title: Pre-treatment with allopurinol or uricase attenuates barrier dysfunction but not inflammation during murine ventilator-induced lung injury.
abstract: BACKGROUND
  Uric acid released from injured tissue is considered a major endogenous danger signal and local instillation of uric acid crystals induces acute lung inflammation via activation of the NLRP3 inflammasome. Ventilator-induced lung injury (VILI) is mediated by the NLRP3 inflammasome and increased uric acid levels in lung lavage fluid are reported. We studied levels in human lung injury and the contribution of uric acid in experimental VILI.
  
  
  METHODS
  Uric acid levels in lung lavage fluid of patients with acute lung injury (ALI) were determined. In a different cohort of cardiac surgery patients, uric acid levels were correlated with pulmonary leakage index. In a mouse model of VILI the effect of allopurinol (inhibits uric acid synthesis) and uricase (degrades uric acid) pre-treatment on neutrophil influx, up-regulation of adhesion molecules, pulmonary and systemic cytokine levels, lung pathology, and regulation of receptors involved in the recognition of uric acid was studied. In addition, total protein and immunoglobulin M in lung lavage fluid and pulmonary wet/dry ratios were measured as markers of alveolar barrier dysfunction.
  
  
  RESULTS
  Uric acid levels increased in ALI patients. In cardiac surgery patients, elevated levels correlated significantly with the pulmonary leakage index. Allopurinol or uricase treatment did not reduce ventilator-induced inflammation, IκB-α degradation, or up-regulation of NLRP3, Toll-like receptor 2, and Toll-like receptor 4 gene expression in mice. Alveolar barrier dysfunction was attenuated which was most pronounced in mice pre-treated with allopurinol: both treatment strategies reduced wet/dry ratio, allopurinol also lowered total protein and immunoglobulin M levels.
  
  
  CONCLUSIONS
  Local uric acid levels increase in patients with ALI. In mice, allopurinol and uricase attenuate ventilator-induced alveolar barrier dysfunction.
authors.affiliation: Laboratory of Experimental Intensive Care and Anesthesiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Ilse.Kuipers@amc.nl
authors.forename: Maria T
authors.initials: MT
authors.lastname: Kuipers
authors.forename: Hamid
authors.initials: H
authors.lastname: Aslami
authors.forename: Alexander P J
authors.initials: AP
authors.lastname: Vlaar
authors.forename: Nicole P
authors.initials: NP
authors.lastname: Juffermans
authors.forename: Anita M
authors.initials: AM
authors.lastname: Tuip-de Boer
authors.forename: Maria A
authors.initials: MA
authors.lastname: Hegeman
authors.forename: Geartsje
authors.initials: G
authors.lastname: Jongsma
authors.forename: Joris J T H
authors.initials: JJ
authors.lastname: Roelofs
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: Marcus J
authors.initials: MJ
authors.lastname: Schultz
authors.forename: Catharina W
authors.initials: CW
authors.lastname: Wieland
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism; D000328:Adult; D000493:Allopurinol / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002199:Capillary Permeability / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000503:physiopathology*; D051195:Toll-Like Receptor 2 / Q000235:genetics; D051197:Toll-Like Receptor 4 / Q000235:genetics; D014503:Urate Oxidase / Q000494:pharmacology* / Q000627:therapeutic use; D014527:Uric Acid / Q000378:metabolism; D055397:Ventilator-Induced Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*
chemical_list: D002352:Carrier Proteins; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C000606205:Nfkbia protein, mouse; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000072000:NF-KappaB Inhibitor alpha; D014527:Uric Acid; D000493:Allopurinol; D014503:Urate Oxidase