Abstract Introduction The lungs are a remarkably communicative organ, interfacing robustly with the circulatory and immune systems. It has been well-established that lung function declines and incidence of chronic lung disease increases with age. There have been many studies describing genetic mechanisms associated with pulmonary fibrosis and senescence, but few investigating the hematologic-pulmonary axis and how cell-cell communication may contribute to the witnessed age-related changes. Methods To examine gene expression changes across the lifespan, patient-matched lung and blood samples from the publicly available GTEx database were stratified by age. Bulk RNA sequencing data from both tissues across young (20-39 years old) and old (60-79 years old) cohorts were analyzed using R bioinformatics tools (bulkSignalR, crossWCGNA). We focused on finding differentially expressed genes (DEGs) belonging to biologically-relevant pathways as defined by the REACTOME database, downstream of ligand-receptor interactions (LRIs). Results Top DEGs in old versus young lung tissue included upregulated genes PTCHD4, ITGBL1, and NALCN; and downregulated genes DEFB4A, MMP12, and BPIFA1. Top DEGs in old versus young blood included upregulated genes FIGN, FGA, and CRP; and downregulated genes LRRN3, REG4, and NOG. Using the REACTOME pathway database, we found that the top age-enriched pathways in lung included upregulation of collagen fiber formation, while blood exhibited upregulation of defensins. Top downregulated pathways in both tissues were those of cell cycle progression. To better contextualize these gene expression patterns and infer blood-lung interactions we utilized bioinformatics tools designed specifically to identify LRIs and looked for DEGs enriched in these signaling pathways. We found the ephrin pathway was enriched in old vs young lung. Moreover, we found that the signaling cascade ligands EFNA2/A4/B3 were increased in old vs young blood, whereas the receptors EPHA5/A6 were significantly upregulated in old vs young lung tissues. Additional receptors FZD5 (involved in WNT signaling) and ADORA2B (implicated in airway surface liquid ASL homeostasis) were identified as differentially expressed in old vs young lung with pathway-level enrichment between blood and lung tissue. Conclusions These data suggest that signaling across tissue compartments (blood to lung) may be relevant for some gene expression changes in lung aging. Independently, the aforementioned genes and pathways have been implicated in lung health, however, they have not been previously associated with inter-tissue communication as it relates to lung aging. The implications for age-associated lung disease merit further research. This abstract is funded by: None
Morrison et al. (Fri,) studied this question.