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A healthy breath is mainly composed of water, carbon dioxide, molecular nitrogen, and oxygen and it contains many species, in small quantities, which are related to the ambient atmosphere and the metabolism. The breath of a person affected by lung cancer presents a concentration of 1-propanol higher than usual. In this context, the development of specific sensors to detect 1-propanol from breath is of high interest. The amount of propanol usually detected on the breath is of few ppb; this small quantity is a handicap for a reliable diagnostic. This limitation can be overcome if the sensor is equipped with a pre-concentrator. Our studies aim to provide an efficient material playing this role. This will contribute to the development of reliable and easy to use lung cancer detectors. For this, we investigate the properties of a few hydrophobic porous materials (chabazite, silicalite-1, and dealuminated faujasite). Hydrophobic structures are used to avoid saturation of materials by the water present in the exhaled breath. Our experimental and simulation results suggest that silicalite −1 (MFI) is the most suitable structure to be used as a pre-concentrator. [ABSTRACT FROM AUTHOR]

Immune cells in the lungs are important for maintaining lung function. The importance of immune cells in defending against lung diseases and infections is increasingly recognized. However, a primary knowledge gaps in current studies of lung immune cells is the understanding of their subtypes and functional heterogeneity. Increasing evidence supports the existence of novel immune cell subtypes that engage in the complex crosstalk between lung‐resident immune cells, recruited immune cells, and epithelial cells. Therefore, further studies on how immune cells respond to perturbations in the pulmonary microenvironment are warranted. This review explores the processes behind the formation of the immune cell niche during lung development, and the characteristics and cell interaction modes of several major lung‐resident immune cells. It indicates that distinct lung microenvironments or inflammatory niches can mediate the formation of different cell subtypes. These findings summarize and clarify paths to identify new cell subtypes that originate from resident progenitor cells and recruited peripheral cells, which are remodeled by the pulmonary microenvironment. The development of new techniques combining transcriptome analysis and location information is essential for identifying new immune cell subtypes and their relative immune niches, as well as for uncovering the molecular mechanisms of immune cell‐mediated lung homeostasis. [ABSTRACT FROM AUTHOR]

The mouse bleomycin model is useful in pre-clinical IPF research to understand pathophysiological mechanisms and pharmacological interventions. In the present study, we systematically investigated the effects of bleomycin at a 60-fold dose range on experimental features of lung fibrosis in the mouse bleomycin model. We analyzed the effect of intratracheal (i.t.) dosing of 0.05–3 U/kg bleomycin on disease phenotypes, including weight loss, morbidity and mortality, pulmonary inflammation, lung collagen content, various BALF biomarkers, and histology in a 14-day mouse model when the animals are in the active phase of fibrosis. In mice, challenge with 1–2 U/kg bleomycin doses induced significant and saturated responses on fibrotic endpoints, confirmed by collagen content, BALF biomarker levels, and marked weight loss compared to the normal control (NC). We observed 100% mortality in 3 U/kg of bleomycin-treated mice. In contrast, 0.05–0.5 U/kg bleomycin doses induced a dose-dependent fibrotic phenotype. The mice challenged with doses of 0.25–0.5 U/kg bleomycin showed optimum body weight loss, a significant increase in pulmonary inflammation, and the fibrotic phenotype compared to NC. Furthermore, we showed 0.25–0.5 U/kg bleomycin increases expression levels of (pro-) fibrotic cytokines, which are the mediators involved in the activation of myofibroblast during fibrogenesis (TGF-β1, IL-13, IL-6, WISP-1, VEGF), angiogenesis (VEGF), matrix remodeling (TIMP-1), and non-invasive lung function biomarker (CRP) compared to NC. A modified Ashcroft scale quantified that the fibrotic changes in the lungs were significantly higher in the lung of mice dosed at 0.25–0.5 U/kg > 0.1 U/kg bleomycin and non-significant in mice lung dosed at 0.05 U/kg bleomycin compared to NC. We demonstrated that the changes due to 0.25–0.5 U/kg i.t. bleomycin on protein biomarkers are enough to drive robust and detectable fibrotic pathology without mortality. The 0.1 U/kg has a moderate phenotype, and 0.05 U/kg had no detectable phenotype. The Goodness of Fit (r2) and Pearson correlation coefficient (r) analyses revealed a positive linear association between change evaluated in all experimental features of fibrosis and bleomycin concentrations (0.05–0.5 U/kg). Here, we provide an examination of a highly calibrated relationship between 60-fold bleomycin concentrations and a set of in vivo readouts that covers various facets of experimental fibrosis. Our study shows that there is a dose-dependent effect of bleomycin on the features of experimental fibrosis at <1 U/kg, whereas saturated responses are achieved at >1 U/kg. Our careful experimental observations, accuracy, and comprehensive data set provided meaningful insights into the effect of bleomycin dose(s) on the fibrotic phenotype, which is valuable in preclinical drug development and lung fibrosis research. In addition, we have presented a set of reproducible frameworks of endpoints that can be used for reliable assessment of the fibrotic phenotype, and in vivo therapeutic intervention(s) with improved accuracy. [ABSTRACT FROM AUTHOR]

As an indigenous species on the Tibetan Plateau, the yak is well adapted to the plateau hypoxic environment. The high-altitude hypoxia adaptation of the yak requires the adaptive reshaping of multiple tissues and organs, especially the lungs. To reveal the adaptive development of yak lungs under hypoxic stress at the tissue and molecular levels, we conducted histomorphological observations as well as transcriptomic and metabolomic studies of yak lungs at three ages (0.5, 2.5, and 4.5 years). The results showed that the lung tissue developed significantly with age. The mean alveolar area was higher (p < 0.01) in 4.5 and 2.5-year-old yaks than in 0.5-year-old yaks. The percentage of elastic fibers, micro-arterial wall thickness, and micro-arterial area showed an increasing trend (p < 0.01) from 0.5-year-old yaks to 2.5-year-old yaks and then to 4.5-year-old yaks. In addition, some critical differentially expressed genes related to angiogenesis (MYC, EPHA2, TNF), fiber formation (EREG), smooth muscle proliferation (HBEGF), erythropoiesis (SOCS3), and hypoxia response (ZFP36) were identified. Some metabolites associated with these genes were also found simultaneously. These findings provide a deeper understanding of the molecular strategies underlying this species' extraordinary ability to survive normally in low-oxygen environments. In conclusion, the lungs of yaks undergo continuous adaptive development under hypoxic stress, and these findings are crucial for understanding the molecular mechanisms by which native species of the Tibetan Plateau survive in harsh environments. [ABSTRACT FROM AUTHOR]

Lung disease development involves multiple cellular processes, including inflammation, cell death, and proliferation. Research increasingly indicates that autophagy and its regulatory proteins can influence inflammation, programmed cell death, cell proliferation, and innate immune responses. Autophagy plays a vital role in the maintenance of homeostasis and the adaptation of eukaryotic cells to stress by enabling the chelation, transport, and degradation of subcellular components, including proteins and organelles. This process is essential for sustaining cellular balance and ensuring the health of the mitochondrial population. Recent studies have begun to explore the connection between autophagy and the development of different lung diseases. This article reviews the latest findings on the molecular regulatory mechanisms of autophagy in lung diseases, with an emphasis on potential targeted therapies for autophagy. [ABSTRACT FROM AUTHOR]

Telocytes (TCs), a novel type of mesenchymal or interstitial cell with specific, very long and thin cellular prolongations, have been found in various mammalian organs and have potential biological functions. However, their existence during lung development is poorly understood. This study aimed to investigate the existence, morphological features, and role of CD34+ SCs/TCs in mouse lungs from foetal to postnatal life using primary cell culture, double immunofluorescence, transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The immunofluorescence double staining profiles revealed positive expression of CD34 and PDGFR‐α, Sca‐1 or VEGFR‐3, and the expression of these markers differed among the age groups during lung development. Intriguingly, in the E18.5 stage of development, along with the CD34+ SCs/TCs, haematopoietic stem cells and angiogenic factors were also significantly increased in number compared with those in the E14.5, E16.5, P0 and P7. Subsequently, TEM confirmed that CD34+ SCs/TCs consisted of a small cell body with long telopodes (Tps) that projected from the cytoplasm. Tps consisted of alternating thin and thick segments known as podomers and podoms. TCs contain abundant endoplasmic reticulum, mitochondria and secretory vesicles and establish close connections with neighbouring cells. Furthermore, SEM revealed characteristic features, including triangular, oval, spherical, or fusiform cell bodies with extensive cellular prolongations, depending on the number of Tps. Our findings provide evidence for the existence of CD34+ SCs/TCs, which contribute to vasculogenesis, the formation of the air‒blood barrier, tissue organization during lung development and homoeostasis. [ABSTRACT FROM AUTHOR]

Congenital lung malformations are fatal at birth in their severe forms. Prevention and early intervention of these birth defects require a comprehensive understanding of the molecular mechanisms of lung development. We find that the loss of inturned (Intu), a cilia and planar polarity effector gene, severely disrupts growth and branching morphogenesis of the mouse embryonic lungs. Consistent with our previous results indicating an important role for Intu in ciliogenesis and hedgehog (Hh) signaling, we find greatly reduced number of primary cilia in both the epithelial and mesenchymal tissues of the lungs. We also find significantly reduced expression of Gli1 and Ptch1 , direct targets of Hh signaling, suggesting disruption of cilia-dependent Hh signaling in Intu mutant lungs. An agonist of the Hh pathway activator, smoothened, increases Hh target gene expression and tubulogenesis in explanted wild type, but not Intu mutant, lungs, suggesting impaired Hh signaling response underlying lung morphogenetic defects in Intu mutants. Furthermore, removing both Gli2 and Intu completely abolishes branching morphogenesis of the lung, strongly supporting a mechanism by which Intu regulates lung growth and patterning through cilia-dependent Hh signaling. Moreover, a transcriptomics analysis identifies around 200 differentially expressed genes (DEGs) in Intu mutant lungs, including known Hh target genes Gli1, Ptch1/2 and Hhip. Genes involved in muscle differentiation and function are highly enriched among the DEGs, consistent with an important role of Hh signaling in airway smooth muscle differentiation. In addition, we find that the difference in gene expression between the left and right lungs diminishes in Intu mutants, suggesting an important role of Intu in asymmetrical growth and patterning of the mouse lungs. [Display omitted] • Loss of Intu leads to reduced size and abnormal branching of mouse embryonic lungs. • Cilia are reduced in Intu mutant lungs. • Hh signaling is reduced in Intu mutant lungs. • Tubulogenesis and branching morphogenesis ae disrupted in Intu mutant lung explants even with a Smoothened agonist. • Hh target genes and smooth muscle-related genes are differentially expressed in Intu mutant lungs. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is a condition of poor alveolar formation that causes chronic breathing impairment in infants born prematurely. Preterm lungs lack surfactant and are vulnerable to oxidative injuries driving the development of BPD. Our recent studies reported that surfactant protein A (SP-A) genetic variants influence susceptibility to neonatal lung disease. SP-A modulates activation of alveolar macrophages and parturition onset in late gestation. We asked whether a lack of SP-A alters alveolarization in a mouse model of hyperoxia-induced BPD. SP-A-deficient and control newborn mice were exposed to either clinically relevant 60% O2 hyperoxia or normoxia for 5–7 days. Alveolar formation was then assessed by mean linear intercept (MLI) and radial alveolar count (RAC) measurements in lung tissue sections. We report that the combination of SP-A deficiency and hyperoxia reduces alveolar growth compared to WT mice. The morphometric analysis of normoxic SP-A-deficient lungs showed lower RAC compared to controls, indicating reduced alveolar number. In the presence of hyperoxia, MLI was higher in SP-A-deficient lungs compared to controls. Differences were statistically significant for female pups. Spatial proteomic profiling of lung tissue sections showed that hyperoxia caused a 4-fold increase in the DNA damage marker γH2Ax in macrophages of SP-A-deficient lungs compared to normoxia. Our short report suggests an important role for SP-A in perinatal lung development and the protection of lung macrophages from oxidant injury. These studies warrant future investigation to discern the temporal interaction of SP-A, gender, oxidant injury, and lung macrophages in perinatal alveolar formation and development of BPD. [ABSTRACT FROM AUTHOR]

The main deterrent to long-term space travel is the risk of Radiation Exposure Induced Death (REID). The National Aeronautics and Space Administration (NASA) has adopted Permissible Exposure Levels (PELs) to limit the probability of REID to 3% for the risk of death due to radiation-induced carcinogenesis. The most significant contributor to current REID estimates for astronauts is the risk of lung cancer. Recently updated lung cancer estimates from Japan's atomic bomb survivors showed that the excess relative risk of lung cancer by age 70 is roughly fourfold higher in females compared to males. However, whether sex differences may impact the risk of lung cancer due to exposure to high charge and energy (HZE) radiation is not well studied. Thus, to evaluate the impact of sex differences on the risk of solid cancer development after HZE radiation exposure, we irradiated Rbfl/fl, Trp53fl/+ male and female mice infected with Adeno-Cre with various doses of 320 kVp X rays or 600 MeV/n 56Fe ions and monitored them for any radiation-induced malignancies. We conducted complete necropsy and histopathology of major organs on 183 male and 157 female mice after following them for 350 days postirradiation. We observed that lung adenomas/carcinomas and esthesioneuroblastomas (ENBs) were the most common primary malignancies in mice exposed to X rays and 56Fe ions, respectively. In addition, 1 Gy 56Fe-ion exposure compared to X-ray exposure led to a significantly increased incidence of lung adenomas/carcinomas (P = 0.02) and ENBs (P < 0.0001) in mice. However, we did not find a significantly higher incidence of any solid malignancies in female mice as compared to male mice, regardless of radiation quality. Furthermore, gene expression analysis of ENBs suggested a distinct gene expression pattern with similar hallmark pathways altered, such as MYC targets and MTORC1 signaling, in ENBs induced by X rays and 56Fe ions. Thus, our data revealed that 56Fe-ion exposure significantly accelerated the development of lung adenomas/carcinomas and ENBs compared to X rays, but the rate of solid malignancies was similar between male and female mice, regardless of radiation quality. [ABSTRACT FROM AUTHOR]

The impact of hormones on the respiratory system constitutes a multifaceted and intricate facet of human biology. We propose a comprehensive review of recent advancements in understanding the interactions between hormones and pulmonary development and function, focusing on pediatric populations. We explore how hormones can influence ventilation, perfusion, and pulmonary function, from regulating airway muscle tone to modulating the inflammatory response. Hormones play an important role in the growth and development of lung tissues, influencing them from early stages through infancy, childhood, adolescence, and into adulthood. Glucocorticoids, thyroid hormones, insulin, ghrelin, leptin, glucagon-like peptide 1 (GLP-1), retinoids, cholecalciferol sex steroids, hormones derived from adipose tissue, factors like insulin, granulocytemacrophage colony-stimulating factor (GM-CSF) and glucagon are key players in modulating respiratory mechanics and inflammation. While ample evidence underscores the impact of hormones on lung development and function, along with sex-related differences in the prevalence of respiratory disorders, further research is needed to clarify their specific roles in these conditions. Further research into the mechanisms underlying hormonal effects is essential for the development of customizing therapeutic approaches for respiratory diseases. Understanding the impact of hormones on lung function could be valuable for developing personalized monitoring approaches in both medical and surgical pediatric settings, in order to improve outcomes and the quality of care for pediatric patients. [ABSTRACT FROM AUTHOR]

Primary lung cancer is the leading cause of cancer‐related death worldwide. Recent statistics estimate 1.8 million new cases and 1.6 million deaths per year. Despite significant advances in surgery, chemotherapy, and radiotherapy, the 5‐year survival rate remains at just 18%. Thermal ablation is an established treatment that is safe and effective. It refers to the local application of controlled heat to induce irreversible cell injury and ultimately tumor apoptosis and necrosis. This approach is particularly suitable for the treatment of small tumors in patients who are not suitable for surgery. However, the lack of suitable benchtop models to assess ablation devices complicates prognostic prediction and the development of effective treatment strategies. In this context, the development of a 3D lung tumor model is presented using a cancer cell‐laden hydrogel composed of 2% hyaluronic acid–tyramine (HA‐TA) and 0.5% agarose, resulting in a tumor mimetic of clinically relevant size. This innovative model provides a valuable platform for testing ablation devices and provides insights that can significantly improve prognostic ability and refine treatment approaches for lung cancer patients. [ABSTRACT FROM AUTHOR]

The respiratory system, including the lungs, is essential for terrestrial life. While recent research has advanced our understanding of lung development, much still relies on animal models and transcriptome analyses. In this study conducted within the Human Developmental Cell Atlas (HDCA) initiative, we describe the protein-level spatiotemporal organization of the lung during the first trimester of human gestation. Using high-parametric tissue imaging with a 30-plex antibody panel, we analyzed human lung samples from 6 to 13 post-conception weeks, generating data from over 2 million cells across five developmental timepoints. We present a resource detailing spatially resolved cell type composition of the developing human lung, including proliferative states, immune cell patterns, spatial arrangement traits, and their temporal evolution. This represents an extensive single-cell resolved protein-level examination of the developing human lung and provides a valuable resource for further research into the developmental roots of human respiratory health and disease. Understanding the development of the lung will inform treatments for congenital diseases and approaches for preterm infant care. Here they map human lung development using high-parametric imaging at the single-cell level to track abundance, proliferation, and spatial organization of key cell types during early gestation. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is the predominant chronic lung disease in preterm infants, linked with various adverse long-term outcomes. Multiple prenatal and postnatal risk factors can impede lung development, leading to BPD. Current management of BPD relies heavily on pharmacotherapies and alterations in ventilatory strategies. However, these interventions only mitigate BPD symptoms without addressing underlying alveolar, vascular, structural, and functional deficiencies. Given the retarded lung development in infants with BPD and the limitations of existing modalities, new therapeutic approaches are imperative. The induced differentiation of stem/progenitor cells and the spatiotemporal expression patterns of growth factors associated with lung developmental processes are critical for lung development reactivation in BPD, which focuses on stimulating pulmonary vasculogenesis and alveolarization. This review summarizes the process of lung development and offers a comprehensive overview of advancements in therapies designed to reinitiate lung development in BPD. Furthermore, we assessed the potential of these therapies for maintaining lung homeostasis and effectively restoring pulmonary structure and function through stem/progenitor cells and growth factors, which have been widely researched. [ABSTRACT FROM AUTHOR]

Background: Congenital rib deformity is a common thoracic deformity that has a potentially far-reaching impact on the growth and lung function development of young children. Early diagnosis and accurate assessment of congenital rib deformity is of great importance. This study was to retrospectively analyze the number, location, and types of deformities, imaging features as well as clinical symptoms of children with congenital rib deformities. Methods: Children who were diagnosed with congenital rib deformities between October 2019 and October 2021 in our hospital were included in this study. The rib deformities were analyzed according to the imaging results of chest X-ray and 3D volume rendering multidetector computed tomography (MDCT). The data were analyzed using SPSS 22.0. Results: A total of 472 male and 186 female children with rib deformities were detected in this study, with a male to female ratio of approximately 2.54:1. Of the deformed ribs, 417 (63.4%) were located on the right side, usually single and unilateral. The most common type of the detected rib deformity were bifid ribs (95.14%). Rib deformity was most common in the fourth rib (46.62%). The majority (76.16%, n = 428) of rib deformities were incidental findings and asymptomatic. Conclusions: Congenital rib deformities in pediatric patients included in our hospital were more frequently observed in males than females, more frequently detected on the right than on the left side. The most common type of rib deformity is the bifid rib. MDCT examination are of great value in the diagnosis of rib deformity and can help guide clinical treatment. [ABSTRACT FROM AUTHOR]

Background: Congenital diaphragmatic hernia (CDH) is a rare disease that affects the development of the diaphragm, leading to abnormal lung development. Unfortunately, there is no established therapy for CDH. Retinoic acid pathways are implicated in the ethology of CDH and macrophages are known to play a role in repairing organ damage. Methods: We have analyzed the effect of several Toll like receptor (TLR) ligands in the nitrofen-induced CDH model in pregnant rats widely used to study this disease and in the G2-GATA4Cre;Wt1fl/fl CDH genetic mice model. Morphometric and histological studies were carried out. Immune cell infiltration was assayed by immunochemistry and immunofluorescence and retinoic pathway gene expression analyzed in vivo and in vitro in macrophages. Results: We found that administering a single dose of atypical TLR2/4 ligands (CS1 or CS2), 3 days after nitrofen, cured diaphragmatic hernia in 73% of the fetuses and repaired the lesion with complete diaphragm closure being on the other hand nontoxic for the mothers or pups. Moreover, these immunomodulators also improved pulmonary hypoplasia and alveolar maturation and vessel hypertrophy, enhancing pulmonary maturity of fetuses. We also found that CS1 treatment rescued the CDH phenotype in the G2-GATA4Cre;Wt1fl/fl CDH genetic mice model. Only 1 out of 11 mutant embryos showed CDH after CS1 administration, whereas CDH prevalence was 70% in untreated mutant embryos. Mechanistically, CS1 stimulated the infiltration of repairing M2 macrophages (CD206+ and Arg1+) into the damaged diaphragm and reduced T cell infiltration. Additionally, those TLR ligands induced retinol pathway genes, including RBP1, RALDH2, RARα, and RARβ, in the affected lungs and the diaphragm and in macrophages in vitro. Conclusions: Our research has shown that TLR ligand immunomodulators that influence anti-inflammatory macrophage activation can be effective in treating CDH, being nontoxic for the mothers or pups suggesting that those TLR ligands are a promising solution for CDH leading to orphan drug designation for CS1. The immune system of the fetus would be responsible for repairing the damage and closure of the hernia in the diaphragm and enhanced proper lung development after CS1 treatment. [ABSTRACT FROM AUTHOR]

Purpose: Firefighting is known to be carcinogenic to humans. However, current lung cancer screening guidelines do not account for occupational exposure. We hypothesize that firefighting is an independent risk factor associated with the development of high-risk lung nodules on low-dose CT (LDCT). Methods: Members of a firefighter's union underwent LDCT at a single institution between April 2022 and June 2023 within a lung cancer screening program. Results were interpreted by designated chest radiologists and reported using the Lung-RADS scoring system. Demographic and radiographic data were recorded, and summary statistics are reported. Results: 1347 individuals underwent lung cancer screening, with a median age of 51 years (IQR 42–58), including 56 (4.2%) females. Overall, 899 (66.7%) were never smokers, 345 (25.6%) were former smokers, and 103 (7.7%) were current smokers. There were 41 firefighters (3.0%) who had high-risk (Lung-RADS 3 or 4) nodules requiring intervention or surveillance, of which 21 (1.5%) were Lung-RADS 3 and 20 (1.5%) that were Lung-RADS 4. Of the firefighters with high-risk nodules, only 6 (14.6%) were eligible for LDCT based on current screening guidelines. There were 7 high-risk nodules (0.5%) that required procedural intervention, 6 (85.7%) of which were from the non-screening eligible cohort. There were also 20 never-smoking firefighters (57.1%) with high-risk nodules that were non-screening eligible. Conclusion: Firefighting, even in the absence of smoking history, may be associated with the development of high-risk lung nodules on LDCT. Carefully selected occupational exposures should be considered in the development of future lung cancer screening guidelines. [ABSTRACT FROM AUTHOR]

Regnase-1 is an RNase that plays a critical role in negatively regulating immune responses by destabilizing inflammatory messenger RNAs (mRNAs). Dysfunction of Regnase-1 can be a major cause of various inflammatory diseases with tissue injury and immune cell infiltration into organs. This study focuses on the role of the RNase activity of Regnase-1 in developing inflammatory diseases. We have constructed mice with a single point mutation at the catalytic center of the Regnase-1 RNase domain, which lacks endonuclease activity. D141N mutant mice demonstrated systemic inflammation, immune cell infiltration into various organs, and progressive development of lung granuloma. CD4+ T cells, mainly affected by this mutation, upregulated the mTORC1 pathway and facilitated the autoimmune trait in the D141N mutation. Moreover, serine/threonine kinase Pim2 contributed to lung inflammation in this mutation. Inhibition of Pim2 kinase activity ameliorated granulomatous inflammation, immune cell infiltration, and proliferation in the lungs. Additionally, Pim2 inhibition reduced the expression of adhesion molecules on CD4+ T cells, suggesting a role for Pim2 in facilitating leukocyte adhesion and migration to inflamed tissues. Our findings provide new insights into the role of Regnase-1 RNase activity in controlling immune functions and underscore the therapeutic relevance of targeting Pim2 to modulate abnormal immune responses. [ABSTRACT FROM AUTHOR]

Thiourea, a widely used agrochemical, is known to inhibit the activity of thyroid peroxidase, a key enzyme in the biosynthetic pathway of thyroid hormones. Thyroid insufficiency compromises the basal metabolic rate in warm‐blooded organisms and embryonic development in vertebrates. In this study, we looked for developmental defects by exposing the zebrafish embryos to an environmentally relevant dose of thiourea (3 mg/mL). Liquid chromatography–tandem mass spectrometry (LC‐MS/MS) was performed to validate thiourea's presence in the treated zebrafish embryos. Structural anomalies like bent tail and pericardial edema were noticed in 96‐h post‐fertilization (hpf) larvae. On histological examination, underdeveloped swim bladder was noticed in 96 hpf larvae exposed to 3 mg/mL thiourea. The treated larvae also failed to follow the characteristic swimming behavior in response to stimuli due to defective swim bladder. Swim bladder being homologous to the lung of tetrapod, the role of Bmp4, a major regulator of lung development, was studied along with the associated regulatory genes. Gene expression analysis revealed that thiourea administration led to the downregulation of bmp4, shh, pcna, anxa5, acta2, and the downstream effector snail3 but the upregulation of caspase3. The protein expression showed a similar trend, wherein Bmp4, Shh, and Pcna were downregulated, but Cleaved Caspase3 showed an increased expression in the treated group. Therefore, it is prudent to presume that exposure to thiourea significantly reduces the expression of Bmp4 and other key regulators; hence, the larvae fail to develop a swim bladder, a vital organ that regulates buoyancy. Thiourea, an agrochemical, inhibits thyroid peroxidase activity, which is crucial for thyroid hormone synthesis. Exposure to thiourea disrupted swim bladder development in zebrafish embryos. Histological examination revealed disorganized tissue layers of swim bladder, indicating its detrimental effect on swim bladder morphogenesis. Thiourea downregulated genes involved in swim bladder development, notably bmp4, acta2, anxa5, and shh. This study highlights the potential developmental toxicity of thiourea and emphasizes the importance of understanding its impact on aquatic organisms. [ABSTRACT FROM AUTHOR]

Background Immature lung development and respiratory morbidity place preterm-born children at high risk of long-term pulmonary sequelae. This systematic review and meta-analysis aims to quantify lung function in preterm-born children and identify risk factors for a compromised lung function. Methods We searched MEDLINE, Embase, Cochrane Library, Web of Science and Scopus for relevant studies published on preterm cohorts born since 1990. Studies comparing forced expiratory volume in 1 s (FEV1) in preterm-born children aged ≥5 years to term-born controls or normative data were included. Study quality was assessed using the Newcastle-Ottawa Scale for cohort studies. Standardised mean differences in FEV1 and secondary spirometry outcomes per study were pooled using meta-analysis. The impact of different demographic and neonatal variables on studies' FEV1 effect sizes was investigated by meta-regression analyses. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. Results We identified 42 studies with unique cohorts including 4743 preterm children and 9843 controls. Median gestational age in the studies was 28.0 weeks and age at assessment ranged from 6.7 to 16.7 years. Preterm children had lower FEV1 than controls (-0.58 SD, 95% CI -0.69--0.47 SD, p<0.001) resulting in a relative risk of 2.9 (95% CI 2.4-3.4) for abnormal outcome, with high certainty of evidence. FEV1 was significantly associated with gestational age, birthweight, bronchopulmonary dysplasia and invasive mechanical ventilation in univariate meta-regression analyses (R2=36-96%). Conclusion This systematic review shows robust evidence of impaired lung function in preterm-born children with a high certainty of evidence. [ABSTRACT FROM AUTHOR]

While the critical role of NKX2-1 and its transcriptional targets in lung morphogenesis and pulmonary epithelial cell differentiation is increasingly known, mechanisms by which chromatin accessibility alters the epigenetic landscape and how NKX2-1 interacts with other co-activators required for alveolar epithelial cell differentiation and function are not well understood. Combined deletion of the histone methyl transferases Prdm3 and Prdm16 in early lung endoderm causes perinatal lethality due to respiratory failure from loss of AT2 cells and the accumulation of partially differentiated AT1 cells. Combination of single-cell RNA-seq, bulk ATAC-seq, and CUT&RUN data demonstrate that PRDM3 and PRDM16 regulate chromatin accessibility at NKX2-1 transcriptional targets critical for perinatal AT2 cell differentiation and surfactant homeostasis. Lineage specific deletion of PRDM3/16 in AT2 cells leads to lineage infidelity, with PRDM3/16 null cells acquiring partial AT1 fate. Together, these data demonstrate that NKX2-1-dependent regulation of alveolar epithelial cell differentiation is mediated by epigenomic modulation via PRDM3/16. Growth and differentiation of pulmonary epithelial cells is precisely controlled to form the alveoli that create the gas exchange region of the lung. Here, the authors demonstrate that epigenetic modulation of the genome by PRDM3/16 mediates NKX2-1 activity to control alveolar cell fate and differentiation during embryonic and perinatal lung development. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is fundamentally characterized by the arrest of lung development and abnormal repair mechanisms, which result in impaired development of the alveoli and microvasculature. Hepatocyte growth factor (HGF), secreted by pulmonary mesenchymal and endothelial cells, plays a pivotal role in the promotion of epithelial and endothelial cell proliferation, branching morphogenesis, angiogenesis, and alveolarization. HGF exerts its beneficial effects on pulmonary vascular development and alveolar simplification primarily through two pivotal pathways: the stimulation of neovascularization, thereby enriching the pulmonary microvascular network, and the inhibition of the epithelial-mesenchymal transition (EMT), which is crucial for maintaining the integrity of the alveolar structure. We discuss HGF and its receptor c-Met, interact with various growth factors throughout the process of lung development and BPD, and form a signaling network with HGF as a hub, which plays the pivotal role in orchestrating and integrating epithelial, endothelial and mesenchymal. [ABSTRACT FROM AUTHOR]

Background: Point-of-care ultrasound is rapidly gaining traction in clinical practice, including primary care. Yet, logistical challenges and geographical isolation hinder skill acquisition. Concurrently, an evidentiary gap exists concerning such guidance's effectiveness and optimal implementation in these settings. Methods: We developed a lung point-of-care ultrasound (POCUS) curriculum for primary care physicians in a rural, medically underserved region of the south of Israel. The course included recorded lectures, pre-course assessments, hands-on training, post-workshop lectures, and individual practice. To evaluate our course, we measured learning outcomes and physicians' proficiency in different lung POCUS domains using hands-on technique assessment and gathered feedback on the course with a multi-modal perception approach: an original written pre- and post-perception and usage questionnaire. Results: Fifty primary care physicians (PCPs) showed significant improvement in hands-on skills, increasing from 6 to 76% proficiency (p < 0.001), and in identifying normal versus abnormal views, improving from 54 to 74% accuracy (p < 0.001). Ten weeks after training, primary care physicians reported greater comfort using lung ultrasound, rising from 10 to 54% (p < 0.001), and improved grasp of its potential and limits, increasing from 27.5% to 84% (p < 0.001). Weekly usage increased from none to 50%, and the number of primary care physicians not using at all decreased from 72 to 26% (p < 0.001). Conclusions: A two-day focused in-person and remote self-learning lung-POCUS training significantly improved primary care physicians' lung ultrasound skills, comfort, and implementation. [ABSTRACT FROM AUTHOR]

Background: It has been proposed that prolonged use of anti-inflammatory and anti-fibrotic drugs diminish the probability of development of lung fibrosis. Prolonged low-dose corticosteroid may prevent remodeling of the lung in survivors. Pirfenidone and colchicine may exhibit anti-fibrotic and anti-inflammatory properties as well. Methods: This retrospective observational study was conducted at post COVID-19 clinic, Mansoura University Hospitals, during the period between October 2020 and March 2022. This study included 104 patients who had COVID-19 pneumonia confirmed either by RT-PCR or radiologically by CT scan and divided into 3 groups; group A (corticosteroids only) included 33 (31.7%) patients, group B (corticosteroids and colchicine) included 56 (53.8%) patients, and group C (corticosteroids, colchicine, and pirfenidone) included 15 (14.4%) patients. All patients were assessed during follow-up visits in post COVID-19 clinic 1 and 3 months after discharge by evaluation of resting SpO2, spirometry, and radiological assessment. Patients' data during hospitalization was collected from hospital electronic systems. Results: There was non-statistically significant improvement in FEV1 in group A while there was statistically significant improvement in FEV1 in groups B and C (P value = 0.002 and 0.041, respectively) 1 month and 3 months after discharge. Group B exhibited more statistically significant improvement in FVC as well compared to group C (P value = 0.003 and 0.025, respectively) while group A showed non-statistically significant improvement in FVC. There was a statistically significant decrease in CT severity score in all the groups during follow-up with P value < 0.001 in groups A and B and to less extent less statistically significant decrease in group C comparing the 3 groups to each other. Conclusion: The use of colchicine added to corticosteroids after acute phase of COVID-19 pneumonia resulted in statistically significant improvement regarding functional and radiological changes during follow-up when compared to corticosteroids alone. The addition of pirfenidone (which is a relatively expensive drug) to corticosteroids and colchicine did not add more statistically significant improvement in functional or radiological changes. [ABSTRACT FROM AUTHOR]

Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in infants and the most frequent adverse outcome of premature birth, despite major efforts to minimize injury. It is thought to result from aberrant repair response triggered by either prenatal or recurrent postnatal injury to the lungs during development. Intrauterine inflammation is an important risk factor for prenatal lung injury, which is also increasingly linked to BPD. However, the specific mechanisms remain unclear. This review summarizes clinical and animal research linking intrauterine inflammation to BPD. We assess how intrauterine inflammation affects lung alveolarization and vascular development. In addition, we discuss prenatal therapeutic strategies targeting intrauterine inflammation to prevent or treat BPD. [ABSTRACT FROM AUTHOR]

Background: Investigations on radiation‐induced lung injury (RILI) have predominantly focused on local effects, primarily those associated with radiation damage to lung parenchyma. However, recent studies from our group and others have revealed that radiation‐induced damage to branching serial structures such as airways and vessels may also have a substantial impact on post‐radiotherapy (RT) lung function. Furthermore, recent results from multiple functional lung avoidance RT trials, although promising, have demonstrated only modest toxicity reduction, likely because they were primarily focused on dose avoidance to lung parenchyma. These observations emphasize the critical need for predictive dose‐response models that effectively incorporate both local and distant RILI effects. Purpose: We develop and validate a predictive model for ventilation loss after lung RT. This model, referred to as P+A, integrates local (parenchyma [P]) and distant (central and peripheral airways [A]) radiation‐induced damage, modeling partial (narrowing) and complete (collapse) obstruction of airways. Methods: In an IRB‐approved prospective study, pre‐RT breath‐hold CTs (BHCTs) and pre‐ and one‐year post‐RT 4DCTs were acquired from lung cancer patients treated with definitive RT. Up to 13 generations of airways were automatically segmented on the BHCTs using a research virtual bronchoscopy software. Ventilation maps derived from the 4DCT scans were utilized to quantify pre‐ and post‐RT ventilation, serving, respectively, as input data and reference standard (RS) in model validation. To predict ventilation loss solely due to parenchymal damage (referred to as P model), we used a normal tissue complication probability (NTCP) model. Our model used this NTCP‐based estimate and predicted additional loss due radiation‐induced partial or complete occlusion of individual airways, applying fluid dynamics principles and a refined version of our previously developed airway radiosensitivity model. Predictions of post‐RT ventilation were estimated in the sublobar volumes (SLVs) connected to the terminal airways. To validate the model, we conducted a k‐fold cross‐validation. Model parameters were optimized as the values that provided the lowest root mean square error (RMSE) between predicted post‐RT ventilation and the RS for all SLVs in the training data. The performance of the P+A and the P models was evaluated by comparing their respective post‐RT ventilation values with the RS predictions. Additional evaluation using various receiver operating characteristic (ROC) metrics was also performed. Results: We extracted a dataset of 560 SLVs from four enrolled patients. Our results demonstrated that the P+A model consistently outperformed the P model, exhibiting RMSEs that were nearly half as low across all patients (13 ± 3 percentile for the P+A model vs. 24 ± 3 percentile for the P model on average). Notably, the P+A model aligned closely with the RS in ventilation loss distributions per lobe, particularly in regions exposed to doses ≥13.5 Gy. The ROC analysis further supported the superior performance of the P+A model compared to the P model in sensitivity (0.98 vs. 0.07), accuracy (0.87 vs. 0.25), and balanced predictions. Conclusions: These early findings indicate that airway damage is a crucial factor in RILI that should be included in dose‐response modeling to enhance predictions of post‐RT lung function. [ABSTRACT FROM AUTHOR]

Repair and regeneration of a diseased lung using stem cells or bioengineered tissues is an exciting therapeutic approach for a variety of lung diseases and critical illnesses. Over the past decade, increasing evidence from preclinical models suggests that mesenchymal stromal cells, which are not normally resident in the lung, can be used to modulate immune responses after injury, but there have been challenges in translating these promising findings to the clinic. In parallel, there has been a surge in bioengineering studies investigating the use of artificial and acellular lung matrices as scaffolds for three-dimensional lung or airway regeneration, with some recent attempts of transplantation in large animal models. The combination of these studies with those involving stem cells, induced pluripotent stem cell derivatives, and/or cell therapies is a promising and rapidly developing research area. These studies have been further paralleled by significant increases in our understanding of the molecular and cellular events by which endogenous lung stem and/or progenitor cells arise during lung development and participate in normal and pathological remodeling after lung injury. For the 2023 Stem Cells, Cell Therapies, and Bioengineering in Lung Biology and Diseases Conference, scientific symposia were chosen to reflect the most cutting-edge advances in these fields. Sessions focused on the integration of "omics" technologies with function, the influence of immune cells on regeneration, and the role of the extracellular matrix in regeneration. The necessity for basic science studies to enhance fundamental understanding of lung regeneration and to design innovative translational studies was reinforced throughout the conference. [ABSTRACT FROM AUTHOR]

Nanomedicines hold promise for the treatment of various diseases. However, treating cancer metastasis remains highly challenging. In this study, we synthesized gold nanorods (AuNRs) containing (α-GC), an immune stimulator, for the treatment of primary cancer, metastasis, and recurrence of the cancer. Therefore, the AuNR were coated with lipid bilayers loaded with α-GC (α-LA). Upon irradiation with 808 nm light, α-LA showed a temperature increase. Intra-tumoral injection of α-LA in mice and local irradiation of the 4T1 breast cancer tumor effectively eliminated tumor growth. We found that the presence of α-GC in α-LA activated dendritic cells and T cells in the spleen, which completely blocked the development of lung metastasis. In mice injected with α-LA for primary breast cancer treatment, we observed antigen-specific T cell responses and increased cytotoxicity against 4T1 cells. We conclude that α-LA is promising for the treatment of both primary breast cancer and its metastasis. Schematic illustration of α-LA-mediated photo-immunotherapy for treatment of primary tumor and prevention of metastatic lung cancer. [Display omitted] • For PTT, AuNRs were coated with lipid film comprising α-galactosylceramide (α-LA). • α-LA with 808 nm laser irradiation eliminated orthotopic 4 T1 breast cancer by PTT. • α-LA also prevented recurrence of lung metastatic 4 T1 cancer. • Anti-metastatic effect of a-LA was mediated by cancer antigen-specific immunity. [ABSTRACT FROM AUTHOR]

Emerging epidemiological evidence indicates perfluorooctane sulfonic acid (PFOS) is increasingly associated with asthma and respiratory viral infections. Animal studies suggest PFOS disrupts lung development and immuno-inflammatory responses, but little is known about the potential consequences on respiratory health and disease risk. Importantly, PFOS exposure during the critical stages of lung development may increase disease risk later in life. Thus, we hypothesized that developmental PFOS exposure will affect lung inflammation and alveolar/airway development in a sex-dependent manner. To address this knowledge gap, timed pregnant Balb/cJ dams were orally dosed with a PFOS (1.0 or 2.0 mg/kg/d) injected mealworm or a vehicle control daily from gestational day (GD) 0.5 to postnatal day (PND) 21, and offspring were sacrificed at PND 22-23. PFOS-exposed male offspring displayed increased alveolar septa thickness. Occludin was also downregulated in the lungs after PFOS exposure in mice, indicative of barrier dysfunction. BALF macrophages were significantly elevated at 2.0 mg/kg/d PFOS in both sexes compared with vehicles, whereas BALF cytokines (TNF-α, IL-6, KC, MIP-1α, MIP-1β, and MCP-1) were suppressed in PFOS-exposed male offspring compared with vehicle controls. Multiplex nucleic acid hybridization assay showed male-specific downregulation of cytokine gene expression in PFOS-exposed mice compared with vehicle mice. Overall, these results demonstrate PFOS exposure exhibits male-specific adverse effects on lung development and inflammation in juvenile offspring, possibly predisposing them to later-in-life respiratory disease. Further research is required to elucidate the mechanisms underlying the sex-differentiated pulmonary toxicity of PFOS. [ABSTRACT FROM AUTHOR]

The reader will come to appreciate: • The association between maternal asthma and neonatal, childhood, and adulthood respiratory morbidities. • How respiratory outcomes associated with maternal asthma may differ with offspring sex. • Potential mechanisms underlying how maternal asthma alters in utero fetal lung development. • Interventions that may improve the respiratory health of offspring of asthmatic mothers. • The association between maternal asthma and neonatal, childhood, and adulthood respiratory morbidities. • How respiratory outcomes associated with maternal asthma may differ with offspring sex. • Potential mechanisms underlying how maternal asthma alters in utero fetal lung development. • Interventions that may improve the respiratory health of offspring of asthmatic mothers. Maternal asthma affects up to 17% of pregnancies and is associated with adverse infant, childhood, and adult respiratory outcomes, including increased risks of neonatal respiratory distress syndrome, childhood wheeze and asthma. In addition to genetics, these poor outcomes are likely due to the mediating influence of maternal asthma on the in-utero environment, altering fetal lung and immune development and predisposing the offspring to later lung disease. Maternal asthma may impair glucocorticoid signalling in the fetus, a process critical for lung maturation, and increase fetal exposure to proinflammatory cytokines. Therefore, interventions to control maternal asthma, increase glucocorticoid signalling in the fetal lung, or Vitamin A, C, and D supplementation to improve alveologenesis and surfactant production may be beneficial for later lung function. This review highlights potential mechanisms underlying maternal asthma and offspring respiratory morbidities and describes how pregnancy interventions can promote optimal fetal lung development in babies of asthmatic mothers. [ABSTRACT FROM AUTHOR]

The severity of pulmonary hypoplasia is a main determinant of outcome for babies with congenital diaphragmatic hernia (CDH). Antenatal administration of extracellular vesicles derived from amniotic fluid stem cells (AFSC-EVs) has been shown to rescue morphological features of lung development in the rat nitrofen model of CDH. Herein, we evaluated whether AFSC-EV administration to fetal rats with CDH is associated with neonatal improvement in lung function. AFSC-EVs were isolated by ultracentrifugation and characterized by size, morphology, and canonical marker expression. At embryonic (E) day 9.5, dams were gavaged with olive oil (control) or nitrofen to induce CDH. At E18.5, fetuses received an intra-amniotic injection of either saline or AFSC-EVs. At E21.5, rats were delivered and subjected to a tracheostomy for mechanical ventilation (flexiVent system). Groups were compared for lung compliance, resistance, Newtonian resistance, tissue damping and elastance. Lungs were evaluated for branching morphogenesis and collagen quantification. Compared to healthy control, saline-treated pups with CDH had fewer airspaces, more collagen deposition, and functionally exhibited reduced compliance and increased airway resistance, elastance, and tissue damping. Conversely, AFSC-EV administration resulted in improvement of lung mechanics (compliance, resistance, tissue damping, elastance) as well as lung branching morphogenesis and collagen deposition. Our studies show that the rat nitrofen model reproduces lung function impairment similar to that of human babies with CDH. Antenatal administration of AFSC-EVs improves lung morphology and function in neonatal rats with CDH. N/A (animal and laboratory study). What is currently known about this topic? • Pulmonary hypoplasia is a primary determinant for the impaired lung function in infants with CDH. • Impaired airway branching and abnormal lung collagen deposition directly affect lung mechanics, such as compliance and resistance. • Antenatal administration of AFSC-EVs rescues features of lung development in human and rodent models of pulmonary hypoplasia. What new information is contained in this article? • Ventilation studies in neonatal rats with CDH reveal that the nitrofen model reproduces lung function impairment like that of human babies with CDH. • Intra-amniotic administration of AFSC-EVs in fetal rats with CDH improves not only postnatal lung branching morphogenesis and collagen levels, but also pulmonary function parameters and pCO 2 blood levels. [ABSTRACT FROM AUTHOR]

Background: Immunoglobulin G subclass deficiencies (IgGsd) comprise a wide clinical spectrum from no symptoms to repeated respiratory infections and risk for the development of lung damage. Our aims were to investigate whether the immunological phenotype of IgGsd patients on and off immunoglobulin replacement therapy (IgRT) was reflected in the clinical features of IgGsd. Method: Thirty patients with IgGsd were included in this prospective study of 18 months of IgRT, followed by 7-18 months of IgRT discontinuation. Blood samples were collected when patients were on and off IgRT and compared with samples from 34 cross-sectional healthy controls. An in-depth lymphocyte phenotyping was performed by flow cytometry and plasma levels of immune checkpoints were assessed. Results: IgG3 subclass deficiency was most common. Patients with IgGsd had decreased levels of activated T cells and B cells and plasma levels of negative immune checkpoint molecules correlated negatively with T cell and B cell activation. The decreased T cell activation level was unaffected by IgRT, while the B cell activation was partly restored. Of note, decreased levels of activated regulatory T cells (Tregs) were found in IgGsd patients and was partly restored during IgRT. The profile of comorbidities did not associate with Treg levels. Discussion: IgGsd is associatedwith decreased B cell and T cell activation including Tregs, and increased plasma levels of negative immune checkpoint molecules. The consequence of reduced activated Tregs in IgGsd remains unclear. Decreased immune cell activation was partly restored during IgRT, demonstrating that IgRT may contribute to improved immune function in patients with IgGsd. [ABSTRACT FROM AUTHOR]

Background: During pseudoglandular stage of the human lung development the primitive bronchial buds are initially conformed by simple tubules lined by endoderm-derived epithelium surrounded by mesenchyme, which will progressively branch into airways and start to form distal epithelial saculles. For first time alveolar type II (AT2) pneumocytes appears. This study aims to characterize the genes and microRNAs involved in this differentiation process and decipher its role in the starting alveolar differentiation. Methods: Gene and microRNA profiling was performed in human embryonic lungs from 7 to 12 post conception weeks (pcw). Protein expression location of candidate genes were analyzed by immunofluorescense in embryonic lung tissue sections. mRNA/miRNA target pairs were identified using computational approaches and their expression was studied in purified epithelial/mesenchymal cell populations and in isolated tips and stalks from the bronchial tree. Additionally, silencing experiments in human embryonic lung mesenchymal cells and in human embryonic tip-derived lung organoids were performed, as well as organoid differentiation studies. AT2 cell markers were studied by qRT-PCR and by immunofluorescence. The TGFB-β phosphorylated pathways was analyzed with membrane protein arrays. Lung explants were cultured in air/liquid interface with/without peptides. Results: We identified 88 differentially expressed genes, including IGFBP3. Although IGFBP3 mRNA was detected in both epithelial and mesenchymal populations, the protein was restricted to the epithelium, indicating post-transcriptional regulation preventing IGFBP3 protein expression in the mesenchyme. MicroRNA profiling identified miR-34a as an IGFBP3 regulator. miR-34a was up-regulated in mesenchymal cells, and its silencing in human embryonic lung mesenchymal cells increased IGFBP3 levels. Additionally, IGFBP3 expression showed a marked downregulation from 7 to 12 pcw, suggesting its involvement in the differentiation process. The differentiation of human tip-derived lung embryonic organoids showed a drastic reduction in IGFBP3, supported by the scRNAseq data. IGFBP3 silencing in organoids activated an alveolar-like differentiation process characterized by stem cell markers downregulation and upregulation of AT2 markers. This process was mediated by TGFβ signalling inhibition and BMP pathway activation. Conclusions: The IGFBP3/miR-34a axis restricts IGFBP3 expression in the embryonic undifferentiated lung epithelium, and the progressive downregulation of IGFBP3 during the pseudoglandular stage is required for alveolar differentiation. [ABSTRACT FROM AUTHOR]

Background: As an indigestible component of human breast milk, Human Milk Oligosaccharides (HMOs) play an important role as a substrate for the establishing microbiome of the newborn. They have further been shown to have beneficial effects on the immune system, lung and brain development. For preterm infants HMO composition of human breast milk may be of particular relevance since the establishment of a healthy microbiome is challenged by multiple disruptive factors associated with preterm birth, such as cesarean section, hospital environment and perinatal antibiotic exposure. In a previous study it has been proposed that maternal probiotic supplementation during late stages of pregnancy may change the HMO composition in human milk. However, there is currently no study on pregnancies which are threatened to preterm birth. Furthermore, HMO composition has not been investigated in association with clinically relevant outcomes of vulnerable infants including inflammation-mediated diseases such as sepsis, necrotizing enterocolitis (NEC) or chronic lung disease. Main body: A randomized controlled intervention study (PROMO = probiotics for human milk oligosaccharides) has been designed to analyze changes in HMO composition of human breast milk after supplementation of probiotics (Lactobacillus acidophilus, Bifidobacterium lactis and Bifidobacterium infantis) in pregnancies at risk for preterm birth. The primary endpoint is HMO composition of 3-fucosyllactose and 3'-sialyllactose in expressed breast milk. We estimate that probiotic intervention will increase these two HMO levels by 50% according to the standardized mean difference between treatment and control groups. As secondary outcomes we will measure preterm infants' clinical outcomes (preterm birth, sepsis, weight gain growth, gastrointestinal complications) and effects on microbiome composition in the rectovaginal tract of mothers at delivery and in the gut of term and preterm infants by sequencing at high genomic resolution. Therefore, we will longitudinally collect bio samples in the first 4 weeks after birth as well as in follow-up investigations at 3 months, one year, and five years of age. Conclusions: We estimate that probiotic intervention will increase these two HMO levels by 50% according to the standardized mean difference between treatment and control groups. The PROMO study will gain insight into the microbiome-HMO interaction at the fetomaternal interface and its consequences for duration of pregnancy and outcome of infants. [ABSTRACT FROM AUTHOR]

Per- and poly-fluoroalkyl substances (PFAS) are a broad class of synthetic compounds widely used in commercial applications. The persistent nature of PFAS in the environment has earned them the epithet "forever chemicals." Concerns arise from widespread exposure to PFAS from occupational, household, and environmental sources. This widespread use of PFAS is particularly concerning, as emerging epidemiological evidence highlights their adverse effects on lung health. Such adverse impacts include impaired fetal lung development, reduced immune function in children, and potential links to lung cancer. Both in vivo and in vitro studies illuminate potential mechanisms underlying such adverse health outcomes subsequent to PFAS inhalation exposure, which may include immunomodulation, oxidative stress, and disruptions to epithelial barriers. However, evidence-based information focusing on the mechanisms of PFAS-mediated lung injury is lacking. Additionally, the discrepancies between data collected from animal and epidemiological studies highlight the need for improved approaches to better understand the toxicity results of PFAS exposure. To address these gaps, we recommend leveraging route-to-route extrapolation for risk assessment, prioritizing research on understudied PFAS, and adopting physiologically relevant, high-throughput approaches. These strategies are aimed at enhancing our understanding of PFAS inhalation effects, aiding in more informed risk management decisions. In this review, we summarize the current literature on PFAS exposure, emphasizing its adverse effects on lung health, particularly through inhalation. We then discuss the current knowledge on mechanisms underlying tissue- and cellular-level adverse outcomes caused by PFAS. [ABSTRACT FROM AUTHOR]

Background: Long-term natural and artificial selection has resulted in many genetic footprints within the genomes of pig breeds across distinct agroecological zones. Nevertheless, the mechanisms by which these signatures contribute to phenotypic diversity and facilitate environmental adaptation remain unclear. Results: Here, we leveraged whole-genome sequencing data from 82 individuals from 6 domestic pig breeds originating in tropical, high-altitude, and frigid regions. Population genetic analysis suggested that habitat isolation significantly shaped the genetic diversity and contributed to population stratification in local Chinese pig breeds. Analysis of selection signals revealed regions under selection for adaptation in tropical (55.5 Mb), high-altitude (43.6 Mb), and frigid (17.72 Mb) regions. The potential functions of the selective sweep regions were linked to certain complex traits that might play critical roles in different geographic environments, including fat coverage in frigid environments and blood indicators in tropical and high-altitude environments. Candidate genes under selection were significantly enriched in biological pathways involved in environmental adaptation. These pathways included blood circulation, protein degradation, and inflammation for adaptation to tropical environments; heart and lung development, hypoxia response, and DNA damage repair for high-altitude adaptation; and thermogenesis, cold-induced vasodilation (CIVD), and the cell cycle for adaptation to frigid environments. By examining the chromatin state of the selection signatures, we identified the lung and ileum as two candidate functional tissues for environmental adaptation. Finally, we identified a mutation (chr1: G246,175,129A) in the cis-regulatory region of ABCA1 as a plausible promising variant for adaptation to tropical environments. Conclusions: In this study, we conducted a genome-wide exploration of the genetic mechanisms underlying the adaptability of local Chinese pig breeds to tropical, high-altitude, and frigid environments. Our findings shed light on the prominent role of cis-regulatory elements in environmental adaptation in pigs and may serve as a valuable biological model of human plateau-related disorders and cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Purpose: Early-onset scoliosis (EOS) has always been a challenging situation for spine surgeons. The aim of treatment is to control the direction of curve progression to allow for the complete development of lungs. Among all the growth constructs available, traditional growth rods (TGR) and magnetically controlled growth rods (MCGR) are most widely used. The MCGR has been introduced a few years back and there is a dearth of long-term follow-up studies. The purpose of this study is to compare the effectiveness of TGR and MCGR for the treatment of EOS. Methods: All patients of EOS managed with either TGR or MCGR were included in the study. The patients managed with other methods or having follow-up < 2-years were excluded from the study. A total of 20 patients were recruited in the MCGR group and 28 patients were recruited in the TGR group. Both groups were matched by etiology, gender, pre-operative radiological parameters, and complications including unplanned surgeries. Results: The mean age in our study was 7.90 years in the MCGR group and 7.46 years in the TGR group. The mean duration of follow-up in the MCGR group was 50.89 months and in the TGR group 94.2 months. Pre-operative cobb's angle in the coronal plane and T1–S1 were comparable in both groups with a mean cobb's angle of 65.4 in MCGR and 70.5 in TGR. The mean T1–S1 length in the MCGR group was 36.1cms and in the TGR group was 35.2 cms (p = 0.18). The average increase in T1–S1 length was 1.3 cm/year in the TGR group and 1.1 cm/year in the MCGR group (p > 0.05). The TGR patients underwent 186 open lengthening surgeries and 11 unplanned surgeries for various complications. The MCGR group has 180 non-invasive lengthening with only 4 unplanned returns to OT for various causes. Conclusion: The curve correction was similar in both TGR and MCGR groups. The average T1–S1 length achieved on final follow-up was similar in both groups. The MCGR patients have attained similar correction with fewer invasive procedures and lesser complications compared to the TGR group. [ABSTRACT FROM AUTHOR]

Background: Donor-specific antibodies (DSAs) are common following lung transplantation (LuTx), yet their role in graft damage is inconclusive. Mean fluorescent intensity (MFI) is the main read-out of DSA diagnostics; however its value is often disregarded when analyzing unwanted post-transplant outcomes such as graft loss or chronic lung allograft dysfunction (CLAD). Here we aim to evaluate an MFI stratification method in these outcomes. Methods: A cohort of 87 LuTx recipients has been analyzed, in which a cutoff of 8000 MFI has been determined for high MFI based on clinically relevant data. Accordingly, recipients were divided into DSA-negative, DSA-low and DSA-high subgroups. Both graft survival and CLAD-free survival were evaluated. Among factors that may contribute to DSA development we analyzed Pseudomonas aeruginosa (P. aeruginosa) infection in bronchoalveolar lavage (BAL) specimens. Results: High MFI DSAs contributed to clinical antibody-mediated rejection (AMR) and were associated with significantly worse graft (HR: 5.77, p < 0.0001) and CLAD-free survival (HR: 6.47, p = 0.019) compared to low or negative MFI DSA levels. Analysis of BAL specimens revealed a strong correlation between DSA status, P. aeruginosa infection and BAL neutrophilia. DSA-high status and clinical AMR were both independent prognosticators for decreased graft and CLAD-free survival in our multivariate Cox-regression models, whereas BAL neutrophilia was associated with worse graft survival. Conclusions: P. aeruginosa infection rates are elevated in recipients with a strong DSA response. Our results indicate that the simultaneous interpretation of MFI values and BAL neutrophilia is a feasible approach for risk evaluation and may help clinicians when to initiate DSA desensitization therapy, as early intervention could improve prognosis. [ABSTRACT FROM AUTHOR]

Objective：To investigate the effectiveness of azithromycin（AZM）on bronchopulmonary dysplasia（BPD）in neonatal rats. Methods：Neonatal rats were randomly assigned to four groups：room air ⁃saline（RA ⁃Saline）group, room air ⁃azithromycin （RA ⁃AZM）group, oxygen ⁃saline（O2 ⁃Saline）group, and oxygen ⁃azithromycin（O2 ⁃AZM）group. The O2 ⁃Saline group and O2 ⁃AZM group were exposed to 95% to 100% oxygen within 12 hours of birth to establish a BPD rat model. The RA⁃AZM and O2 ⁃AZM groups received daily intraperitoneal injections of AZM at a dosage of 40 mg/kg from postnatal day 1 to day 10, while the RA⁃Saline and O2 ⁃Saline groups were administered an equal volume of saline. The survival rate of the rats was carefully observed. qPCR analysis was conducted to detect the expression of inflammatory factors and chemokines. Additionally, the alveolar mean linear intercept（MLI), the formation of secondary alveolar septa, and pulmonary vascular density were measured to assess the impact of AZM on lung development in BPD neonatal rats. Immunohistochemical detection of neutrophils and macrophages in lung tissue was also performed to evaluate the anti⁃inflammatory effect of AZM on inflammatory cells. Results：Compared to the O2 ⁃Saline group, the 10⁃day survival rate of rats in the O2 ⁃ AZM group did not exhibit a statistically significant difference（P > 0.05). qPCR analysis revealed that the expressions of interleukin ⁃6（IL ⁃6), monocyte chemotactic protein ⁃1（MCP ⁃1), and plasminogen activator inhibitor ⁃1（PAI ⁃1）were significantly reduced in the O2 ⁃AZM group compared to the O2 ⁃ Saline group（P < 0.05), while the expression of cytokine induced neutrophil chemoattractant ⁃1（CINC ⁃1）showed no significant difference（P > 0.05). ELISA analysis further confirmed a significant reduction in IL⁃6 levels in the O2 ⁃AZM group compared to the O2 ⁃Saline group（P < 0.05). Immunohistochemical analysis revealed a marked reduction in the accumulation of macrophages and neutrophils in the lung tissues of the O2 ⁃AZM group, along with an increase in pulmonary vascular density and the count of secondary alveolar septa, all of which were statistically significant. Furthermore, HE pathological examination revealed a significantly shortened MLI in the O2 ⁃AZM group compared to the O2 ⁃Saline group, indicating a statistically significant difference（P < 0.05). Conclusion：AZM reduces the release of inflammatory factors and chemokines in lung tissues of neonatal rats exposed to hyperoxia, inhibits the chemotaxis or recruitment of inflammatory cells, and alleviates BPD⁃like lung injury in neonatal rats after hyperoxia exposure. [ABSTRACT FROM AUTHOR]

Alveoli are complex microenvironments composed of various cell types, including epithelial, fibroblast, endothelial, and immune cells, which work together to maintain a delicate balance in the lung environment, ensuring proper growth, development, and an effective response to lung injuries. However, prolonged inflammation or aging can disrupt normal interactions among these cells, leading to impaired repair processes and a substantial decline in lung function. Therefore, it is essential to understand the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. We explored the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. These interactions occur through the secretion of signaling factors and play crucial roles in the response to injury, repair mechanisms, and the development of fibrosis in the lungs. Specifically, we focused on the regulation of alveolar type 2 cells by fibroblasts, endothelial cells, and macrophages. In addition, we explored the diverse phenotypes of fibroblasts at different stages of life and in response to lung injury, highlighting their impact on matrix production and immune functions. Furthermore, we summarize the various phenotypes of macrophages in lung injury and fibrosis as well as their intricate interplay with other cell types. This interplay can either contribute to the restoration of immune homeostasis in the alveoli or impede the repair process. Through a comprehensive exploration of these cell interactions, we aim to reveal new insights into the molecular mechanisms that drive lung injury toward fibrosis and identify potential targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Sarcoidosis and Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) are two rare entities primarily characterised by the development of Interstitial Lung Disease (ILD) in the context of systemic immune dysregulation. These two conditions partially share the immunological background and pathologic findings, with granuloma as the main common feature. In this narrative review, we performed a careful comparison between sarcoidosis and GLILD, with an overview of their main similarities and differences, starting from a clinical perspective and ending with a deeper look at the immunopathogenesis and possible target therapies. Sarcoidosis occurs in immunocompetent individuals, whereas GLILD occurs in patients affected by common variable immunodeficiency (CVID). Moreover, peculiar extrapulmonary manifestations and radiological and histological features may help distinguish the two diseases. Despite that, common pathogenetic pathways have been suggested and both these disorders can cause progressive impairment of lung function and variable systemic granulomatous and non-granulomatous complications, leading to significant morbidity, reduced quality of life, and survival. Due to the rarity of these conditions and the extreme clinical variability, there are still many open questions concerning their pathogenesis, natural history, and optimal management. However, if studied in parallel, these two entities might benefit from each other, leading to a better understanding of their pathogenesis and to more tailored treatment approaches. [ABSTRACT FROM AUTHOR]

Flow cytometry and fluorescence‐activated cell sorting are widely used to study endothelial cells, for which the generation of viable single‐cell suspensions is an essential first step. Two enzymatic approaches, collagenase A and dispase, are widely employed for endothelial cell isolation. In this study, the utility of both enzymatic approaches, alone and in combination, for endothelial cell isolation from juvenile and adult mouse lungs was assessed, considering the number, viability, and subtype composition of recovered endothelial cell pools. Collagenase A yielded an 8‐12‐fold superior recovery of viable endothelial cells from lung tissue from developing mouse pups, compared to dispase, although dispase proved superior in efficiency for epithelial cell recovery. Single‐cell RNA‐Seq revealed that the collagenase A approach yielded a diverse endothelial cell subtype composition of recovered endothelial cell pools, with broad representation of arterial, capillary, venous, and lymphatic lung endothelial cells; while the dispase approach yielded a recovered endothelial cell pool highly enriched for one subset of general capillary endothelial cells, but poor representation of other endothelial cells subtypes. These data indicate that tissue dissociation markedly influences the recovery of endothelial cells, and the endothelial subtype composition of recovered endothelial cell pools, as assessed by single‐cell RNA‐Seq. [ABSTRACT FROM AUTHOR]

The lack of physiologically relevant in vitro models has hampered progress in understanding human lung development and disease. Here, we describe a protocol in which human induced pluripotent stem cells (hiPSCs) undergo stepwise differentiation into definitive endoderm (>88% population) to three-dimensional (3D) lung organoids (LORGs), which contain both epithelial and mesenchymal cellular architecture and display proximal and distal airway patterning. These LORGs can maintained for more than 90 days by re-embedding in the Matrigel. We show the utility of LORGs for disease modeling and drug screening by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and treatment with antiviral drugs.

Premature infants with bronchopulmonary dysplasia (BPD) have impaired alveolar gas exchange due to alveolar simplification and dysmorphic pulmonary vasculature. Advances in clinical care have improved survival for infants with BPD, but the overall incidence of BPD remains unchanged because we lack specific therapies to prevent this disease. Recent work has suggested a role for increased transforming growth factor-beta (TGFβ) signaling and myofibroblast populations in BPD pathogenesis, but the functional significance of each remains unclear. Here, we utilize multiple murine models of alveolar simplification and comparative single-cell RNA sequencing to identify shared mechanisms that could contribute to BPD pathogenesis. Single-cell RNA sequencing reveals a profound loss of myofibroblasts in two models of BPD and identifies gene expression signatures of increased TGFβ signaling, cell cycle arrest, and impaired proliferation in myofibroblasts. Using pharmacologic and genetic approaches, we find no evidence that increased TGFβ signaling in the lung mesenchyme contributes to alveolar simplification. In contrast, this is likely a failed compensatory response, since none of our approaches to inhibit TGFβ signaling protect mice from alveolar simplification due to hyperoxia while several make simplification worse. In contrast, we find that impaired myofibroblast proliferation is a central feature in several murine models of BPD, and we show that inhibiting myofibroblast proliferation is sufficient to cause pathologic alveolar simplification. Our results underscore the importance of impaired myofibroblast proliferation as a central feature of alveolar simplification and suggest that efforts to reverse this process could have therapeutic value in BPD.

Cells called alveolar myofibroblasts, which have a central role in the development of the lung after birth, receive an orchestrated input from a range of different signaling pathways.

Abstract Immune cells in the lungs are important for maintaining lung function. The importance of immune cells in defending against lung diseases and infections is increasingly recognized. However, a primary knowledge gaps in current studies of lung immune cells is the understanding of their subtypes and functional heterogeneity. Increasing evidence supports the existence of novel immune cell subtypes that engage in the complex crosstalk between lung‐resident immune cells, recruited immune cells, and epithelial cells. Therefore, further studies on how immune cells respond to perturbations in the pulmonary microenvironment are warranted. This review explores the processes behind the formation of the immune cell niche during lung development, and the characteristics and cell interaction modes of several major lung‐resident immune cells. It indicates that distinct lung microenvironments or inflammatory niches can mediate the formation of different cell subtypes. These findings summarize and clarify paths to identify new cell subtypes that originate from resident progenitor cells and recruited peripheral cells, which are remodeled by the pulmonary microenvironment. The development of new techniques combining transcriptome analysis and location information is essential for identifying new immune cell subtypes and their relative immune niches, as well as for uncovering the molecular mechanisms of immune cell‐mediated lung homeostasis.

Lung megakaryocytes (Mks) are a unique subset of Mks that are distinct from their bone marrow counterparts. Recent evidence suggests that lung Mks favor an immune phenotype, but have unclear contributions to the total platelet mass. In this issue of the JCI, Livada et al. used an array of complementary in vivo labeling and tracing models in mice to investigate a longstanding question of where lung Mks are derived. By combining these models with stressed conditions, the authors assessed the contribution of lung Mks to total platelet counts in a homeostatic and thrombocytopenic state. Mks were minor contributors to the circulating pool of platelets during homeostasis but increased output during thrombocytopenia. These findings add critical understanding to the development of lung Mks and demonstrate the dynamic potential of these specialized cells to respond to thrombocytopenia. [ABSTRACT FROM AUTHOR]

Mutations in the FOXF1 gene, a key transcriptional regulator of pulmonary vascular development, cause Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins, a lethal lung disease affecting newborns and infants. Identification of new FOXF1 upstream regulatory elements is critical to explain why frequent non-coding FOXF1 deletions are linked to the disease. Herein, we use multiome single-nuclei RNA and ATAC sequencing of mouse and human patient lungs to identify four conserved endothelial and mesenchymal FOXF1 enhancers. We demonstrate that endothelial FOXF1 enhancers are autoactivated, whereas mesenchymal FOXF1 enhancers are regulated by EBF1 and GLI1. The cell-specificity of FOXF1 enhancers is validated by disrupting these enhancers in mouse embryonic stem cells using CRISPR/Cpf1 genome editing followed by lineage-tracing of mutant embryonic stem cells in mouse embryos using blastocyst complementation. This study resolves an important clinical question why frequent non-coding FOXF1 deletions that interfere with endothelial and mesenchymal enhancers can lead to the disease. Mutations in FOXF1, a key transcriptional regulator of pulmonary vascular development, cause Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. Here, the authors discovered four genomic regions that control cell type-specific activity of Foxf1 during lung development and show that disrupting these regions via genetic deletions leads to alveolar capillary dysplasia. [ABSTRACT FROM AUTHOR]

Abnormal lung development can cause congenital pulmonary cysts, the mechanisms of which remain largely unknown. Although the cystic lesions are believed to result directly from disrupted airway epithelial cell growth, the extent to which developmental defects in lung mesenchymal cells contribute to abnormal airway epithelial cell growth and subsequent cystic lesions has not been thoroughly examined. In the present study using genetic mouse models, we dissected the roles of bone morphogenetic protein (BMP) receptor 1a (Bmpr1a)-mediated BMP signaling in lung mesenchyme during prenatal lung development and discovered that abrogation of mesenchymal Bmpr1a disrupted normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions. Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were found in the cystic airways of the mesenchymal Bmpr1a knockout lungs. In addition, ectopic mesenchymal expression of BMP ligands and airway epithelial perturbation of the Sox2-Sox9 proximal-distal axis were detected in the mesenchymal Bmpr1a knockout lungs. However, deletion of Smad1/5, two major BMP signaling downstream effectors, from the lung mesenchyme did not phenocopy the cystic abnormalities observed in the mesenchymal Bmpr1a knockout lungs, suggesting that a Smad-independent mechanism contributes to prenatal pulmonary cystic lesions. These findings reveal for the first time the role of mesenchymal BMP signaling in lung development and a potential pathogenic mechanism underlying congenital pulmonary cysts. [ABSTRACT FROM AUTHOR]