title: Systemic inflammation after aortic cross clamping is influenced by Toll-like receptor 2 preconditioning and deficiency.
abstract: BACKGROUND
  The perioperative morbidity and mortality of abdominal aortic aneurysm repair is linked to systemic inflammation. Important triggers of the latter are Toll-like receptors (TLRs), which play a central role in innate immunity. Ischemia/reperfusion (I/R) injury can be influenced by either TLR stimulation before I/R (preconditioning) or TLR dysfunction (deficiency or polymorphism). The influence of TLR2 stimulation or deficiency on systemic cytokine release and organ damage after aortic cross clamping has not been evaluated yet.
  
  
  METHODS
  Wild type (WT) and TLR2-deficient mice were subjected to 1 h ischemia and 2 or 4 h reperfusion of the infrarenal aorta. One group of WT mice was preconditioned with the synthetic TLR2 agonist Pam(3)Cys-Ser-Lys(4) (Pam(3)CSK(4)). Sham-operated animals without I/R served as controls. Plasma levels of interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, granulocyte macrophage-colony stimulating factor, tumor necrosis factor-α, alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), and creatinine were measured.
  
  
  RESULTS
  I/R injury caused by transient clamping of the infrarenal aorta led to a time-dependent increase of all measured cytokines except IL-4, IL-5, and granulocyte macrophage-colony stimulating factor. This was accompanied by elevated markers of organ damage (ALT, AST, and LDH) except creatinine. Preconditioning with Pam(3)CSK(4) led to lower plasma concentrations of all cytokines, with the exception of anti-inflammatory IL-10 which was significantly upregulated. Furthermore, ALT, AST, and LDH plasma concentrations were lower in the preconditioning group. TLR2-deficient mice similarly showed reduced signs of systemic inflammation and organ damage, although less distinctive. IL-2, IL-6, IL-12, ALT, and LDH were time dependently lower compared with WT mice. IL-10 concentration was higher in TLR2-deficient mice compared with WT.
  
  
  CONCLUSIONS
  Both, preconditioning via TLR2 and TLR2 deficiency, ameliorate systemic inflammation and organ damage during I/R injury caused by clamping of the infrarenal aorta. Compared with untreated WT animals, Pam(3)CSK(4) preconditioned and TLR2-deficient mice showed lower concentrations of pro-inflammatory cytokines, whereas anti-inflammatory IL-10 was elevated in both groups. This was accompanied by reduced organ dysfunction parameters.
authors.affiliation: Clinic of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Frankfurt, Frankfurt, Germany. alexander.koch@kgu.de
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.forename: Michelle
authors.initials: M
authors.lastname: Pernow
authors.forename: Carmen
authors.initials: C
authors.lastname: Barthuber
authors.forename: Jan
authors.initials: J
authors.lastname: Mersmann
authors.forename: Kai
authors.initials: K
authors.lastname: Zacharowski
authors.forename: Dirk
authors.initials: D
authors.lastname: Grotemeyer
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000601:surgery*; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000209:etiology*; D019194:Ischemic Preconditioning; D055666:Lipopeptides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000502:physiology*
chemical_list: D016207:Cytokines; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2