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.

Dysregulated alveolar epithelial cell progenitor function and identity in Hermansky-Pudlak syndrome pulmonary fibrosis.

Hermansky-Pudlak syndrome (HPS) is a genetic disorder associated with pulmonary fibrosis in specific subtypes, including HPS-1 and HPS-2. Single mutant HPS1 and HPS2 mice display increased fibrotic sensitivity while double mutant HPS1/2 mice exhibit spontaneous fibrosis with aging, which has been attributed to HPS mutations in alveolar epithelial type II (AT2) cells. Unifying mechanisms of AT2 cell dysfunction in genetic and sporadic fibrotic lung diseases remain unknown. Incorporating AT2 cell lineage tracing in HPS mice, we observed a progressive decline in AT2 cell numbers with aging and aberrant differentiation with increased AT2-derived alveolar epithelial type I cells. HPS AT2 cell proliferation was impaired ex vivo and in vivo , suggesting an intrinsic progenitor defect. Transcriptomic analysis of HPS AT2 cells revealed elevated expression of genes associated with aberrant differentiation and cellular senescence. Through lineage tracing and organoid modeling, we demonstrated that HPS AT2 cells were primed to persist in a Krt8 + reprogrammed transitional state, mediated by p53 activity. These findings suggest that pulmonary fibrosis in HPS may be driven by AT2 cell progenitor dysfunction in the setting of p53-mediated senescence, highlighting a novel potential therapeutic target in HPS and suggesting unifying mechanisms underlying HPS and other forms of pulmonary fibrosis.

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.

Estimating the effect of nintedanib on forced vital capacity in children and adolescents with fibrosing interstitial lung disease using a Bayesian dynamic borrowing approach.

BACKGROUND: The rarity of childhood interstitial lung disease (chILD) makes it challenging to conduct powered trials. In the InPedILD trial, among 39 children and adolescents with fibrosing ILD, there was a numerical benefit of nintedanib versus placebo on change in forced vital capacity (FVC) over 24 weeks (difference in mean change in FVC % predicted of 1.21 [95% confidence interval: -3.40, 5.81]). Nintedanib has shown a consistent effect on FVC across populations of adults with different diagnoses of fibrosing ILD. METHODS: In a Bayesian dynamic borrowing analysis, prespecified before data unblinding, we incorporated data on the effect of nintedanib in adults and the data from the InPedILD trial to estimate the effect of nintedanib on FVC in children and adolescents with fibrosing ILD. The data from adults were represented as a meta-analytic predictive (MAP) prior distribution with mean 1.69 (95% credible interval: 0.49, 3.08). The adult data were weighted according to expert judgment on their relevance to the efficacy of nintedanib in chILD, obtained in a formal elicitation exercise. RESULTS: Combined data from the MAP prior and InPedILD trial analyzed within the Bayesian framework resulted in a median difference between nintedanib and placebo in change in FVC % predicted at Week 24 of 1.63 (95% credible interval: -0.69, 3.40). The posterior probability for superiority of nintedanib versus placebo was 95.5%, reaching the predefined success criterion of at least 90%. CONCLUSION: These findings, together with the safety data from the InPedILD trial, support the use of nintedanib in children and adolescents with fibrosing ILDs.

Pulmonary injury after radioactive iodine therapy in pediatric papillary thyroid cancer: a case report.

INTRODUCTION: Radiation-induced lung injury is a rare complication of radioactive iodine therapy (RAIT) in pediatric thyroid cancer treatment. In this case report, we describe a pediatric patient with an ERC1::RET-positive classic papillary thyroid carcinoma who developed progressive respiratory symptoms and chest imaging abnormalities following RAIT for lymph node and pulmonary disease. CASE PRESENTATION: A pediatric patient with ERC1::RET-positive classic papillary thyroid carcinoma was hospitalized for pulmonary decompensation three months following one empiric dose of RAIT. Testing revealed no evidence of infection or progression of pulmonary metastases, and there was no improvement with empiric antibiotic therapy for pneumonia. Despite empiric anti-inflammatory therapies, the patient remains symptomatic from a respiratory standpoint with requirement for supplemental oxygen and evidence of fibrotic changes on chest imaging. CONCLUSIONS: This patient's pulmonary condition is consistent with radiation-induced pulmonary injury including development of pulmonary fibrosis. With the availability of RET fusion targeted inhibitors, this case highlights a rare pulmonary side effect of radioactive iodine for clinicians to recognize. Upfront targeted therapy protocols may help avoid radioactive iodine-associated adverse reactions.

Developmental progression of the nasopharyngeal microbiome during childhood and association with the lower airway microbiome.

Background: The upper (URT) and lower (LRT) respiratory tract feature distinct environments and responses affecting microbial colonization but investigating the relationship between them is technically challenging. We aimed to identify relationships between taxa colonizing the URT and LRT and explore their relationship with development during childhood. Methods: We employed V4 16S rDNA sequencing to profile nasopharyngeal swabs and tracheal aspirates collected from 183 subjects between 20 weeks and 18 years of age. These samples were collected prior to elective procedures at the Children's Hospital of Philadelphia over the course of 20 weeks in 2020, from otherwise healthy subjects enrolled in a study investigating potential reservoirs of SARS-CoV-2. Findings: After extraction, sequencing, and quality control, we studied the remaining 124 nasopharyngeal swabs and 98 tracheal aspirates, including 85 subject-matched pairs of samples. V4 16S rDNA sequencing revealed that the nasopharynx is colonized by few, highly-abundant taxa, while the tracheal aspirates feature a diverse assembly of microbes. While no taxa co-occur in the URT and LRT of the same subject, clusters of microbiomes in the URT correlate with clusters of microbiomes in the LRT. The clusters identified in the URT correlate with subject age across childhood development. Interpretations: The correlation between clusters of taxa across sites may suggest a mutual influence from either a third site, such as the oropharynx, or host-extrinsic, environmental features. The identification of a pattern of upper respiratory microbiota development across the first 18 years of life suggests that the patterns observed in early childhood may extend beyond the early life window.

The US national registry for childhood interstitial and diffuse lung disease: Report of study design and initial enrollment cohort.

INTRODUCTION: Childhood interstitial and diffuse lung disease (chILD) encompasses a broad spectrum of rare disorders. The Children's Interstitial and Diffuse Lung Disease Research Network (chILDRN) established a prospective registry to advance knowledge regarding etiology, phenotype, natural history, and management of these disorders. METHODS: This longitudinal, observational, multicenter registry utilizes single-IRB reliance agreements, with participation from 25 chILDRN centers across the U.S. Clinical data are collected and managed using the Research Electronic Data Capture (REDCap) electronic data platform. RESULTS: We report the study design and selected elements of the initial Registry enrollment cohort, which includes 683 subjects with a broad range of chILD diagnoses. The most common diagnosis reported was neuroendocrine cell hyperplasia of infancy, with 155 (23%) subjects. Components of underlying disease biology were identified by enrolling sites, with cohorts of interstitial fibrosis, immune dysregulation, and airway disease being most commonly reported. Prominent morbidities affecting enrolled children included home supplemental oxygen use (63%) and failure to thrive (46%). CONCLUSION: This Registry is the largest longitudinal chILD cohort in the United States to date, providing a powerful framework for collaborating centers committed to improving the understanding and treatment of these rare disorders.

Clinical scope and healthcare utilization in childhood interstitial lung disease at a tertiary center.

Childhood interstitial lung disease (chILD) is a heterogeneous group of diffuse lung diseases that can be challenging to diagnose. With relative rarity of individual entities, data are limited on disease prevalence, care patterns, and healthcare utilization. The objective of this study was to evaluate chILD prevalence and review diagnostic and clinical care patterns at our center. A single-center, retrospective cohort study was conducted of patients receiving care at the Children's Hospital of Philadelphia (CHOP) between 1 January 2019 and 31 December 2021. Through query of selected ICD-10 billing codes relevant for chILD and medical chart review, a total of 306 patients were identified receiving pulmonary care during this period. Respiratory symptom onset was documented to have developed before 2 years of age for 40% of cases. The most common diagnostic categories included those with oncologic disease (21.2%), bronchiolitis obliterans (10.1%), and connective tissue disease (9.5%). Genetic testing was performed in 49% of cases, while 36% underwent lung biopsy. Hospitalization at CHOP had occurred for 80.4% of patients, with 45.1% ever hospitalized in an intensive care unit. One-third of children had required chronic supplemental oxygen. Seven (2.3%) patients died during this 3-year period. Collectively, these data demonstrate the scope of chILD and extent of health care utilization at a large volume tertiary care center. This approach to cohort identification and EMR-driven data collection in chILD provides new opportunities for cohort analysis and will inform the feasibility of future studies.

Lung biopsy in the diagnosis and management of chILD.

Children's interstitial and diffuse lung disease (chILD) comprises a large number of diverse entities ranging from disorders of lung development, maturation and function unique in infancy to immune-mediated, environmental, vascular and other conditions overlapping with adult disease. Pathologic evaluation of the lung has played a central role in characterizing many of these disorders, resulting in revised nomenclature and classifications to help guide clinical management(1-4). Technological advancements are rapidly uncovering genetic and molecular underpinnings of these conditions, as well as widening the phenotypes which bridge adult disease, often reducing the perceived need for diagnostic lung biopsy. As such the decision to get a lung biopsy in chILD is frequently for rapid ascertainment of disease in a critically ill child or when clinical presentation, imaging and laboratory studies fail to provide a cohesive diagnosis needed for treatment. While there have been modifications in surgical procedures for lung biopsy that minimize postoperative morbidity, it remains a high-risk invasive procedure, especially in a medically complex patient(5). Thus, it is essential that the lung biopsy be handled properly to maximize diagnostic yield, including close communication between the clinician, radiologist, surgeon, and pathologist before biopsy to determine best sampling site(s) and prioritization of tissue utilization. This review provides an overview of optimal handling and evaluation of a surgical lung biopsy for suspected chILD, with emphasis on specific conditions in which pathologic features play a critical role in providing an integrated diagnosis and guiding management.

Nintedanib in children and adolescents with fibrosing interstitial lung diseases.

BACKGROUND: Childhood interstitial lung disease (ILD) comprises a spectrum of rare ILDs affecting infants, children and adolescents. Nintedanib is a licensed treatment for pulmonary fibrosis in adults. The primary objectives of the InPedILD trial were to determine the dose-exposure and safety of nintedanib in children and adolescents with fibrosing ILD. METHODS: Patients aged 6-17 years with fibrosing ILD on high-resolution computed tomography and clinically significant disease were randomised 2:1 to receive nintedanib or placebo for 24 weeks and then open-label nintedanib. Dosing was based on weight-dependent allometric scaling. Co-primary end-points were the area under the plasma concentration-time curve at steady state (AUCτ,ss) at weeks 2 and 26 and the proportion of patients with treatment-emergent adverse events at week 24. RESULTS: 26 patients received nintedanib and 13 patients received placebo. The geometric mean (geometric coefficient of variation) AUCτ,ss for nintedanib was 175 µg·h·L-1 (85.1%) in patients aged 6-11 years and 160 µg·h·L-1 (82.7%) in patients aged 12-17 years. In the double-blind period, adverse events were reported in 84.6% of patients in each treatment group. Two patients discontinued nintedanib due to adverse events. Diarrhoea was reported in 38.5% and 15.4% of the nintedanib and placebo groups, respectively. Adjusted mean±se changes in percentage predicted forced vital capacity at week 24 were 0.3±1.3% in the nintedanib group and -0.9±1.8% in the placebo group. CONCLUSIONS: In children and adolescents with fibrosing ILD, a weight-based dosing regimen resulted in exposure to nintedanib similar to adults and an acceptable safety profile. These data provide a scientific basis for the use of nintedanib in this patient population.

CXCL12 defines lung endothelial heterogeneity and promotes distal vascular growth.

There is a growing amount of data uncovering the cellular diversity of the pulmonary circulation and mechanisms governing vascular repair after injury. However, the molecular and cellular mechanisms contributing to the morphogenesis and growth of the pulmonary vasculature during embryonic development are less clear. Importantly, deficits in vascular development lead to significant pediatric lung diseases, indicating a need to uncover fetal programs promoting vascular growth. To address this, we used a transgenic mouse reporter for expression of Cxcl12, an arterial endothelial hallmark gene, and performed single-cell RNA sequencing on isolated Cxcl12-DsRed+ endothelium to assess cellular heterogeneity within pulmonary endothelium. Combining cell annotation with gene ontology and histological analysis allowed us to segregate the developing artery endothelium into functionally and spatially distinct subpopulations. Expression of Cxcl12 is highest in the distal arterial endothelial subpopulation, a compartment enriched in genes for vascular development. Accordingly, disruption of CXCL12 signaling led to, not only abnormal branching, but also distal vascular hypoplasia. These data provide evidence for arterial endothelial functional heterogeneity and reveal conserved signaling mechanisms essential for pulmonary vascular development.

The Association between Exposures and Disease Characteristics in Familial Pulmonary Fibrosis.

Rationale: Heterogeneous characteristics are observed in familial pulmonary fibrosis (FPF), suggesting that nongenetic factors contribute to disease manifestations. Objectives: To determine the relationship between environmental exposures and disease characteristics of FPF, including the morphological characteristics on chest computed tomography (CT) scan, and timing of FPF symptom onset, lung transplantation, or death. Methods: Subjects with FPF with an exposure questionnaire and chest CT were selected from a prospective cohort at Vanderbilt. Disease characteristics were defined by lung parenchymal findings on chest CT associated with fibrotic hypersensitivity pneumonitis (fHP) or usual interstitial pneumonia (UIP) and by time from birth to symptom onset or a composite of lung transplantation or death. After assessing the potential for confounding by sex or smoking, adjusted logistic or Cox proportional hazards regression models identified exposures associated with fHP or UIP CT findings. Findings were validated in a cohort of patients with sporadic pulmonary fibrosis enrolled in the LTRC (Lung Tissue Research Consortium) study. Results: Among 159 subjects with FPF, 98 (61.6%) were males and 96 (60.4%) were ever-smokers. Males were less likely to have CT features of fHP, including mosaic attenuation (FPF: adjusted [for sex and smoking] odds ratio [aOR], 0.27; 95% confidence interval [CI], 0.09-0.76; P = 0.01; LTRC: aOR, 0.35; 95% CI, 0.21-0.61; P = 0.0002). Organic exposures, however, were not consistently associated with fHP features in either cohort. Smoking was a risk factor for honeycombing in both cohorts (FPF: aOR, 2.19; 95% CI, 1.12-4.28; P = 0.02; LTRC: aOR, 1.69; 95% CI, 1.22-2.33; P = 0.002). Rock dust exposure may also be associated with honeycombing, although the association was not statistically-significant when accounting for sex and smoking (FPF: aOR, 2.27; 95% CI, 0.997-5.15; P = 0.051; LTRC: aOR, 1.51; 95% CI, 0.97-2.33; P = 0.07). In the FPF cohort, ever-smokers experienced a shorter transplant-free survival (adjusted hazard ratio, 1.64; 95% CI, 1.07-2.52; P = 0.02), whereas sex was not associated with differential survival (male adjusted hazard ratio, 0.75; 95% CI, 0.50-1.14; P = 0.18). Conclusions: In FPF, smoking contributes to shortened transplant-free survival and development of honeycombing, a finding that is also likely applicable to sporadic pulmonary fibrosis. Females are more likely to manifest CT features of fHP (mosaic attenuation), a finding that was incompletely explained by sex differences in exposures. These findings may have implications for pulmonary fibrosis classification and management.

Thromboxane-Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis.

Rationale: Although persistent fibroblast activation is a hallmark of idiopathic pulmonary fibrosis (IPF), mechanisms regulating persistent fibroblast activation in the lungs have not been fully elucidated. Objectives: On the basis of our observation that lung fibroblasts express TBXA2R (thromboxane-prostanoid receptor) during fibrosis, we investigated the role of TBXA2R signaling in fibrotic remodeling. Methods: We identified TBXA2R expression in lungs of patients with IPF and mice and studied primary mouse and human lung fibroblasts to determine the impact of TBXA2R signaling on fibroblast activation. We used TBXA2R-deficient mice and small-molecule inhibitors to investigate TBXA2R signaling in preclinical lung fibrosis models. Measurements and Main Results: TBXA2R expression was upregulated in fibroblasts in the lungs of patients with IPF and in mouse lungs during experimental lung fibrosis. Genetic deletion of TBXA2R, but not inhibition of thromboxane synthase, protected mice from bleomycin-induced lung fibrosis, thereby suggesting that an alternative ligand activates profibrotic TBXA2R signaling. In contrast to thromboxane, F2-isoprostanes, which are nonenzymatic products of arachidonic acid induced by reactive oxygen species, were persistently elevated during fibrosis. F2-isoprostanes induced TBXA2R signaling in fibroblasts and mediated a myofibroblast activation profile due, at least in part, to potentiation of TGF-ß (transforming growth factor-ß) signaling. In vivo treatment with the TBXA2R antagonist ifetroban reduced profibrotic signaling in the lungs, protected mice from lung fibrosis in three preclinical models (bleomycin, Hermansky-Pudlak mice, and radiation-induced fibrosis), and markedly enhanced fibrotic resolution after bleomycin treatment. Conclusions: TBXA2R links oxidative stress to fibroblast activation during lung fibrosis. TBXA2R antagonists could have utility in treating pulmonary fibrosis.

Dysregulated myosin in Hermansky-Pudlak syndrome lung fibroblasts is associated with increased cell motility.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by improper biogenesis of lysosome-related organelles (LROs). Lung fibrosis is the leading cause of death among adults with HPS-1 and HPS-4 genetic types, which are associated with defects in the biogenesis of lysosome-related organelles complex-3 (BLOC-3), a guanine exchange factor (GEF) for a small GTPase, Rab32. LROs are not ubiquitously present in all cell types, and specific cells utilize LROs to accomplish dedicated functions. Fibroblasts are not known to contain LROs, and the function of BLOC-3 in fibroblasts is unclear. Here, we report that lung fibroblasts isolated from patients with HPS-1 have increased migration capacity. Silencing HPS-1 in normal lung fibroblasts similarly leads to increased migration. We also show that the increased migration is driven by elevated levels of Myosin IIB. Silencing HPS1 or RAB32 in normal lung fibroblasts leads to increased MYOSIN IIB levels. MYOSIN IIB is downstream of p38-MAPK, which is a known target of angiotensin receptor signaling. Treatment with losartan, an angiotensin receptor inhibitor, decreases MYOSIN IIB levels and impedes HPS lung fibroblast migration in vitro. Furthermore, pharmacologic inhibition of angiotensin receptor with losartan seemed to decrease migration of HPS lung fibroblasts in vivo in a zebrafish xenotransplantation model. Taken together, we demonstrate that BLOC-3 plays an important role in MYOSIN IIB regulation within lung fibroblasts and contributes to fibroblast migration.

Neurobehavioral morbidity of pediatric mild sleep-disordered breathing and obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea is associated with neurobehavioral dysfunction, but the relationship between disease severity as measured by the apnea-hypopnea index and neurobehavioral morbidity is unclear. The objective of our study is to compare the neurobehavioral morbidity of mild sleep-disordered breathing versus obstructive sleep apnea. METHODS: Children 3-12 years old recruited for mild sleep-disordered breathing (snoring with obstructive apnea-hypopnea index < 3) into the Pediatric Adenotonsillectomy Trial for Snoring were compared to children 5-9 years old recruited for obstructive sleep apnea (obstructive apnea-hypopnea 2-30) into the Childhood Adenotonsillectomy Trial. Baseline demographic, polysomnographic, and neurobehavioral outcomes were compared using univariable and multivariable analysis. RESULTS: The sample included 453 participants with obstructive sleep apnea (median obstructive apnea-hypopnea index 5.7) and 459 participants with mild sleep-disordered breathing (median obstructive apnea-hypopnea index 0.5). By polysomnography, participants with obstructive sleep apnea had poorer sleep efficiency and more arousals. Children with mild sleep-disordered breathing had more abnormal executive function scores (adjusted odds ratio 1.96, 95% CI 1.30-2.94) compared to children with obstructive sleep apnea. There were also elevated Conners scores for inattention (adjusted odds ratio 3.16, CI 1.98-5.02) and hyperactivity (adjusted odds ratio 2.82, CI 1.83-4.34) in children recruited for mild sleep-disordered breathing. CONCLUSIONS: Abnormal executive function, inattention, and hyperactivity were more common in symptomatic children recruited into a trial for mild sleep-disordered breathing compared to children recruited into a trial for obstructive sleep apnea. Young, snoring children with only minimally elevated apnea-hypopnea levels may still be at risk for deficits in executive function and attention. TRIAL REGISTRATION: Pediatric Adenotonsillectomy for Snoring (PATS), NCT02562040; Childhood Adenotonsillectomy Trial (CHAT), NCT00560859.

Area deprivation and respiratory morbidities in children with bronchopulmonary dysplasia.

INTRODUCTION: Infants and children diagnosed with bronchopulmonary dysplasia (BPD) have a higher likelihood of recurrent hospitalizations and asthma-like symptoms. Socio-environmental factors that influence the frequency and severity of pulmonary symptoms in these children during the preschool age are poorly understood. In this study, we used the Area Deprivation Index (ADI) to evaluate the relationship between the socio-environmental exposures in children with BPD and respiratory outcomes during the first few years of life. METHODS: A registry of subjects recruited from outpatient BPD clinics at Johns Hopkins University (n = 909) and the Children's Hospital of Philadelphia (n = 125) between January 2008 and October 2021 was used. Subjects were separated into tertiles by ADI scores aggregated to ZIP codes. Caregiver questionnaires were used to assess the frequency of respiratory morbidities and acute care usage for respiratory symptoms. RESULTS: The mean gestational age of subjects was 26.8 ± 2.6 weeks with a mean birthweight of 909 ± 404 g. The highest tertile (most deprived) of ADI was significantly associated with emergency department visits (aOR 1.72; p = 0.009), hospital readmissions (aOR 1.66; p = 0.030), and activity limitations (aOR 1.55; p = 0.048) compared to the lowest tertile. No association was seen with steroid, antibiotic or rescue medication use, trouble breathing, or nighttime symptoms. CONCLUSION: In this study, children with BPD who lived in areas of higher deprivation were more likely to be rehospitalized and have ED visits for respiratory reasons. Identifying socio-environmental factors that contribute to adverse pulmonary outcomes in children with BPD may provide opportunities for earlier interventions to improve long-term pulmonary outcomes.

Insights into the Pathogenesis of Pulmonary Fibrosis from Genetic Diseases.

Pulmonary fibrosis is a disease process associated with significant morbidity and mortality, with limited therapeutic options owing to an incomplete understanding of the underlying pathophysiology. Mechanisms driving the fibrotic cascade have been elucidated through studies of rare and common variants in surfactant-related and telomere-related genes in familial and sporadic forms of pulmonary fibrosis, as well as in multisystem Mendelian genetic disorders that present with pulmonary fibrosis. In this translational review, we outline insights into the pathophysiology of pulmonary fibrosis derived from genetic forms of the disease, with a focus on model systems, shared cellular and molecular mechanisms, and potential targets for therapy.

Excess neuropeptides in lung signal through endothelial cells to impair gas exchange.

Although increased neuropeptides are often detected in lungs that exhibit respiratory distress, whether they contribute to the condition is unknown. Here, we show in a mouse model of neuroendocrine cell hyperplasia of infancy, a pediatric disease with increased pulmonary neuroendocrine cells (PNECs), excess PNEC-derived neuropeptides are responsible for pulmonary manifestations including hypoxemia. In mouse postnatal lung, prolonged signaling from elevated neuropeptides such as calcitonin gene-related peptide (CGRP) activate receptors enriched on endothelial cells, leading to reduced cellular junction gene expression, increased endothelium permeability, excess lung fluid, and hypoxemia. Excess fluid and hypoxemia were effectively attenuated by either prevention of PNEC formation, inactivation of CGRP gene, endothelium-specific inactivation of CGRP receptor gene, or treatment with CGRP receptor antagonist. Neuropeptides were increased in human lung diseases with excess fluid such as acute respiratory distress syndrome. Our findings suggest that restricting neuropeptide function may limit fluid and improve gas exchange in these conditions.

Junctional epidermolysis bullosa with extensive lung involvement in three patients with a LAMB3 Mutation.

Junctional epidermolysis bullosa (JEB) is characterized by skin and mucous membrane fragility leading to easy blistering. Blistering may be the result of multiple genetic mutations, including the LAMB3 gene encoding a subunit of laminin 332, an important protein in the basement membrane zone. The clinical presentation of JEB includes blistering and granulation tissue forming anywhere on the skin including around oral and nasal cavities, fingers, toes, and within mucous membranes such as the upper respiratory tract. Lung pathology associated with JEB is less commonly reported; we describe three children with LAMB3 pathogenic variants with extensive lung injury contributing to decline in clinical status and likely leading to their demise early in life.