Abstract
Sepsis is a leading cause of death among patients in the intensive care unit, resulting from multi‐organ failure. Activity of xanthine oxidoreductase (XOR), a reactive oxygen species (ROS) producing enzyme, is known to be elevated in nonsurvivors of sepsis compared to survivors. We have previously demonstrated that XOR is critical for ventilator‐induced lung injury. Using febuxostat, a novel nonpurine inhibitor of XOR, we sought to determine the role of XOR inhibition in a murine model of sepsis‐induced lung injury and mortality. C57BL/6J mice were subjected to intravenous (IV) lipopolysaccharide (LPS) for various time points, and lungs were harvested for analyses. Subsets of mice were treated with febuxostat, pre or post LPS exposure, or vehicle. Separate groups of mice were followed up for mortality after LPS exposure. After 24 hr of IV LPS , mice exhibited an increase in XOR activity in lung tissue and a significant increase in pulmonary endothelial barrier disruption. Pretreatment of animals with febuxostat before exposure to LPS, or treatment 4 h after LPS, resulted in complete abrogation of XOR activity. Inhibition of XOR with febuxostat did not prevent LPS‐induced pulmonary vascular permeability at 24 h, however, it accelerated recovery of the pulmonary endothelial barrier integrity in response to LPS exposure. Furthermore, treatment with febuxostat resulted in significant reduction in mortality. Inhibition of XOR with febuxostat accelerates recovery of the pulmonary endothelial barrier and prevents LPS‐induced mortality, whether given before or after exposure to LPS.
Highlights
Sepsis is a devastating illness with an annual incidence of 750,000, representing nearly 10% of all intensive care unit (ICU) admissions with a mortality approaching 30% (Angus and van der Poll 2013)
As sepsis leads to multi-organ failure and eventual death, we sought to create a murine model of sepsis that mimics organ dysfunction and increased mortality
As we sought to create a severe sepsis model that results in lung injury, we chose a dose of 9.5 mg/kg of LPS for subsequent studies
Summary
Sepsis is a devastating illness with an annual incidence of 750,000, representing nearly 10% of all intensive care unit (ICU) admissions with a mortality approaching 30% (Angus and van der Poll 2013). Sepsis constitutes a complex systemic inflammatory response initiated by microbial factors that perpetuate proinflammatory mediators, a key pathophysiological consequence of sepsis leading to endothelial barrier disruption (Angus and van der Poll 2013; Goldenberg et al 2011). Injury to this barrier in any given vital organ leads to extravasation of proteinaceous fluid as well as inflammatory cells from the intravascular space resulting in local tissue hypoxia, organ dysfunction, and organ failure (Angus and van der Poll 2013; Goldenberg et al 2011).
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