title: Mesenteric ischemia-reperfusion injury up-regulates certain CC, CXC, and XC chemokines and results in multi-organ injury in a time-dependent manner.
abstract: BACKGROUND
  Trauma patients who develop multi-organ dysfunction have increased systemic levels of chemotactic cytokines. Ischemia-reperfusion (IR) injury to the gut may play a role. The purpose of this study was to examine chemokine production in a mouse model of mesenteric IR injury. Given the pre-eminent role of the neutrophil, there has been much investigation of the CXC chemokines, but very limited research on the CC and XC chemokines. We hypothesized that intestinal IR injury would induce remote organ injury and enhance serum CC and XC chemokine levels.
  
  
  METHODS
  Fasted female C57BL6 mice were anesthetized prior to laparotomy. In IR animals, the superior mesenteric artery (SMA) was occluded for 30, 45, or 75 min, while controls underwent sham laparotomy, n = 5-7 per group. After the indicated time point, the incision was closed and the mouse was allowed to recover for six hours. Following euthanasia, serum levels of 15 chemokines (10 CC, 4 CXC, and 1 XC) were assessed and histopathologic analyses performed.
  
  
  RESULTS
  Seventy-five minutes of SMA occlusion was the key time frame for significant serum cytokine level up-regulation, intestinal and remote organ injury, and neutrophil influx into tissues. With 75 min of intestinal ischemia, significantly elevated serum levels, as compared to shams, were noted for seven CC chemokines: MCP-1, MCP-3, MIP-1β, MIP-3β, eotaxin, MDC, and RANTES. Levels of the XC chemokine lymphotactin also increased. Levels of MIP-2, IP-10, and KC/GRO (CXC chemokines) rose significantly. MIP-1α levels were only significantly increased at 45 min IR. We did not find any significant IR injury-induced changes in levels of MCP-5, MIP-1γ, or GCP-2, at any ischemia time frame. Serum levels of IL-6 correspondingly increased significantly with longer ischemia times.
  
  
  CONCLUSIONS
  The novel finding of this study is the demonstration of significant systemic increases in the CC chemokines eotaxin, MCP-3, MDC, MIP-3β in a time-dependent manner, along with tissue injury. The data suggest a complex response to IR injury whereby chemokines that are active on a variety of leukocytes may play a role in inducing local and remote tissue injury.
authors.affiliation: Department of Surgery, Stony Brook University School of Medicine, Stony Brook, NY 11794-8191.
authors.forename: Randeep S
authors.initials: RS
authors.lastname: Jawa
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Erin
authors.initials: E
authors.lastname: Quist
authors.affiliation: School of Allied Health Professions, AH Research, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Boyer
authors.affiliation: College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198.
authors.forename: Valerie K
authors.initials: VK
authors.lastname: Shostrom
authors.affiliation: Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-3280.
authors.forename: David W
authors.initials: DW
authors.lastname: Mercer
mesh_terms: D000818:Animals; D019742:Chemokines, CC / Q000097:blood*; D019743:Chemokines, CXC / Q000097:blood*; D005260:Female; D007422:Intestines / Q000098:blood supply / Q000473:pathology*; D017538:Mesenteric Artery, Superior / Q000473:pathology*; D008643:Mesentery / Q000098:blood supply / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D009504:Neutrophils; D015427:Reperfusion Injury / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D019742:Chemokines, CC; D019743:Chemokines, CXC
keywords: chemokine; cytokine; ischemia; ischemia-reperfusion; reperfusion