Pre-Treatment with Allopurinol or Uricase Attenuates Barrier Dysfunction but Not Inflammation during Murine Ventilator-Induced Lung Injury

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.

Neutrophil Extracellular Traps Stimulate Proinflammatory Responses in Human Airway Epithelial Cells

“…They also showed that local administration of exogenous UA crystals recapitulates lung inflammation and repair. Local UA levels are also increased in patients with ALI, a syndrome characterized by the accumulation of neutrophils in the lung accompanied by the development of interstitial edema and an intense inflammatory response [23] . In fact, neutrophils rapidly infiltrate the pulmonary parenchyma after hypovolemic shock, intestinal ischemia/reperfusion, or endotoxin administration [8] , while the depletion of neutrophils reduces pulmonary edema and proinflammatory cytokine production after hemorrhage or endotoxemia [56] .…”

“…Considering that both UA and MSU induce NET formation [10,37] , our findings, which indicated that these NET markedly increased the production of proinflammatory cytokine by the airway epithelial cells, suggest that NET could contribute to the exacerbation of lung inflammation, not only upon bleomycin administration but also in ALI. Recent studies reported increased UA levels in lung lavage fluid in a murine ventilator-induced lung injury (VILI) model [23] , and demonstrated that mechanical ventilation, together with LPS instillation, induced NET formation [57] . In this murine model, mechanical ventilation plus LPS was associated with increased airway levels of HMGB-1 and IL-1β, and a tendency to increase the CCL2/MCP-1 and IL-6 concentrations.…”

“…Locally, the concentration of UA can exceed the saturation point in body fluids and precipitate and form MSU [6] . Increased local UA levels are found in different pathologies, among them in patients with ALI [23] . Both UA and MSU have been shown to promote cell-death-induced inflammation [6,21] .…”

Investigating the Role of Nucleotide-Binding Oligomerization Domain–Like Receptors in Bacterial Lung Infection

“…The translational relevance of NLR research is most evident in the novel therapeutic targets it has identified. Caspase-1, IL-1b, and IL-1 receptor antagonists, and the uric acid inhibitors, uricase and allopurinol, have been tested in animal models with varied success in combating deleterious NLR-mediated inflammation (57)(58)(59)(60). The next logical step for NLR research may incorporate environmental stressors (i.e., CS, ventilator support), with bacterial challenge, thus enhancing our understanding of NLRmediated antibacterial immunity within a framework relevant to human disease.…”

Mechanisms of ventilator-induced lung injury in healthy lungs

“…Uric acid is a potent product of catabolism that can act synergistically through the NLRP3 pathway in patients with acute lung injury. In this line, Kuipers et al 41 showed that pretreatment with allopurinol, which blocks uric acid synthesis by inhibiting the enzyme xanthine oxidoreductase, or uricase, which oxidizes uric acid into allantoin and water, did not reduce pulmonary neutrophil influx or pulmonary and plasma cytokine levels. Although both treatment strategies attenuated the lung wet/dry ratio, only allopurinol reduced total protein and IgM levels in BALF and was associated with a clear trend toward lower lung edema scores on histopathology.…”