Neonatal hyperoxia induces sex-dependent pulmonary cellular and transcriptomic changes in an experimental mouse model of bronchopulmonary dysplasia

Sheng, Xia; Ellis, Lisandra Vila; Winkley, Konner; Menden, Heather; Mabry, Sherry M; Louiselle, Daniel; Gibson, Margaret; Grundberg, Elin; Chen, Jichao; Sampath, Venkatesh

doi:10.1101/2022.07.12.499826

Cited by 4 publications

(2 citation statements)

References 113 publications

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“…We also observed changes in the pulmonary transcriptome and related regulatory pathways (Fig. S1) that are consistent with similar observations [9][10][11][12] showing type 2 immune polarization and extensive alterations in alveolar epithelial and endothelial cell populations in response to hyperoxia-induced lung injury.…”

Section: Hyperoxia Exposure Alters Lung Morphology and Functionsupporting

confidence: 90%

Antimicrobial peptides modulate lung injury by altering the intestinal microbiota

Abdelgawad

Nicola

Martin

et al. 2023

Preprint

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Mammalian mucosal barriers secrete antimicrobial peptides (AMPs) as critical host-derived regulators of the microbiota. However, mechanisms that support homeostasis of the microbiota in response to inflammatory stimuli such as supraphysiologic oxygen remain unclear. Here, we show that neonatal mice breathing supraphysiologic oxygen or direct exposure of intestinal organoids to supraphysiologic oxygen suppress the intestinal expression of AMPs and alters the composition of the intestinal microbiota. Oral supplementation of the prototypical AMP lysozyme to hyperoxia exposed neonatal mice reduced hyperoxia-induced alterations in their microbiota and was associated with decreased lung injury. Our results identify a gut-lung axis driven by intestinal AMP expression and mediated by the intestinal microbiota that is linked to lung injury. Together, these data support that intestinal AMPs modulate lung injury and repair.

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Section: Hyperoxia Exposure Alters Lung Morphology and Functionsupporting

confidence: 90%

Antimicrobial peptides modulate lung injury by altering the intestinal microbiota

Abdelgawad

Nicola

Martin

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…Finally, we identified that the specific intercellular communication networks and the ligand-receptor pairs that are impacted by neonatal hyperoxia exposure. Xia et al have reported sex-specific differences in the lung cell sub- populations using different hyperoxia exposure model using 85% FiO2 for 14 days after birth (115).…”

Section: Discussionmentioning

confidence: 99%

Remarkable sex-specific differences at Single-Cell Resolution in Neonatal Hyperoxic Lung Injury

Cantu

Gutierrez

Dong

et al. 2022

Preprint

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Exposure to supraphysiological concentrations of oxygen (hyperoxia) predisposes to bronchopulmonary dysplasia (BPD), which is characterized by abnormal alveolarization and pulmonary vascular development, in preterm neonates. Neonatal hyperoxia exposure is used to recapitulate the phenotype of human BPD in murine models. Male sex is considered an independent predictor for the development of BPD, but the main mechanisms underlying sexually dimorphic outcomes are unknown. Our objective was to investigate sex-specific and cell-type specific transcriptional changes that drive injury in the neonatal lung exposed to hyperoxia at single-cell resolution and delineate the changes in cell-cell communication networks in the developing lung. We used single cell RNA sequencing (scRNAseq) to generate transcriptional profiles of >35000 cells isolated from the lungs of neonatal male and female C57BL/6 mice exposed to 95% FiO2 between PND1-5 (saccular stage of lung development) or normoxia and euthanized at PND7 (alveolar stage of lung development). ScRNAseq identified 22 cell clusters with distinct populations of endothelial, epithelial, mesenchymal, and immune cells. Our data identified that the distal lung vascular endothelium (composed of aerocytes and general capillary endothelial cells) is exquisitely sensitive to hyperoxia exposure with the emergence of an intermediate capillary endothelial population with both aCaP and gCaP markers. We also identified a myeloid derived suppressor cell population from the lung neutrophils. Sexual dimorphism was evident in all lung cell subpopulations but was striking among the lung immune cells. Finally, we identified that the specific intercellular communication networks and the ligand-receptor pairs that are impacted by neonatal hyperoxia exposure.

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The fungal intestinal microbiota predict the development of bronchopulmonary dysplasia in very low birthweight newborns

Willis

Silverberg

Martin

et al. 2023

Preprint

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Rationale: Bronchopulmonary dysplasia (BPD) is the most common morbidity affecting very preterm infants. Gut microbial communities contribute to multiple lung diseases, and alterations of the gut microbiome may be a factor in BPD pathogenesis. Objective: To determine if features of the multikingdom gut microbiome predict the development of BPD in very low birthweight newborns. Methods: We performed a prospective, observational cohort study comparing the multikingdom fecal microbiota of 147 very low birthweight infants with BPD or post-prematurity respiratory disease (PPRD) by sequencing bacterial 16S and fungal ITS2 ribosomal RNA. To address the potential causative relationship between gut dysbiosis and BPD, we used fecal microbiota transplant in an antibiotic-pseudohumanized mouse model. Comparisons were made using RNA sequencing, quantitative confocal microscopy, lung morphometry, and oscillometry. Measurements and Main Results: We analyzed 100 fecal microbiome samples collected during the second week of life. Infants who later developed BPD showed an obvious fungal dysbiosis as compared to infants with PPRD (P = 0.0209). Instead of fungal communities dominated by Candida and Saccharomyces, the microbiota of infants who developed BPD were characterized by the abundance of Aureobasidium and a greater diversity of rarer fungi in less interconnected community architectures. On successful colonization, the gut microbiota from infants with BPD augmented lung injury in the offspring of recipient animals. We identified alterations in the murine lung and intestinal microbiomes and transcriptional alterations associated with augmented lung injury. Conclusions: The gut fungal microbiome of infants who will develop BPD is dysbiotic and may contribute to disease pathogenesis.

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Neonatal hyperoxia induces sex-dependent pulmonary cellular and transcriptomic changes in an experimental mouse model of bronchopulmonary dysplasia

Cited by 4 publications

References 113 publications

Antimicrobial peptides modulate lung injury by altering the intestinal microbiota

Antimicrobial peptides modulate lung injury by altering the intestinal microbiota

Remarkable sex-specific differences at Single-Cell Resolution in Neonatal Hyperoxic Lung Injury

The fungal intestinal microbiota predict the development of bronchopulmonary dysplasia in very low birthweight newborns

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