescribed an ICS after NICU discharge but before their first pulmonary appointment, and 6.9% were prescribed an ICS at the completion of initial pulmonary visit. Children started on an ICS as outpatients had a higher likelihood of ER visits (adjusted odds ratio: 2.68 ± 0.7), hospitalizations (4.81 ± 1.16), and a diagnosis of asthma (3.58 ± 0.84), compared to children never on an ICS. Of those diagnosed with asthma, children prescribed an ICS in the outpatient setting received the diagnosis at an earlier age. No associations between NICU BPD severity scores and ICS use were found. CONCLUSIONS: This study identifies an outpatient BPD phenotype associated with ICS use and ICS initiation independent of NICU severity score. Additionally, outpatient ICS initiation correlates with a subsequent diagnosis of asthma and acute care usage in children with BPD.

Transcriptional profiling of peripheral blood mononuclear cells identifies inflammatory phenotypes in Ataxia Telangiectasia.

INTRODUCTION: Ataxia telangiectasia (A-T) is an autosomal recessive neurodegenerative disease with widespread systemic manifestations and marked variability in clinical phenotypes. In this study, we sought to determine whether transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) defines subsets of individuals with A-T beyond mild and classic phenotypes, enabling identification of novel features for disease classification and treatment response to therapy. METHODS: Participants with classic A-T (n = 77), mild A-T (n = 13), and unaffected controls (n = 15) were recruited from two outpatient clinics. PBMCs were isolated and bulk RNAseq was performed. Plasma was also isolated in a subset of individuals. Affected individuals were designated mild or classic based on ATM mutations and clinical and laboratory features. RESULTS: People with classic A-T were more likely to be younger and IgA deficient and to have higher alpha-fetoprotein levels and lower % forced vital capacity compared to individuals with mild A-T. In classic A-T, the expression of genes required for V(D)J recombination was lower, and the expression of genes required for inflammatory activity was higher. We assigned inflammatory scores to study participants and found that inflammatory scores were highly variable among people with classic A-T and that higher scores were associated with lower ATM mRNA levels. Using a cell type deconvolution approach, we inferred that CD4 + T cells and CD8 + T cells were lower in number in people with classic A-T. Finally, we showed that individuals with classic A-T exhibit higher SERPINE1 (PAI-1) mRNA and plasma protein levels, irrespective of age, and higher FLT4 (VEGFR3) and IL6ST (GP130) plasma protein levels compared with mild A-T and controls. CONCLUSION: Using a transcriptomic approach, we identified novel features and developed an inflammatory score to identify subsets of individuals with different inflammatory phenotypes in A-T. Findings from this study could be used to help direct treatment and to track treatment response to therapy.

Factors associated with liberation from home mechanical ventilation and tracheostomy decannulation in infants and children with severe bronchopulmonary dysplasia.

OBJECTIVE: To identify factors associated with the timing of ventilator liberation and tracheostomy decannulation among infants with severe bronchopulmonary dysplasia (sBPD) who required chronic outpatient invasive ventilation. STUDY DESIGN: Multicenter retrospective study of 154 infants with sBPD on outpatient ventilators. Factors associated with ventilator liberation and decannulation were identified using Cox regression models and multilevel survival models. RESULTS: Ventilation liberation and decannulation occurred at median ages of 27 and 49 months, respectively. Older age at transition to a portable ventilator and at discharge, higher positive end expiratory pressure, and multiple respiratory readmissions were associated with delayed ventilator liberation. Surgical management of gastroesophageal reflux was associated with later decannulation. CONCLUSIONS: Ventilator liberation timing was impacted by longer initial admissions and higher ventilator pressure support needs, whereas decannulation timing was associated with more aggressive reflux management. Variation in the timing of events was primarily due to individual-level factors, rather than center-level factors.