title: C1-esterase inhibitor attenuates the inflammatory response during human endotoxemia.
abstract: OBJECTIVE
  Besides its role in regulation of the complement and contact system, C1-esterase inhibitor has other immunomodulating effects that could prove beneficial in patients with acute inflammation such as during sepsis or after trauma. We examined the immunomodulating properties of C1-esterase inhibitor during human experimental endotoxemia, in which the innate immune system is activated in the absence of activation of the classic complement pathway.
  
  
  METHODS
  Double-blind placebo-controlled study.
  
  
  METHODS
  Research intensive care unit of the Radboud University Nijmegen Medical Centre.
  
  
  METHODS
  Twenty healthy volunteers.
  
  
  METHODS
  Intravenous injection of 2 ng/kg Escherichia coli lipopolysaccharide. Thirty minutes thereafter (to prevent binding of lipopolysaccharide), C1-esterase inhibitor concentrate (100 U/kg, n = 10) or placebo (n = 10) was infused.
  
  
  RESULTS
  Pro- and anti-inflammatory mediators, markers of endothelial and complement activation, hemodynamics, body temperature, and symptoms were measured. C1-esterase inhibitor reduced the release of proinflammatory cytokines as well as C-reactive protein (peak levels of: interleukin-6 1521 ± 209 vs. 932 ± 174 pg/mL [p = .04], tumor necrosis factor-α 1213 ± 187 vs. 827 ± 167 pg/mL [p = .10], monocyte chemotactic protein-1 6161 ± 1302 vs. 3373 ± 228 pg/mL [p = .03], interleukin-1β 34 ± 5 vs. 23 ± 2 pg/mL [p < .01], C-reactive protein 39 ± 4 vs. 29 ± 2 mg/L [p = .02]). In contrast, release of the anti-inflammatory cytokine interleukin-10 was increased by C1-esterase inhibitor (peak level 73 ± 11 vs. 121 ± 18 pg/mL, p = .02). The increase in interleukin-1 receptor antagonist tended to be smaller in the C1-esterase inhibitor group, but this effect did not reach statistical significance (p = .07). Markers for endothelial activation were increased after lipopolysaccharide infusion, but no significant differences between groups were observed. The lipopolysaccharide-induced changes in heart rate, blood pressure, body temperature, and symptoms (all p < .001 over time) were not influenced by C1-esterase inhibitor. Complement fragment C4 was not increased after lipopolysaccharide challenge.
  
  
  CONCLUSIONS
  This study is the first to demonstrate that C1-esterase inhibitor exerts anti-inflammatory effects in the absence of classic complement activation in humans.
authors.affiliation: Department of Intensive Care Medicine, Radboud University Nijmegen Medical Centre, The Netherlands.
authors.forename: Mirrin J
authors.initials: MJ
authors.lastname: Dorresteijn
authors.forename: Tjaakje
authors.initials: T
authors.lastname: Visser
authors.forename: Laura A E
authors.initials: LA
authors.lastname: Cox
authors.forename: Martijn P
authors.initials: MP
authors.lastname: Bouw
authors.forename: Janesh
authors.initials: J
authors.lastname: Pillay
authors.forename: Anky H L
authors.initials: AH
authors.lastname: Koenderman
authors.forename: Paul F W
authors.initials: PF
authors.lastname: Strengers
authors.forename: Luke P H
authors.initials: LP
authors.lastname: Leenen
authors.forename: Johannes G
authors.initials: JG
authors.lastname: van der Hoeven
authors.forename: Leo
authors.initials: L
authors.lastname: Koenderman
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
mesh_terms: D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D002097:C-Reactive Protein / Q000032:analysis; D050718:Complement C1 Inhibitor Protein / Q000627:therapeutic use*; D003181:Complement C4 / Q000032:analysis; D051056:Complement Inactivating Agents / Q000627:therapeutic use*; D004311:Double-Blind Method; D019446:Endotoxemia / Q000188:drug therapy* / Q000503:physiopathology; D004731:Endotoxins / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D053583:Interleukin-1beta / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D055815:Young Adult
chemical_list: D050718:Complement C1 Inhibitor Protein; D003181:Complement C4; D051056:Complement Inactivating Agents; D004731:Endotoxins; D053583:Interleukin-1beta; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; C044101:endotoxin, Escherichia coli; D002097:C-Reactive Protein