title: Effects of intra-abdominal sepsis on atherosclerosis in mice.
abstract: BACKGROUND
  Sepsis 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  ApoE-/- 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).
  
  
  CONCLUSIONS
  Using 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.
authors.forename: Ata Murat
authors.initials: AM
authors.lastname: Kaynar
authors.forename: Sachin
authors.initials: S
authors.lastname: Yende
authors.forename: Lin
authors.initials: L
authors.lastname: Zhu
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Frederick
authors.forename: Robin
authors.initials: R
authors.lastname: Chambers
authors.forename: Christine L
authors.initials: CL
authors.lastname: Burton
authors.forename: Melinda
authors.initials: M
authors.lastname: Carter
authors.forename: Donna Beer
authors.initials: DB
authors.lastname: Stolz
authors.forename: Brittani
authors.initials: B
authors.lastname: Agostini
authors.forename: Alyssa D
authors.initials: AD
authors.lastname: Gregory
authors.forename: Shanmugam
authors.initials: S
authors.lastname: Nagarajan
authors.forename: Steven D
authors.initials: SD
authors.lastname: Shapiro
authors.forename: Derek C
authors.initials: DC
authors.lastname: Angus
mesh_terms: D000005:Abdomen; D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000473:pathology; D015415:Biomarkers / Q000097:blood; D015815:Cell Adhesion Molecules / Q000378:metabolism; D016207:Cytokines / Q000097:blood / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression; D008297:Male; D008810:Mice, Inbred C57BL; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D018805:Sepsis / Q000097:blood / Q000150:complications*; D015431:Weight Loss
chemical_list: D015415:Biomarkers; D015815:Cell Adhesion Molecules; D016207:Cytokines; D012333:RNA, Messenger