Abstract
IntroductionUric 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.MethodsUric 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.ResultsUric 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.ConclusionsLocal uric acid levels increase in patients with ALI. In mice, allopurinol and uricase attenuate ventilator-induced alveolar barrier dysfunction.
Highlights
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
Uric Acid Levels in bronchoalveolar lavage fluid (BALF) of acute lung injury (ALI) Patients Baseline characteristics of cardiac surgery patients developing transfusion-related ALI and their controls were described in detail previously [14] and are demonstrated in Data S2
Patients with lung injury had significantly higher uric acid levels in BALF when compared to patients without ALI
Summary
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. In the last decade it became clear that injured tissue releases endogenous danger molecules, referred to as damageassociated molecular patterns (DAMPs) or alarmins, which trigger the same immune receptors and initiate inflammation in the absence of infection [6]. In a more recent study we showed that VILI is mediated by NLRP3 inflammasome activation [10] Since these experiments were performed in uninfected animals it is thought that pattern recognition receptors are activated by exposure to endogenous danger molecules. Studies demonstrated that DAMPs are released as a consequence of (injurious) MV [11]
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