T-Helper 17 Cells as Potential Mediators of Fluoroquinolone Induced Aortic Aneurysms

C. Eckholdt, G. Lambert, Z. Connelly, W. Chriss, S. Cheng, R. White
Louisiana State University Health Sciences Center, Shreveport, Shreveport, Louisiana

Purpose: Aortic aneurysms are a common and potentially fatal disease with several etiologies. Recent studies have pointed to an increased rate of aneurysm formation in patients exposed to fluoroquinolone antibiotics. The purpose of this study was to develop a further understanding of this connection, and identify cellular targets for future studies.

Methods: The publicly available Comparative Toxicogenomic Database was utilized to identify all known genetic targets of fluoroquinolones. Next, the endothelial database (EndoDB), a database of endothelial cell transcriptomics data, was used to identify which genes may be uniquely present within the endothelial cells of the aortic wall. This was accomplished by comparing genes that are differentially expressed between aortic and iliac endothelial cells. These iliac endothelial cells are exposed to similar hemodynamic conditions but are not associated with the same increased rates of aneurysm formation after exposure to fluoroquinolones, serving as an ideal comparison group for aortic endothelial cells. This group of genes, differentially expressed between aortic and iliac endothelial cells, was then cross-referenced with the fluoroquinolone-targeted list, and a gene ontology analysis was performed to identify the common cellular function and biological processes across these common genes.

Results: 2296 genes were identified to have a known interaction with fluoroquinolones. When comparing the aortic and iliac endothelial cell gene lists, 228 differentially expressed pathways comprising thousands of genes were identified. Of these 228 pathways, 240 genes were differentially expressed between the two groups. These were then cross-referenced with the known fluoroquinolone-targeted genes, yielding 50 unique genes. These genes play roles in multiple distinct sub-group pathways. Further gene ontology analysis revealed the most influential gene pathways, of which the top five genes related to T-helper 17 cell differentiation and recruitment. Other top pathways include leukocyte tethering or rolling and adhesion to vascular endothelial cells. These results point to inflammatory conditions present within the aortic wall, propagated by fluoroquinolones, predisposing the aorta the development of aneurysmal disease.

Conclusion: This study identified 50 genes that are influenced by fluoroquinolones and uniquely expressed within aortic endothelial cells. This is the first study to identify the role of the T-helper 17 cell pathway with aortic aneurysms, providing a mechanism to account for increased rates of aneurysm in patients exposed to fluoroquinolones.

Identify the source of the funding for this research project: None