Abstract
Several retrospective studies suggest that prior use of statins can reduce hospital mortality in patients diagnosed with either bacteraemia or sepsis. In an accompanying abstract we demonstrated that pre-treatment with simvastatin prevents LPS-induced hyporesponsiveness of the porcine isolated coronary artery (PCA); an observation consistent with the clinical data. Although this effect of simvastatin is qualitatively similar to that of a known inhibitor of inducible nitric oxide synthase (1400 W), it unlikely that direct inhibition of the enzyme is implicated. We have investigated whether the beneficial effect of simvastatin on LPS-induced changes in the PCA involves alteration in the induction of nitric oxide synthase (iNOS).
Highlights
Lungs play an important role in the body’s defenseMedicine and 4Department of Pathology, Academic Medical against a variety of pathogens, but this network of immune systemCenter, University of Amsterdam, Amsterdam, the Netherlands; mediated defense can be deregulated during acute pulmonaryTropical Medicine, Mahidol University, Bangkok, Thailand; 6Center
This of B. pseudomallei when compared with WT mice, corresponding can be further strengthened by the presence of alternatively with increased pulmonary and hepatic inflammation. uPAR KO activated alveolar macrophages (AAMacs) or foam cells in lungs of mice demonstrated significantly reduced neutrophil migration mice with pneumonia after the third post infection day and their towards the pulmonary compartment after inoculation with number kept on increasing until the seventh post infection day, B. pseudomallei
Additional studies or foam cells were seen in lungs of septic mice on histoshowed that uPAR deficiency did not influence hemostatic and pathological examination, lungs were seen to be infiltrated with fibrinolytic responses during severe melioidosis
Summary
Lungs play an important role in the body’s defenseMedicine and 4Department of Pathology, Academic Medical against a variety of pathogens, but this network of immune systemCenter, University of Amsterdam, Amsterdam, the Netherlands; mediated defense can be deregulated during acute pulmonaryTropical Medicine, Mahidol University, Bangkok, Thailand; 6Center. Conclusions Simvastatin suppressed the induction of nitric oxide caused by LPS and the associated increase in nitrite/nitrate production This finding helps to explain our observation that simvastatin prevented LPS-induced hyporesponsiveness of the coronary artery, and is consistent with clinical studies suggesting that prior use of statins may afford protection against bacterial sepsis. While most animal models of sepsis have studied polymicrobial or Gram-negative sepsis from an abdominal origin in young animals, the most common presentation in the medical ICU is in older individuals (median age 64 years), with Gram-positive bacteria (predominantly Staphylococcus aureus) infection in the lung. High mobility group box 1 (HMGB1) is a pleiotropic cytokine, implicated in the pathophysiology of sepsis This alarmin, usually located in the nucleus, is released after tissue injury and activates various innate immunity receptors, leading to sustained inflammatory response. Several studies suggest independent functioning of S100A9, making it an interesting candidate biomarker in septic syndromes
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