Reduction of activated macrophages after ischaemiareperfusion injury diminishes oxidative stress and ameliorates renal damage
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 (FcR) 1 in the activated state of macrophages is poorly defined. We induced a LIRS via 30 min of ischaemia in uninephrectomized rats, transgenic for the human FcR1. Six hours after reperfusion, the treatment group was injected with a recombinant immunotoxin (IT) H22(scFv)-ETA targeted against human FcR1, 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. 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 mol/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. Reduction of FcR1-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.