Background: Sepsis with multi-organ failure has an unacceptably high mortality rate of 25-30% despite the use of antibiotics and modern intensive care. Attenuating the multi-organ failure and finding new biomarkers for early detection of septic shock would be of high clinical relevance in order to improve outcome. Aim: The aim of this thesis was to study if inhaled nitric oxide (iNO) in combination with steroids could attenuate multi-organ failure in a porcine model of endotoxemia. We further aimed to investigate the dynamics of circulating citrullinated histone H3 (H3Cit), a recently proposed biomarker in sepsis, in a human model of endotoxemia. Since microvesicles (MVs) have been shown to be elevated in sepsis, a further objective of this thesis was to investigate whether H3Cit could be detected bound to MVs. Methods: A randomized controlled trial (RCT) with 30 domestic piglets exposed to lipopolysaccharide (LPS)-alone, LPS + iNO, LPS + IV steroid, LPS + iNO + IV steroid or anesthesia only (Control) was conducted in paper I. Various biomarkers were measured at endpoint in order to evaluate organ function after 30 hrs of endotoxic shock. In paper II, an ELISA-based assay quantifying plasma H3Cit was developed and methodologically validated in accordance to recommended ELISA validation requirements. This ELISA, as well as a flow cytometric assay quantifying MV-bound H3Cit, was used in plasma samples at baseline and then 2, 4 and 7 hrs after LPS-injection in a placebo controlled RCT including 22 healthy volunteers in Paper III. Results: LPS + iNO+ IV steroid tended to require less norepinephrine and were significantly less acidotic (p < 0.05) compared to LPS-only in the porcine model of endotoxemia. No significant differences could, however, be detected in other clinical variables. Circulating H3Cit, quantified by the ELISA assay, which was validated with high specificity, precision and stability, rose significantly after LPS injection in the human model of endotoxemia. Similar elevations were seen when ...