Leveraging Integrated RNA Sequencing to Decipher Adrenomedullin's Protective Mechanisms in Experimental Bronchopulmonary Dysplasia

Authors

Subarna Palit
Amrit Kumar Shrestha
Shyam Thapa
Sandra L Grimm
Cristian Coarfa
Fabian Theis
Lukas M Simon
Binoy Shivanna

Publication Date

6-19-2024

Journal

Genes

DOI

10.3390/genes15060806

PMID

38927741

PMCID

PMC11202456

PubMedCentral® Posted Date

6-19-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Adrenomedullin, Bronchopulmonary Dysplasia, Animals, Mice, Humans, Sequence Analysis, RNA, Disease Models, Animal, Lipopolysaccharides, Lung, Killer Cells, Natural, Transcriptome, bronchopulmonary dysplasia, adrenomedullin, RNA-seq, natural killer cells

Abstract

Bronchopulmonary dysplasia (BPD) is a chronic lung disease commonly affecting premature infants, with limited therapeutic options and increased long-term consequences. Adrenomedullin (Adm), a proangiogenic peptide hormone, has been found to protect rodents against experimental BPD. This study aims to elucidate the molecular and cellular mechanisms through which Adm influences BPD pathogenesis using a lipopolysaccharide (LPS)-induced model of experimental BPD in mice. Bulk RNA sequencing of Adm-sufficient (wild-type or Adm+/+) and Adm-haplodeficient (Adm+/−) mice lungs, integrated with single-cell RNA sequencing data, revealed distinct gene expression patterns and cell type alterations associated with Adm deficiency and LPS exposure. Notably, computational integration with cell atlas data revealed that Adm-haplodeficient mouse lungs exhibited gene expression signatures characteristic of increased inflammation, natural killer (NK) cell frequency, and decreased endothelial cell and type II pneumocyte frequency. Furthermore, in silico human BPD patient data analysis supported our cell type frequency finding, highlighting elevated NK cells in BPD infants. These results underscore the protective role of Adm in experimental BPD and emphasize that it is a potential therapeutic target for BPD infants with an inflammatory phenotype.

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