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Mechanisms of vascular damage following bacterial peritonitis in peritoneal dialysis patients

Cetin, Esra 2023. Mechanisms of vascular damage following bacterial peritonitis in peritoneal dialysis patients. PhD Thesis, Cardiff University.
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Chronic Kidney Disease (CKD) is associated with markedly increased cardiovascular (CV) morbidity and mortality. In patients on PD, CV death is up to 10 times more likely than in the general population and this risk further increases following each episode of infectious peritonitis, a common occurrence in PD patients. However, the mechanisms by which infection-induced acute peritoneal inflammation leads to increased long-term CV risk are incompletely understood. This study revealed that a single peritoneal bacterial infection in mice leads to systemic inflammatory changes, maintained up to 28 days, that are expected to promote vascular inflammation and atherosclerosis development. These included i) higher proportion of inflammatory innate immune leukocytes, ii) increased pro-inflammatory cytokine release, iii) higher expression of adhesion molecules, and iv) increased blood and aortic inflammatory and atherosclerosis-associated gene expression. Because CKD itself and the PD process are known to impact the quality and extent of inflammatory responses, we verified that these findings were maintained in nephropathic animals and animals chronically exposed to PD fluids. In parallel to these changes, we found that a peritonitis episode was accompanied by elevated plasma levels of a specific TLR DAMP, Calprotectin, both in animals and PD patients. In vitro, Calprotectin could promote typical vascular inflammatory and pro atherosclerotic responses: notably i) chemokine-directed monocyte migration, ii) foam cell formation by macrophages, via a reduction of cholesterol efflux and iii) loss of endothelial resistance. In vivo, Calprotectin blockade robustly inhibited the short and long-term systemic and vascular inflammatory consequences of peritonitis, demonstrating that specific targeting of Calprotectin is a promising therapeutic strategy to reduce chronic inflammation, and ultimately to lower CV risk, following an infection episode.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 18 September 2023
Last Modified: 20 Sep 2023 14:04

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