Reduction of Renal Ischemia-Reperfusion Injury in 5-Lipoxygenase Knockout Mice and by the 5-Lipoxygenase Inhibitor Zileuton

Abstract

The role of 5-lipoxygenase (5-LOX) in the pathophysiology of renal ischemia/reperfusion (I/R) injury is not known. Here we investigate the effects of 1) the 5-LOX inhibitor zileuton and 2) 5-LOX gene knockout (5-LOX Ϫ/Ϫ ) mice on renal dysfunction and injury caused by I/R of the kidney in mice. Wild-type mice treated with zileuton (3 mg/kg i.v.) or 5-LOX Ϫ/Ϫ mice were subjected to bilateral renal artery occlusion (30 min) followed by reperfusion (24 h). Plasma urea, creatinine, and aspartate aminotransferase (AST) were measured as markers of renal dysfunction and reperfusion injury. Kidneys were used for histological evaluation of renal injury. Renal myeloperoxidase activity was measured and used as an indicator of polymorphonuclear leukocyte (PMN) infiltration and renal expression of intercellular adhesion molecule-1 (ICAM-1) was determined using immunohistochemistry. Administration of zileuton before I/R significantly reduced the degree of renal dysfunction (urea, creatinine) and injury (AST, histology). In addition, zileuton reduced the expression of ICAM-1 and the associated PMN infiltration caused by I/R of the mouse kidney. Compared with wild-type mice, the degree of renal dysfunction, injury, and inflammation caused by I/R in 5-LOX Ϫ/Ϫ mice was also significantly reduced, confirming the pathophysiological role of 5-LOX in the development of renal I/R injury. We propose that 1) endogenous 5-LOX metabolites enhance the degree of renal injury, dysfunction, and inflammation caused by I/R of the kidney by promoting the expression of adhesion molecules, and 2) inhibitors of 5-LOX may be useful in the treatment of conditions associated with I/R of the kidney.

Zileuton Reduces Inflammatory Reaction and Brain Damage Following Permanent Cerebral Ischemia in Rats

“…5-LOX, a key enzyme in LT biosynthesis, is implicated in several inflammationassociated diseases [17], including acute ischemic stroke [7]. Zileuton, a selective 5-LOX inhibitor, possesses the anti-inflammatory property and exerts an inhibitory effect on the inflammatory diseases [18,19]. Our previous study showed that zileuton reduces cerebral infarct volume and brain edema 24 h after the onset of ischemia in rats [13].…”

Mice Lacking the 110-kD Isoform of Poly(ADP-Ribose) Glycohydrolase Are Protected against Renal Ischemia/Reperfusion Injury

“…There is some evidence that both the MPO and naphthol-AS-D-chloracetate esterase assays can cross-react with monocytes and macrophages (23). We recently demonstrated, however, that PMN counts from histologic sections and MPO activity correlate positively (24). Kidneys were homogenized in a solution that contained 0.5% hexa-decyl-trimethyl-ammonium bromide and 10 mM 3-(N-morpholino)-propane-sulfonic acid dissolved in 80 mM sodium phosphate buffer (pH 7) and centrifuged for 30 min at 20,000 ϫ g at 4°C.…”

Leukotrienes: Mediators that have been typecast as villains

“…The 5-LO -/-mice provided evidence that LTs contributed to inflammatory diseases, including zymosaninduced peritonitis [58], collagen-and autoantibodyinduced arthritis [59,60], pulmonary inflammation induced by IL-13 [61], and cerulein-induced pancreatitis [62]. Additionally, the 5-LO-deficient mice indicated that LTs were involved in the development of hypoxia-induced chronic pulmonary hypertension [63], airway hyperresponsiveness [64], lupus [65], allograft rejection [66], bleomycin-induced pulmonary fibrosis [67], and ischemia-reperfusion injuries [68,69].…”