title: Modulation of chemokine gradients by apheresis redirects leukocyte trafficking to different compartments during sepsis, studies in a rat model.
abstract: BACKGROUND
  Prior work suggests that leukocyte trafficking is determined by local chemokine gradients between the nidus of infection and the plasma. We recently demonstrated that therapeutic apheresis can alter immune mediator concentrations in the plasma, protect against organ injury, and improve survival. Here we aimed to determine whether the removal of chemokines from the plasma by apheresis in experimental peritonitis changes chemokine gradients and subsequently enhances leukocyte localization into the infected compartment, and away from healthy tissues.
  
  
  METHODS
  In total, 76 male adult Sprague-Dawley rats weighing 400 g to 600 g were included in this study. Eighteen hours after inducing sepsis by cecal ligation and puncture, we randomized these rats to apheresis or sham treatment for 4 hours. Cytokines, chemokines, and leukocyte counts from blood, peritoneal cavity, and lung were measured. In a separate experiment, we labeled neutrophils from septic donor animals and injected them into either apheresis or sham-treated animals. All numeric data with normal distributions were compared with one-way analysis of variance, and numeric data not normally distributed were compared with the Mann-Whitney U test.
  
  
  RESULTS
  Apheresis significantly removed plasma cytokines and chemokines, increased peritoneal fluid-to-blood chemokine (C-X-C motif ligand 1, ligand 2, and C-C motif ligand 2) ratios, and decreased bronchoalveolar lavage fluid-to-blood chemokine ratios, resulting in enhanced leukocyte recruitment into the peritoneal cavity and improved bacterial clearance, but decreased recruitment into the lung. Apheresis also reduced myeloperoxidase activity and histologic injury in the lung, liver, and kidney. These Labeled donor neutrophils exhibited decreased localization in the lung when infused into apheresis-treated animals.
  
  
  CONCLUSIONS
  Our results support the concept of chemokine gradient control of leukocyte trafficking and demonstrate the efficacy of apheresis to target this mechanism and reduce leukocyte infiltration into the lung.
authors.forename: Zhi-Yong
authors.initials: ZY
authors.lastname: Peng
authors.forename: Jeffery V
authors.initials: JV
authors.lastname: Bishop
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wen
authors.forename: Michele M
authors.initials: MM
authors.lastname: Elder
authors.forename: Feihu
authors.initials: F
authors.lastname: Zhou
authors.forename: Anan
authors.initials: A
authors.lastname: Chuasuwan
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: Carter
authors.forename: Jason E
authors.initials: JE
authors.lastname: Devlin
authors.forename: A Murat
authors.initials: AM
authors.lastname: Kaynar
authors.forename: Kai
authors.initials: K
authors.lastname: Singbartl
authors.forename: Francis
authors.initials: F
authors.lastname: Pike
authors.forename: Robert S
authors.initials: RS
authors.lastname: Parker
authors.forename: Gilles
authors.initials: G
authors.lastname: Clermont
authors.forename: William J
authors.initials: WJ
authors.lastname: Federspiel
authors.forename: John A
authors.initials: JA
authors.lastname: Kellum
mesh_terms: D000818:Animals; D001781:Blood Component Removal / Q000379:methods*; D018925:Chemokines / Q000097:blood / Q000378:metabolism*; D004195:Disease Models, Animal; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D010529:Peritoneal Cavity / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000097:blood / Q000378:metabolism*; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D018925:Chemokines