title: Neutrophil-independent mechanisms of caspase-1- and IL-18-mediated ischemic acute tubular necrosis in mice.
abstract: Having recently described the injurious role of caspase-1-mediated production of the proinflammatory cytokine IL-18 in ischemic acute renal failure (ARF), we report here on the effect of the newly developed caspase inhibitor Quinoline-Val-Asp(Ome)-CH(2)-OPH (OPH-001) on caspase-1, IL-18, neutrophil infiltration, and renal function in ischemic ARF. C57BL/6 mice with ischemic ARF treated with OPH-001 had a marked (100%) reduction in blood urea nitrogen (BUN) and serum creatinine and a highly significant reduction in morphological acute tubular necrosis (ATN) score compared with vehicle-treated mice. OPH-001 significantly reduced the increase in caspase-1 activity and IL-18 and prevented neutrophil infiltration in the kidney during ischemic ARF. To evaluate whether this lack of neutrophil infiltration was contributing to the protection against ischemic ARF, a model of neutrophil depletion was developed. Neutrophil-depleted mice had a small (18%) reduction in serum creatinine during ischemic ARF but no reduction in ATN score despite a lack of neutrophil infiltration in the kidney. Remarkably, caspase-1 activity and IL-18 were significantly increased in the kidney in neutrophil-depleted mice with ARF. In addition, IL-18 antiserum-treated neutrophil-depleted mice with ischemic ARF had a significant (75%) reduction in serum creatinine and a significant reduction in ATN score compared with vehicle-treated neutrophil-depleted mice. These results suggest a novel neutrophil-independent mechanism of IL-18-mediated ischemic ARF.
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, 4200 East 9th Avenue, Denver, Colorado 80262, USA.
authors.forename: Vyacheslav Y
authors.initials: VY
authors.lastname: Melnikov
authors.forename: Sarah
authors.initials: S
authors.lastname: Faubel
authors.forename: Britta
authors.initials: B
authors.lastname: Siegmund
authors.forename: M Scott
authors.initials: MS
authors.lastname: Lucia
authors.forename: Danica
authors.initials: D
authors.lastname: Ljubanovic
authors.forename: Charles L
authors.initials: CL
authors.lastname: Edelstein
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D020170:Caspase 1 / Q000378:metabolism*; D053148:Caspase 3; D061945:Caspase Inhibitors; D003404:Creatinine / Q000097:blood; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007668:Kidney / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D007683:Kidney Tubular Necrosis, Acute / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D007687:Kidney Tubules, Proximal / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D011804:Quinolines / Q000494:pharmacology
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000906:Antibodies; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D018836:Inflammation Mediators; D020382:Interleukin-18; D011804:Quinolines; C468548:quinoline-val-asp(OMe)-CH2-OPH; D003404:Creatinine; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020170:Caspase 1