title: Reduction of activated macrophages after ischaemia-reperfusion injury diminishes oxidative stress and ameliorates renal damage.
abstract: BACKGROUND
  Macrophages are major effectors of the local inflammatory response syndrome (LIRS) and influence the extent of ischaemia/reperfusion injury, thereby impacting organ function. Several subgroups of macrophages exist, representing distinct modes of action. The specific role of the subset expressing Fc gamma receptor (FcγR) 1 in the activated state of macrophages is poorly defined.
  
  
  METHODS
  We induced a LIRS via 30 min of ischaemia in uninephrectomized rats, transgenic for the human FcγR1. Six hours after reperfusion, the treatment group was injected with a recombinant immunotoxin (IT) H22(scFv)-ETA' targeted against human FcγR1, which induced apoptosis of target cells. The placebo group received normal saline (NS). Contralateral kidneys served as healthy controls (Ctr). After 24 h of reperfusion, the animals were analysed.
  
  
  RESULTS
  Targeted treatment with IT resulted in preserved renal function [NS versus IT treatment and baseline (creatinine: 69.2 ± 2.6, 54.7 ± 3.4 and 27.3 ± 1.0 μmol/L; P < 0.001)]. The number of all infiltrating monocytes were significantly reduced (CD68-positive cells per view field: NS 3.8 ± 0.4, IT 2.5 ± 0.2 and Ctr 1.2 ± 0.4; P < 0.05), renal histology improved and there was a reduced expression of renal fibronectin (NS 4.0 ± 0.4, IT 2.3 ± 0.2 and Ctr 1.1 ± 0.1; P < 0.001). Following IT administration, we also observed less expression of renal monocyte chemoattractant protein-1-positive cells per view field (NS 19.0 ± 1, IT 10.1 ± 0.8 and Ctr 2.0 ± 0.3; P < 0.001) as well as reduced systemic and local oxidative stress [serum malondialdehyde (MDA): NS 340 ± 30, IT 224 ± 36 versus baseline 140 ± 5 nmol/mL; P < 0.01]; renal MDA arbitrary units of fluorescence intensity: NS 3.7 ± 0.2, IT 1.8 ± 0.3 and Ctr 0.4 ± 0.2; P < 0.001.
  
  
  CONCLUSIONS
  Reduction of FcγR1-up-regulated monocytic cells leads to preserved renal function and morphology in a rat model of ischaemia-triggered LIRS. Our results show that targeting activated macrophages is a valuable approach for ameliorating ischaemia-induced tissue injury.
authors.affiliation: Department of Surgery, RWTH Aachen, Aachen, Germany.
authors.forename: Ngwi G
authors.initials: NG
authors.lastname: Fet
authors.forename: Anette
authors.initials: A
authors.lastname: Fiebeler
authors.forename: Uwe
authors.initials: U
authors.lastname: Klinge
authors.forename: Joon-Keun
authors.initials: JK
authors.lastname: Park
authors.forename: Stefan
authors.initials: S
authors.lastname: Barth
authors.forename: Theo
authors.initials: T
authors.lastname: Thepen
authors.forename: René H
authors.initials: RH
authors.lastname: Tolba
mesh_terms: D058186:Acute Kidney Injury / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D056704:Adaptive Immunity; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D000922:Immunotoxins / Q000627:therapeutic use; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; C489017:FCGR1A protein, human; D000922:Immunotoxins; D017452:Receptors, IgG