Early Lung Development Research Articles

Striving for healthy lungs: Enhancing respiratory outcomes of prematurity.

Infants born prematurely are born in a critical developmental time period and because of arrest of lung maturation at that period their pulmonary functions are below the normal for their age. Early lung development has a lifelong effect on respiratory health and disease. Can we affect that sequence of events and change the outcome of chronic lung disease of prematurity?

The molecular and cellular choreography of early mammalian lung development.

Mammalian lung development starts from a specific cluster of endodermal cells situated within the ventral foregut region. With the orchestrating of delicate choreography of transcription factors, signaling pathways, and cell-cell communications, the endodermal diverticulum extends into the surrounding mesenchyme, and builds the cellular and structural basis of the complex respiratory system. This review provides a comprehensive overview of the current molecular insights of mammalian lung development, with a particular focus on the early stage of lung cell fate differentiation and spatial patterning. Furthermore, we explore the implications of several congenital respiratory diseases and the relevance to early organogenesis. Finally, we summarize the unprecedented knowledge concerning lung cell compositions, regulatory networks as well as the promising prospect for gaining an unbiased understanding of lung development and lung malformations through state-of-the-art single-cell omics.

Integration of multiomics analysis to reveal the major pathways of vitamin A deficiency aggravates acute respiratory distress syndrome in neonatal rats

Acute respiratory distress syndrome (ARDS) is a major disease that threatens the life and health of neonates. Vitamin A (VA) can participate in early fetal lung development and affect lung immune function. Researches revealed that the serum VA level in premature infants with ARDS was lower than that in premature infants without ARDS of the same gestational age, and premature infants with VA deficiency (VAD) were more likely to develop ARDS. Moreover, the VA levels can be used as a predictor of the development and severity of neonatal ARDS. However, the critical question here is; Does ARDS develop due to VAD in these systemic diseases? Or does ARDS develop because these diseases cause VAD? We hypothesize that VAD may aggravate neonatal ARDS by affecting immunity, metabolism, barriers and other pathways. In this article, we used multiomics analysis to find that VAD may aggravate ARDS mainly through the Fc epsilon RI signaling pathway, the HIF-1 signaling pathway, glutathione metabolism, and valine, leucine and isoleucine degradation signaling pathways, which may provide the molecular pathogenic mechanism behind the pathology of VAD-aggravated ARDS and can also provide potential molecular targets for subsequent research on ARDS.

Human pluripotent stem cell fate trajectories toward lung and hepatocyte progenitors

In this study, we interrogate molecular mechanisms underlying the specification of lung progenitors from human pluripotent stem cells (hPSCs). We employ single-cell RNA-sequencing with high temporal precision, alongside an optimized differentiation protocol, to elucidate the transcriptional hierarchy of lung specification to chart the associated single-cell trajectories. Our findings indicate that Sonic hedgehog, TGF-β, and Notch activation are essential within an ISL1/NKX2-1 trajectory, leading to the emergence of lung progenitors during the foregut endoderm phase. Additionally, the induction of HHEX delineates an alternate trajectory at the early definitive endoderm stage, preceding the lung pathway and giving rise to a significant hepatoblast population. Intriguingly, neither KDR+ nor mesendoderm progenitors manifest as intermediate stages in the lung and hepatic lineage development. Our multistep model offers insights into lung organogenesis and provides a foundation for in-depth study of early human lung development and modeling using hPSCs.

Development of a novel humanized mouse model to study bronchopulmonary dysplasia.

The role of circulating fetal monocytes in bronchopulmonary dysplasia is not known. We utilized a humanized mouse model that supports human progenitor cell engraftment (MISTRG) to test the hypothesis that prenatal monocyte programming alters early lung development and response to hyperoxia. Cord blood-derived monocytes from 10 human infants were adoptively transferred into newborn MISTRG mice at p0 (1 × 106 cells/mouse, intrahepatic injection) followed by normoxia versus hyperoxia (85% oxygen × 14 days). Lungs were harvested at p14 for alveolar histology (alveolar count, perimeter and area) and vascular parameters (vWF staining for microvessel density, Fulton's index). Human CD45 staining was conducted to compare presence of hematopoietic cells. Murine lung parameters were compared among placebo and monocyte-injected groups. The individual profiles of the 10 patients were further considered, including gestational age (GA; n = 2 term, n = 3 moderate/late preterm, and n = 5 very preterm infants) and preeclampsia (n = 4 patients). To explore the monocyte microenvironment of these patients, 30 cytokines/chemokines were measured in corresponding human plasma by multiplex immunoassay. Across the majority of patients and corresponding mice, MISTRG alveolarization was simplified and microvessel density was decreased following hyperoxia. Hyperoxia-induced changes were seen in both placebo (PBS) and monocyte-injected mice. Under normoxic conditions, alveolar development was altered modestly by monocytes as compared with placebo (P < 0.05). Monocyte injection was associated with increased microvessel density at P14 as compared with placebo (26.7 ± 0.73 vs. 18.8 ± 1.7 vessels per lung field; P < 0.001). Pooled analysis of patients revealed that injection of monocytes from births complicated by lower GA and preeclampsia was associated with changes in alveolarization and vascularization under normoxic conditions. These differences were modified by hyperoxia. CD45+ cell count was positively correlated with plasma monocyte chemoattractant protein-1 (P < 0.001) and macrophage inflammatory protein-1β (P < 0.01). Immunohistochemical staining for human CD206 and mouse F4/80 confirmed absence of macrophages in MISTRG lungs at P14. Despite the inherent absence of macrophages in early stages of lung development, immunodeficient MISTRG mice revealed changes in alveolar and microvascular development induced by human monocytes. MISTRG mice exposed to neonatal hyperoxia may serve as a novel model to study isolated effects of human monocytes on alveolar and pulmonary vascular development.

Intrauterine Smoke Exposure, microRNA Expression during Human Lung Development, and Childhood Asthma.

Intrauterine smoke (IUS) exposure during early childhood has been associated with a number of negative health consequences, including reduced lung function and asthma susceptibility. The biological mechanisms underlying these associations have not been established. MicroRNAs regulate the expression of numerous genes involved in lung development. Thus, investigation of the impact of IUS on miRNA expression during human lung development may elucidate the impact of IUS on post-natal respiratory outcomes. We sought to investigate the effect of IUS exposure on miRNA expression during early lung development. We hypothesized that miRNA-mRNA networks are dysregulated by IUS during human lung development and that these miRNAs may be associated with future risk of asthma and allergy. Human fetal lung samples from a prenatal tissue retrieval program were tested for differential miRNA expression with IUS exposure (measured using placental cotinine concentration). RNA was extracted and miRNA-sequencing was performed. We performed differential expression using IUS exposure, with covariate adjustment. We also considered the above model with an additional sex-by-IUS interaction term, allowing IUS effects to differ by male and female samples. Using paired gene expression profiles, we created sex-stratified miRNA-mRNA correlation networks predictive of IUS using DIABLO. We additionally evaluated whether miRNAs were associated with asthma and allergy outcomes in a cohort of childhood asthma. We profiled pseudoglandular lung miRNA in n = 298 samples, 139 (47%) of which had evidence of IUS exposure. Of 515 miRNAs, 25 were significantly associated with intrauterine smoke exposure (q-value < 0.10). The IUS associated miRNAs were correlated with well-known asthma genes (e.g., ORM1-Like Protein 3, ORDML3) and enriched in disease-relevant pathways (oxidative stress). Eleven IUS-miRNAs were also correlated with clinical measures (e.g., Immunoglobulin E andlungfunction) in children with asthma, further supporting their likely disease relevance. Lastly, we found substantial differences in IUS effects by sex, finding 95 significant IUS-miRNAs in male samples, but only four miRNAs in female samples. The miRNA-mRNA correlation networks were predictive of IUS (AUC = 0.78 in males and 0.86 in females) and suggested that IUS-miRNAs are involved in regulation of disease-relevant genes (e.g., A disintegrin and metalloproteinase domain 19 (ADAM19), LBH regulator of WNT signaling (LBH)) and sex hormone signaling (Coactivator associated methyltransferase 1(CARM1)). Our study demonstrated differential expression of miRNAs by IUS during early prenatal human lung development, which may be modified by sex. Based on their gene targets and correlation to clinical asthma and atopy outcomes, these IUS-miRNAs may be relevant for subsequent allergy and asthma risk. Our study provides insight into the impact of IUS in human fetal lung transcriptional networks and on the developmental origins of asthma and allergic disorders.

Single-cell RNA sequencing reveals the developmental program underlying proximal–distal patterning of the human lung at the embryonic stage

The lung is the primary respiratory organ in human, in which the proximal airway and the distal alveoli are responsible for air conduction and gas exchange, respectively. However, the regulation of proximal–distal patterning at the embryonic stage of human lung development is largely unknown. Here we investigated the early lung development of human embryos at weeks 4–8 post fertilization (Carnegie stages 12–21) using single-cell RNA sequencing, and obtained a transcriptomic atlas of 169,686 cells. We observed discernible gene expression patterns of proximal and distal epithelia at week 4, upon the initiation of lung organogenesis. Moreover, we identified novel transcriptional regulators of the patterning of proximal (e.g., THRB and EGR3) and distal (e.g., ETV1 and SOX6) epithelia. Further dissection revealed various stromal cell populations, including an early-embryonic BDNF+ population, providing a proximal–distal patterning niche with spatial specificity. In addition, we elucidated the cell fate bifurcation and maturation of airway and vascular smooth muscle progenitor cells at the early stage of lung development. Together, our study expands the scope of human lung developmental biology at early embryonic stages. The discovery of intrinsic transcriptional regulators and novel niche providers deepens the understanding of epithelial proximal–distal patterning in human lung development, opening up new avenues for regenerative medicine.

A topographic atlas defines developmental origins of cell heterogeneity in the human embryonic lung

The lung contains numerous specialized cell types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell heterogeneity, we created a comprehensive topographic atlas of early human lung development. Here we report 83 cell states and several spatially resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated single-cell RNA sequencing and spatially resolved transcriptomics into a web-based, open platform for interactive exploration. We show distinct gene expression programmes, accompanying sequential events of cell differentiation and maturation of the secretory and neuroendocrine cell types in proximal epithelium. We define the origin of airway fibroblasts associated with airway smooth muscle in bronchovascular bundles and describe a trajectory of Schwann cell progenitors to intrinsic parasympathetic neurons controlling bronchoconstriction. Our atlas provides a rich resource for further research and a reference for defining deviations from homeostatic and repair mechanisms leading to pulmonary diseases.

Comparative study of e-cigarette aerosol and cigarette smoke effect on ex vivo embryonic chick lung explants

Electronic cigarette usage has significantly expanded among young people and pregnant women in the last decade. Although there are already some data regarding the short- and long-term consequences of e-cigarettes on human health, their effect on embryo and lung development still needs to be fully disclosed. In this sense, this study describes, for the first time, the impact of electronic cigarette aerosol on early lung development. For this purpose, ex vivo chick (Gallus gallus) embryonic lungs were cultured in vitro for 48 h in e-cigarette aerosol exposed-medium or unexposed medium. Chick lung explants were also cultured in a cigarette smoke-exposed medium for comparison purposes. Lung explants were morphologically analyzed to assess the impact on lung growth. Additionally, TNF-α levels were determined in the supernatant as a marker of pro-inflammatory response. The results suggest that electronic cigarette aerosol impairs lung growth and promotes lung inflammation. However, its impact on early lung growth seems less detrimental than conventional cigarette smoke. This work provides significant data regarding the impact of e-cig aerosol, adding to the efforts to fully understand its effect on embryo development. The validation of these effects may eventually lead to new tobacco control recommendations for pregnant women.

Acute Lung Functional and Airway Remodeling Effects of an Inhaled Highly Selective Phosphodiesterase 4 Inhibitor in Ventilated Preterm Lambs Exposed to Chorioamnionitis.

Phosphodiesterase (PDE) inhibition has been identified in animal studies as a new treatment option for neonatal lung injury, and as potentially beneficial for early lung development and function. However, our group could show that the inhaled PDE4 inhibitor GSK256066 could have dose-dependent detrimental effects and promote lung inflammation in the premature lung. In this study, the effects of a high and a low dose of GSK256066 on lung function, structure and alveolar development were investigated. In a triple hit lamb model of Ureaplasma-induced chorioamnionitis, prematurity, and mechanical ventilation, 21 animals were treated as unventilated (NOVENT) or 24 h ventilated controls (Control), or with combined 24 h ventilation and low dose (iPDE1) or high dose (iPDE10) treatment with inhaled GSK 256066. We found that high doses of an inhaled PDE4 inhibitor impaired oxygenation during mechanical ventilation. In this group, the budding of secondary septae appeared to be decreased in the preterm lung, suggesting altered alveologenesis. Ventilation-induced structural and functional changes were only modestly ameliorated by a low dose of PDE4 inhibitor. In conclusion, our findings indicate the narrow therapeutic window of PDE4 inhibitors in the developing lung.

FGFR2b signalling restricts lineage-flexible alveolar progenitors during mouse lung development and converges in mature alveolar type 2 cells

The specification, characterization, and fate of alveolar type 1 and type 2 (AT1 and AT2) progenitors during embryonic lung development are poorly defined. Current models of distal epithelial lineage formation fail to capture the heterogeneity and dynamic contribution of progenitor pools present during early development. Furthermore, few studies explore the pathways involved in alveolar progenitor specification and fate. In this paper, we build upon our previously published work on the regulation of airway epithelial progenitors by fibroblast growth factor receptor 2b (FGFR2b) signalling during early (E12.5) and mid (E14.5) pseudoglandular stage lung development. Our results suggest that a significant proportion of AT2 and AT1 progenitors are lineage-flexible during late pseudoglandular stage development, and that lineage commitment is regulated in part by FGFR2b signalling. We have characterized a set of direct FGFR2b targets at E16.5 which are likely involved in alveolar lineage formation. These signature genes converge on a subpopulation of AT2 cells later in development and are downregulated in AT2 cells transitioning to the AT1 lineage during repair after injury in adults. Our findings highlight the extensive heterogeneity of pneumocytes by elucidating the role of FGFR2b signalling in these cells during early airway epithelial lineage formation, as well as during repair after injury.

Maternal immune activation (MIA) impairs neonatal lung ILC2 establishment, function, and airway hyperresponsiveness

Abstract We have recently shown that prenatal inflammation induced by maternal immune activation (MIA) imparts lasting changes to innate immunity by driving the inappropriate expansion and persistence of lymphoid-biased progenitors during fetal life. To test how perturbation during this critical window drives immune dysfunction, we examined underlying changes to lung type-2 innate lymphoid cells (ILC2s) and susceptibility to airway hyperresponsiveness following MIA. MIA induction via a single-low dose injection of poly (I:C) at mid-gestation altered the establishment of a fetal liver (FL) ILC-committed progenitor, increasing cell number and frequency both one- and three-days post MIA. MIA also enhanced lung ILC2 proliferation postnatally, resulting in a robustly expanded ILC2 compartment at postnatal day (P)14 that persisted into adulthood. Concomitant with a greater inflammatory profile, MIA-treated ILC2s were hyperactivated, producing more IL5 and IL13 in-vitro. Lung cytokine levels remained relatively static across early lung development in MIA or saline conditions, suggesting changes to ILC2 proliferation and hyperactivation are cell-intrinsic. Furthermore, hyperactivated ILC2s led to remodeling of the lung immune landscape as observed by expansion of B-, T-, NK-, NKT-cells, alveolar macrophages and eosinophils, but ILC2s were the first immune population to expand in cell number. Altogether, our data suggest MIA imparts lasting changes to lung immunity by perturbing the establishment of committed ILC progenitors in the FL, altering the production of neonatal lung ILC2s poised to hyperactively respond to secondary immune activation, potentially contributing to greater allergic airway hyperresponsiveness. Supported by grants from NIH/NICHD (T32HD007491

L‐Citrulline Attenuates Effects of Serotonin Signalling During Proliferation of Pulmonary Artery Smooth Muscle Cells in Pulmonary Hypertension

IntroductionPremature infants are at risk for bronchopulmonary dysplasia (BPD), a disorder characterized by abnormal pulmonary development. Inflammation is one major component in causing BPD, which can further lead to abnormal vascular remodelling, causing pulmonary hypertension (PH). During this process, pulmonary artery smooth muscle cell (PASMC) proliferation and hypertrophy contribute to the thickening of the pulmonary artery wall, leading to heightened blood pressures. 5‐hydroxytryptamine (5‐HT) or serotonin has been implicated in PH and is involved in the pathogenesis of PH in adults. Meanwhile, L‐citrulline, a nitric oxide donor, has been effective in reducing PH in acute models of BPD. The role of 5‐HT signalling on PASMC proliferation during early pulmonary vascular development is currently unknown. Thus, the objective of this study is to establish the effect of 5‐HT on PASMC proliferation in a newborn model of early lung development, and to elucidate the interaction of 5‐HT on proliferation of PASMCs in the presence of LPS and L‐citrulline.MethodsSprague Dawley rat pups were grown and euthanized on postnatal day 4, after which the pulmonary arteries (PA) were isolated. Primary cultures of PASMCs were grown from PA explants and treated with varying concentrations of 5‐HT. Proliferation and cell viability assays were performed to measure growth and cell viability after exposure to 5‐HT and L‐citrulline (4mM). Lysate samples were also prepared with the cells to measure protein expression via Western blotting for Cyclin D1, an important protein involved in regulation of the cell cycle, and phosphorylated AKT (p‐AKT), which is involved in cell survival. To investigate the effects of inflammation on 5‐HT signalling, PASMCs were exposed to lipopolysaccharide (LPS, 3 µg/mL) and lysate samples were prepared to measure changes in the expression of the 5‐HT2A receptor.ResultsProliferation assays illustrated a dose‐dependent increase in growth of PASMCs exposed to 5‐HT, reaching a peak 150% growth rate (p &lt; 0.05). Western blots revealed a three‐fold increase in Cyclin D1 expression (p &lt; 0.01) and two‐fold increase in p‐AKT expression (p &lt; 0.05) in PASMCs exposed to 5‐HT compared to protein expression of control PASMCs. Both changes were abrogated in PASMCs exposed to both L‐citrulline and 5‐HT, bringing expression of both proteins to control levels. When exposed to LPS, PASMCs have heightened expression of 5‐HT2A, reaching nearly two times higher than in control PASMCs. This effect is also reversed in PASMCs exposed to LPS and L‐citrulline (p &lt; 0.05).ConclusionOur preliminary data support a role for 5‐HT in pathogenesis on BPD‐PH in the presence and absence of inflammation in a newborn model of lung development, and L‐citrulline may be an attractive safe therapeutic option to reverse or mitigate inflammation induced PH in a newborn model, which could later be translated to human infants.

Sex-Specific Differences in MicroRNA Expression During Human Fetal Lung Development.

Background: Sex-specific differences in fetal lung maturation have been well described; however, little is known about the sex-specific differences in microRNA (miRNA) expression during human fetal lung development. Interestingly, many adult chronic lung diseases also demonstrate sex-specific differences in prevalence. The developmental origins of health and disease hypothesis suggests that these sex-specific differences in fetal lung development may influence disease susceptibility later in life. In this study, we performed miRNA sequencing on human fetal lung tissue samples to investigate differential expression of miRNAs between males and females in the pseudoglandular stage of lung development. We hypothesized that differences in miRNA expression are present between sexes in early human lung development and may contribute to the sex-specific differences seen in pulmonary diseases later in life. Methods: RNA was isolated from human fetal lung tissue samples for miRNA sequencing. The count of each miRNA was modeled by sex using negative binomial regression models in DESeq2, adjusting for post-conception age, age2, smoke exposure, batch, and RUV factors. We tested for differential expression of miRNAs by sex, and for the presence of sex-by-age interactions to determine if miRNA expression levels by age were distinct between males and females. Results: miRNA expression profiles were generated on 298 samples (166 males and 132 females). Of the 809 miRNAs expressed in human fetal lung tissue during the pseudoglandular stage of lung development, we identified 93 autosomal miRNAs that were significantly differentially expressed by sex and 129 miRNAs with a sex-specific pattern of miRNA expression across the course of the pseudoglandular period. Conclusion: Our study demonstrates differential expression of numerous autosomal miRNAs between the male and female developing human lung. Additionally, the expression of some miRNAs are modified by age across the pseudoglandular stage in a sex-specific way. Some of these differences in miRNA expression may impact susceptibility to pulmonary disease later in life. Our results suggest that sex-specific miRNA expression during human lung development may be a potential mechanism to explain sex-specific differences in lung development and may impact subsequent disease susceptibility.

Protein interaction networks provide insight into fetal origins of chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) is a leading cause of death in adults that may have origins in early lung development. It is a complex disease, influenced by multiple factors including genetic variants and environmental factors. Maternal smoking during pregnancy may influence the risk for diseases during adulthood, potentially through epigenetic modifications including methylation.MethodsIn this work, we explore the fetal origins of COPD by utilizing lung DNA methylation marks associated with in utero smoke (IUS) exposure, and evaluate the network relationships between methylomic and transcriptomic signatures associated with adult lung tissue from former smokers with and without COPD. To identify potential pathobiological mechanisms that may link fetal lung, smoke exposure and adult lung disease, we study the interactions (physical and functional) of identified genes using protein–protein interaction networks.ResultsWe build IUS-exposure and COPD modules, which identify connected subnetworks linking fetal lung smoke exposure to adult COPD. Studying the relationships and connectivity among the different modules for fetal smoke exposure and adult COPD, we identify enriched pathways, including the AGE-RAGE and focal adhesion pathways.ConclusionsThe modules identified in our analysis add new and potentially important insights to understanding the early life molecular perturbations related to the pathogenesis of COPD. We identify AGE-RAGE and focal adhesion as two biologically plausible pathways that may reveal lung developmental contributions to COPD. We were not only able to identify meaningful modules but were also able to study interconnections between smoke exposure and lung disease, augmenting our knowledge about the fetal origins of COPD.

Metabolomic profiling of human pluripotent stem cell differentiation into lung progenitors

SummaryMetabolism is vital to cellular function and tissue homeostasis during human lung development. In utero, embryonic pluripotent stem cells undergo endodermal differentiation toward a lung progenitor cell fate that can be mimicked in vitro using induced human pluripotent stem cells (hiPSCs) to study genetic mutations. To identify differences between wild-type and surfactant protein B (SFTPB)-deficient cell lines during endoderm specification toward lung, we used an untargeted metabolomics approach to evaluate the developmental changes in metabolites. We found that the metabolites most enriched during the differentiation from pluripotent stem cell to lung progenitor cell, regardless of cell line, were sphingomyelins and phosphatidylcholines, two important lipid classes in lung development. The SFTPB mutation had no metabolic impact on early endodermal lung development. The identified metabolite signatures during lung progenitor cell differentiation may be utilized as biomarkers for normal embryonic lung development.

Focus on Early COPD: Definition and Early Lung Development.

Chronic obstructive pulmonary disease (COPD) is a disease with high incidence rate and mortality rates worldwide. It is the third leading cause of death in the world. Nevertheless, little progress has been made in treating and preventing the disease. Under these circumstances, the concept of “early COPD” was proposed. Although this concept is not new, most health-care workers do not fully understand early COPD and tend to confuse it with mild COPD. In this review, we mainly discuss the definition of early COPD and the developmental trajectory of lung function. Although patients with early COPD have no symptoms, their lung function is already lower than that of normal people. A relatively complete definition is needed to identify this group of people. Reduced lung function is the diagnostic criterion for COPD, but lung development is a long-term dynamic process. In addition to smoking and air pollution, we should pay more attention to prenatal and childhood risk factors, for example, parents smoking, birth weight, preterm birth, mode of delivery, childhood respiratory infections and childhood asthma. Health-care workers need to be fully aware of early COPD, to reduce the morbidity of COPD and take effective measures to prevent these risk factors.

A Developmental Role of the Cystic Fibrosis Transmembrane Conductance Regulator in Cystic Fibrosis Lung Disease Pathogenesis.

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein is a cAMP-activated anion channel that is critical for regulating fluid and ion transport across the epithelium. This process is disrupted in CF epithelia, and patients harbouring CF-causing mutations experience reduced lung function as a result, associated with the increased rate of mortality. Much progress has been made in CF research leading to treatments that improve CFTR function, including small molecule modulators. However, clinical outcomes are not necessarily mutation-specific as individuals harboring the same genetic mutation may present with varying disease manifestations and responses to therapy. This suggests that the CFTR protein may have alternative functions that remain under-appreciated and yet can impact disease. In this mini review, we highlight some notable research implicating an important role of CFTR protein during early lung development and how mutant CFTR proteins may impact CF airway disease pathogenesis. We also discuss recent novel cell and animal models that can now be used to identify a developmental cause of CF lung disease.

Influence of Nutrition and Maternal Bonding on Postnatal Lung Development in the Newborn Pig.

BackgroundMicrobial colonization and immune cell maturation coincide at mucosal sites and are decisive for postnatal lung development. How external factors influence neonatal pulmonary immune development is poorly understood.ObjectiveTo elucidate the impact of key determinants in early life, nutrition, and maternal bonding, on postnatal lung maturation in a human-relevant animal model. To investigate the underlying immunological changes of impaired lung maturation and study the mechanisms of conversion.MethodsNewborn piglets were kept with or without isolation from their mothers and fed bovine milk-based infant formula or received milk of sow. Lung growth, histomorphology, respiratory immune responses, and lung microbiota were analyzed. Mother- and sow-milk-deprived piglets received maternal material or were reintroduced to the maternal environment at varying intervals to study options for reversal.ResultsFormula feeding combined with isolation of newborn piglets resulted in disturbed postnatal lung maturation. Reduced lung growth correlated with dampened IL-33 expression, impaired lung myeloid cell activation, and decreased Th1 differentiation, along with diminished richness and diversity of the lung microbiota. Transfer of bacteria-enriched maternal material reversed the negative effects on pulmonary immune maturation. Early (within 3 days) but not late (within 7 days) reintroduction to the mother allowed restoration of normal lung development.ConclusionOur findings reveal that lung growth, respiratory immunity, and microbial lung colonization in newborns depend on postnatal diet and maternal contact, and targeting these key regulators could promote lung development during this critical life stage.SummaryDisturbances in natural diet and reduced maternal contact during the neonatal period impair postnatal lung maturation. In pediatrics, timely breast milk feeding and intensive maternal bonding represent valuable intervention measures to promote early postnatal lung development.

Respiratory Viral and Bacterial Factors That Influence Early Childhood Asthma.

Asthma is a chronic respiratory condition characterised by episodes of shortness of breath due to reduced airway flow. The disease is triggered by a hyperreactive immune response to innocuous allergens, leading to hyper inflammation, mucus production, changes in structural cells lining the airways, and airway hyperresponsiveness. Asthma, although present in adults, is considered as a childhood condition, with a total of about 6.2 million children aged 18 and below affected globally. There has been progress in understanding asthma heterogeneity in adults, which has led to better patient stratification and characterisation of multiple asthma endotypes with distinct, but overlapping inflammatory features. The asthma inflammatory profile in children is not well-defined and heterogeneity of the disease is less described. Although many factors such as genetics, food allergies, antibiotic usage, type of birth, and cigarette smoke exposure can influence asthma development particularly in children, respiratory infections are thought to be the major contributing factor in poor lung function and onset of the disease. In this review, we focus on viral and bacterial respiratory infections in the first 10 years of life that could influence development of asthma in children. We also review literature on inflammatory immune heterogeneity in asthmatic children and how this overlaps with early lung development, poor lung function and respiratory infections. Finally, we review animal studies that model early development of asthma and how these studies could inform future therapies and better understanding of this complex disease.