Abstract
IntroductionSepsis and other infections are associated with late cardiovascular events. Although persistent inflammation is implicated, a causal relationship has not been established. We tested whether sepsis causes vascular inflammation and accelerates atherosclerosis.MethodsWe performed prospective, randomized animal studies at a university research laboratory involving adult male ApoE-deficient (ApoE−/−) and young C57B/L6 wild-type (WT) mice. In the primary study conducted to determine whether sepsis accelerates atherosclerosis, we fed ApoE−/− mice (N = 46) an atherogenic diet for 4 months and then performed cecal ligation and puncture (CLP), followed by antibiotic therapy and fluid resuscitation or a sham operation. We followed mice for up to an additional 5 months and assessed atheroma in the descending aorta and root of the aorta. We also exposed 32 young WT mice to CLP or sham operation and followed them for 5 days to determine the effects of sepsis on vascular inflammation.ResultsApoE−/− mice that underwent CLP had reduced activity during the first 14 days (38% reduction compared to sham; P < 0.001) and sustained weight loss compared to the sham-operated mice (−6% versus +9% change in weight after CLP or sham surgery to 5 months; P < 0.001). Despite their weight loss, CLP mice had increased atheroma (46% by 3 months and 41% increase in aortic surface area by 5 months; P = 0.03 and P = 0.004, respectively) with increased macrophage infiltration into atheroma as assessed by immunofluorescence microscopy (0.52 relative fluorescence units (rfu) versus 0.97 rfu; P = 0.04). At 5 months, peritoneal cultures were negative; however, CLP mice had elevated serum levels of interleukin 6 (IL-6) and IL-10 (each at P < 0.05). WT mice that underwent CLP had increased expression of intercellular adhesion molecule 1 in the aortic lumen versus sham at 24 hours (P = 0.01) that persisted at 120 hours (P = 0.006). Inflammatory and adhesion genes (tumor necrosis factor α, chemokine (C-C motif) ligand 2 and vascular cell adhesion molecule 1) and the adhesion assay, a functional measure of endothelial activation, were elevated at 72 hours and 120 hours in mice that underwent CLP versus sham-operations (all at P <0.05).ConclusionsUsing a combination of existing murine models for atherosclerosis and sepsis, we found that CLP, a model of intra-abdominal sepsis, accelerates atheroma development. Accelerated atheroma burden was associated with prolonged systemic, endothelial and intimal inflammation and was not explained by ongoing infection. These findings support observations in humans and demonstrate the feasibility of a long-term follow-up murine model of sepsis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-014-0469-1) contains supplementary material, which is available to authorized users.
Highlights
Sepsis and other infections are associated with late cardiovascular events
To explore aortic inflammation in the early phases of sepsis, we examined protein and mRNA expression of inflammatory markers (MCP-1 and tumor necrosis factor α (TNF-α)) and adhesion molecules (intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1)) and endothelial activation in the aorta on days 1, 3, and 5 after sham or cecal ligation and puncture (CLP) surgery in WT mice
Weight gain remained different up to 5 months, when the CLP group had lost 6% of body weight compared to a 9% gain among the sham-operated mice (P < 0.001)
Summary
Sepsis and other infections are associated with late cardiovascular events. persistent inflammation is implicated, a causal relationship has not been established. We tested whether sepsis causes vascular inflammation and accelerates atherosclerosis. Several studies have suggested a link between acute cardiovascular events (such as cardiac event–related death, acute myocardial infarction and stroke) and prior infection [1,2,3,4]. Ongoing infection in vessel walls was first thought to be the cause of accelerated atherosclerosis, but this link has never been established [4]. We previously demonstrated that human sepsis survivors often have persistent inflammation after the infection has resolved, which is associated with an increased risk of subsequent cardiovascular death [5]. We hypothesized that sepsis may lead to persistent vascular inflammation, which in turn could accelerate the growth or destabilization of atheromatous plaques. We hypothesized that the dysregulated immune response characteristic of sepsis may have a persistent “tail” that accelerates the progression of underlying cardiovascular disease [6]
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