Effects of intra-abdominal sepsis on atherosclerosis in mice

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.

IL-33 contributes to sepsis-induced long-term immunosuppression by expanding the regulatory T cell population

“…Severe sepsis was performed in mice using a clinically relevant model of polymicrobial peritonitis induced by caecal ligation and puncture (CLP), which has been used extensively to investigate sepsis12132324252627. BALB/c mice undergoing lethal CLP were treated with antibiotics (Supplementary Fig.…”

Late mortality after sepsis: propensity matched cohort study

“…Mice that recover from experimental sepsis have accelerated development of atherosclerosis,35 they die with subsequent bacterial or fungal challenge,36 37 38 and they show increased tumor growth 39. High rates of infection, cancer, and deaths related to cardiovascular disease have also been seen in studies of humans who survive sepsis 40.…”

Orthopedic surgery increases atherosclerotic lesions and necrotic core area in ApoE−/− mice

“…A few experimental studies addressed the effects of acute systemic inflammation on atherosclerosis. A recent murine model of intra-abdominal sepsis suggested that atherosclerotic plaque area was enhanced by sustained systemic, endothelial and intimal inflammation, and was not explained by infection itself 25 . More specifically, an increase in intra-plaque macrophages was observed 5 months after the induction of sepsis via cecal ligation and puncture.…”