title: The xanthine oxidase inhibitor Febuxostat reduces tissue uric acid content and inhibits injury-induced inflammation in the liver and lung.
abstract: Necrotic cell death in vivo induces a robust neutrophilic inflammatory response and the resulting inflammation can cause further tissue damage and disease. Dying cells induce this inflammation by releasing pro-inflammatory intracellular components, one of which is uric acid. Cells contain high levels of intracellular uric acid, which is produced when purines are oxidized by the enzyme xanthine oxidase. Here we test whether a non-nucleoside xanthine oxidase inhibitor, Febuxostat (FBX), can reduce intracellular uric acid levels and inhibit cell death-induced inflammation in two different murine tissue injury models; acid-induced acute lung injury and acetaminophen liver injury. Infiltration of inflammatory cells induced by acid injection into lungs or peritoneal administration of acetaminophen was evaluated by quantification with flow cytometry and tissue myeloperoxidase activity in the presence or absence of FBX treatment. Uric acid levels in serum and tissue were measured before giving the stimuli and during inflammation. The impact of FBX treatment on the peritoneal inflammation caused by the microbial stimulus, zymosan, was also analyzed to see whether FBX had a broad anti-inflammatory effect. We found that FBX reduced uric acid levels in acid-injured lung tissue and inhibited acute pulmonary inflammation triggered by lung injury. Similarly, FBX reduced uric acid levels in the liver and inhibited inflammation in response to acetaminophen-induced hepatic injury. In contrast, FBX did not reduce inflammation to zymosan, and therefore is not acting as a general anti-inflammatory agent. These results point to the potential of using agents like FBX to treat cell death-induced inflammation.
authors.affiliation: Department of Pathology, UMass Medical School, Worcester, MA 01605, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kataoka
authors.affiliation: Department of Pathology, UMass Medical School, Worcester, MA 01605, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Yang
authors.affiliation: Department of Pathology, UMass Medical School, Worcester, MA 01605, USA. Electronic address: Kenneth.rock@umassmed.edu.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Rock
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D000069465:Febuxostat; D005764:Gastroesophageal Reflux / Q000188:drug therapy / Q000503:physiopathology; D006074:Gout Suppressants / Q000008:administration & dosage / Q000627:therapeutic use; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D055370:Lung Injury / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008810:Mice, Inbred C57BL; D009336:Necrosis; D020556:Neutrophil Infiltration / Q000187:drug effects; D010537:Peritoneum / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010538:Peritonitis / Q000097:blood / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D014527:Uric Acid / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D006074:Gout Suppressants; D013844:Thiazoles; D000069465:Febuxostat; D014527:Uric Acid; D014969:Xanthine Oxidase
keywords: Acetaminophen; Acetaminophen: CID 1983; Allopurinol: CID 2094; Febuxostat; Febuxostat: CID 134018; Inflammation; Liver damage; Lung damage; Uric acid