MOVING FORWARD
Dr Guadalupe González-Mateo, Head of the Science Area at Premium Research actively contributed to the development of this article, published in 2023.
Bacterial infections and the associated inflammation have been linked to an increased long-term cardiovascular (CV) risk. In patients undergoing peritoneal dialysis (PD), bacterial peritonitis is a common complication, and each episode further raises the risk of late-stage cardiovascular mortality. However, the underlying mechanisms remain unclear, hindering the development of safe and effective anti-inflammatory interventions.
Damage-Associated Molecular Patterns (DAMPs) are known to drive the acute inflammatory response to infections. However, their potential role in sustaining long-term vascular inflammation and CV risk following infection resolution in the context of PD had not been previously explored.
In our study, a single episode of bacterial peritonitis in mice—resolved within 24 hours—triggered systemic and vascular immune-mediated inflammatory responses that promote cardiovascular disease and persisted for up to 28 days. These responses included elevated levels of circulating inflammatory leukocytes with increased expression of adhesion molecules, higher plasma cytokine concentrations, and enhanced aortic expression of genes linked to inflammation and atherosclerosis. Similar effects were observed in infected nephropathic mice and were amplified in those routinely exposed to PD fluids.
A single peritonitis episode led to elevated plasma levels of the DAMP calprotectin, observed in both PD patients and mice, with this increase sustained for up to 28 days. In vitro, the ability of supernatants from infected cell cultures to trigger key pro-inflammatory and pro-atherosclerotic responses—such as monocyte chemotaxis and foam cell formation—was found to be calprotectin-dependent. In vivo, calprotectin blockade significantly inhibited both the short- and long-term peripheral and vascular consequences of peritonitis.
These findings demonstrate that calprotectin is a promising therapeutic target to reduce persistent vascular inflammatory damage following infection—particularly PD-associated peritonitis—and could ultimately help to lower cardiovascular risk.
Reference:
Cetin E, Mazzarino M, González-Mateo GT, Kopytina V, Meran S, Fraser D, López-Cabrera M, Labéta MO and Raby A-C (2023). Calprotectin blockade inhibits long-term vascular pathology following peritoneal dialysis-associated bacterial infection. Front. Cell. Infect. Microbiol. 13:1285193. doi: 10.3389/fcimb.2023.1285193
