Association of immune cell recruitment and BPD development

Heydarian, Motaharehsadat; Schulz, Christian; Stoeger, Tobias; Hilgendorff, Anne

doi:10.1186/s40348-022-00148-w

Cited by 14 publications

(8 citation statements)

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“…Recent studies revealed that immune response plays an important role in the pathological process of BPD. 7 A genomic study conducted by Revhaug et al reported that the immune system-related genes were impacted in a murine experimental model of BPD. 8 Hyperoxia could evoke the innate immune response by promoting the generation of chemokines and cytokines and recruiting the immune cells to the pulmonary tissue in BPD model subsequently.…”

Section: Introductionmentioning

confidence: 99%

CD8A is a Promising Biomarker Associated with Immunocytes Infiltration in Hyperoxia-Induced Bronchopulmonary Dysplasia

Du¹,

Zuo²,

Xiong³

et al. 2023

JIR

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Background: Bronchopulmonary dysplasia (BPD) refers to a chronic lung disease which is commonly observed in preterm infants. It can usually be caused by several pathological processes that endanger the long-term lung development, such as inflammation and immune dysfunction. Methods: In this study, a bioinformatics approach was applied to identify the differentially expressed immune-related genes (DEIRGs). We downloaded the transcriptional profiles (GSE32472 dataset) from the Gene Expression Omnibus (GEO) database and performed gene set enrichment analysis (GSEA). Cell type Identification By Estimating Relative Subsets of RNA Transcripts (CIBERSORT), microenvironment cell populations counter (MCPcounter), and Estimation of STromal and Immune cells in Malignant Tumor tissues using Expression data (ESTIMATE) were used for the analysis of the immune cell infiltration landscape of BPD. A weighted co-expression network was subsequently constructed using weighted gene co-expression network analysis (WGCNA) to screen candidate differentially expressed immune related genes (DEIRGs). Results: GSEA results indicated that immune-related pathways were mainly involved in BPD. Ten significantly different immune cell types were observed between BPD and normal groups. A total of 228 DEGs in the turquoise module were identified, and 31 DEIRGs were further identified. Cluster of the differentiation 8 alpha (CD8A) expression was down-regulated in BPD, and its expression was validated by the GSE25286, GSE25293, GSE99633 datasets and qRT-PCR. In addition, CD8A expression was closely associated with immune cells infiltration, especially T cells CD8 and neutrophil. Conclusion: A distinct immune cell infiltration landscape was found between BPD and normal group. CD8A can be a novel candidate biomarker for BPD, which plays an essential role in the onset and progress of hyperoxia-related BPD via the disruption of immune cell functions.

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Section: Introductionmentioning

confidence: 99%

CD8A is a Promising Biomarker Associated with Immunocytes Infiltration in Hyperoxia-Induced Bronchopulmonary Dysplasia

Du¹,

Zuo²,

Xiong³

et al. 2023

JIR

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“…Despite several attempts to characterize these immune phenomena in the context of different pre- and postnatal risk factors driving BPD, comprehensive knowledge that informs diagnostic and therapeutic strategies at an early disease stage is missing. In the injured neonatal lung, both clinical and experimental studies have confirmed the presence of lung macrophages (MФ) and their respective signaling molecules ( 8 , 9 ). These key players of innate immunity undergo a complex process of maturation and are in neonates characterized by shared and distinct functions when compared to adult MФ including lipopolysaccharide-induced activation, Fc receptor-dependent phagocytosis, and differences in polarization with interferon-gamma (IFNγ) or interleukin (IL)-10 ( 10 , 11 ).…”

Section: Introductionmentioning

confidence: 99%

Monocyte signature as a predictor of chronic lung disease in the preterm infant

et al. 2023

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IntroductionInflammation is a key driver of morbidity in the vulnerable preterm infant exposed to pre- and postnatal hazards and significantly contributes to chronic lung disease, i.e. bronchopulmonary dysplasia (BPD). However, the early changes in innate immunity associated with BPD development are incompletely understood.MethodsIn very immature preterm infants below 32 weeks gestational age (GA; n=30 infants), monocyte subtypes were identified by Flow Cytometry at birth and throughout the postnatal course including intracellular TNF expression upon LPS stimulation. Complementing these measurements, cytokine end growth factor expression profiles (Luminex® xMAP®; n=110 infants) as well as gene expression profiles (CodeLinkTM Human I Bioarray; n=22) were characterized at birth.ResultsThe abundance of monocyte subtypes differed between preterm and term neonates at birth. Specifically, CD14++CD16+ (intermediate) monocytes demonstrated a dependency on PMA and elevated levels of nonclassical (CD14+CD16++) monocytes characterized preterm infants with developing BPD. Postnatally, lung injury was associated with an increase in intermediate monocytes, while high levels of nonclassical monocytes persisted. Both subtypes were revealed as the main source of intracellular TNF-α expression in the preterm infant. We identified a cytokine and growth factor expression profile in cord blood specimen of preterm infants with developing BPD that corresponded to the disease-dependent regulation of monocyte abundances. Multivariate modeling of protein profiles revealed FGF2, sIL-2 Rα, MCP-1, MIP1a, and TNF-α as predictors of BPD when considering GA. Transcriptome analysis demonstrated genes predicting BPD to be overrepresented in inflammatory pathways with increased disease severity characterized by the regulation of immune and defense response pathways and upstream regulator analysis confirmed TNF-α, interleukin (IL) -6, and interferon α as the highest activated cytokines in more severe disease. Whereas all BPD cases showed downstream activation of chemotaxis and activation of inflammatory response pathways, more severe cases were characterized by an additional activation of reactive oxygen species (ROS) synthesis.DiscussionIn the present study, we identified the early postnatal presence of nonclassical (CD14+CD16++) and intermediate (CD14++CD16+) monocytes as a critical characteristic of BPD development including a specific response pattern of monocyte subtypes to lung injury. Pathophysiological insight was provided by the protein and transcriptome signature identified at birth, centered around monocyte and corresponding granulocyte activation and highlighting TNFα as a critical regulator in infants with developing BPD. The disease severity-dependent expression patterns could inform future diagnostic and treatment strategies targeting the monocytic cell and its progeny.

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“…However, in fetal lungs exposed to LPS+10058F4, we observed suppression in IL1β and CXCL1 compared to LPS-exposed group, and suppression in TNF-α compared to both controls and LPS-exposed group. IL1β, TNF-α and CXCL1 dysregulation are well-associated with IAI and BPD ( Ambalavanan et al, 2009 ; Cappelletti et al, 2020 ; Heydarian et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

c-Myc Drives inflammation of the maternal-fetal interface, and neonatal lung remodeling induced by intra-amniotic inflammation

Tan,

Tong,

Alvarez-Cubela

et al. 2024

Front. Cell Dev. Biol.

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Background: Intra-amniotic inflammation (IAI) is associated with increased risk of preterm birth and bronchopulmonary dysplasia (BPD), but the mechanisms by which IAI leads to preterm birth and BPD are poorly understood, and there are no effective therapies for preterm birth and BPD. The transcription factor c-Myc regulates various biological processes like cell growth, apoptosis, and inflammation. We hypothesized that c-Myc modulates inflammation at the maternal-fetal interface, and neonatal lung remodeling. The objectives of our study were 1) to determine the kinetics of c-Myc in the placenta, fetal membranes and neonatal lungs exposed to IAI, and 2) to determine the role of c-Myc in modulating inflammation at the maternal-fetal interface, and neonatal lung remodeling induced by IAI.Methods: Pregnant Sprague-Dawley rats were randomized into three groups: 1) Intra-amniotic saline injections only (control), 2) Intra-amniotic lipopolysaccharide (LPS) injections only, and 3) Intra-amniotic LPS injections with c-Myc inhibitor 10058-F4. c-Myc expression, markers of inflammation, angiogenesis, immunohistochemistry, and transcriptomic analyses were performed on placenta and fetal membranes, and neonatal lungs to determine kinetics of c-Myc expression in response to IAI, and effects of prenatal systemic c-Myc inhibition on lung remodeling at postnatal day 14.Results: c-Myc was upregulated in the placenta, fetal membranes, and neonatal lungs exposed to IAI. IAI caused neutrophil infiltration and neutrophil extracellular trap (NET) formation in the placenta and fetal membranes, and neonatal lung remodeling with pulmonary hypertension consistent with a BPD phenotype. Prenatal inhibition of c-Myc with 10058-F4 in IAI decreased neutrophil infiltration and NET formation, and improved neonatal lung remodeling induced by LPS, with improved alveolarization, increased angiogenesis, and decreased pulmonary vascular remodeling.Discussion: In a rat model of IAI, c-Myc regulates neutrophil recruitment and NET formation in the placenta and fetal membranes. c-Myc also participates in neonatal lung remodeling induced by IAI. Further studies are needed to investigate c-Myc as a potential therapeutic target for IAI and IAI-associated BPD.

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Association of immune cell recruitment and BPD development

Cited by 14 publications

References 149 publications

CD8A is a Promising Biomarker Associated with Immunocytes Infiltration in Hyperoxia-Induced Bronchopulmonary Dysplasia

CD8A is a Promising Biomarker Associated with Immunocytes Infiltration in Hyperoxia-Induced Bronchopulmonary Dysplasia

Monocyte signature as a predictor of chronic lung disease in the preterm infant

c-Myc Drives inflammation of the maternal-fetal interface, and neonatal lung remodeling induced by intra-amniotic inflammation

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