BackgroundThe efficacy of sivelestat in the treatment of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) has not been established. In part, this is due to the wide variety of factors involved in the etiology of ALI/ARDS. In this study, we examined the efficacy of sivelestat in patients with ALI/ARDS associated with abdominal sepsis.MethodsThe subjects were 49 patients with ALI/ARDS after surgery for abdominal sepsis. The efficacy of sivelestat was retrospectively assessed in two treatment groups, ie, a sivelestat group (n = 34) and a non-sivelestat group (n = 15).ResultsThe sivelestat group showed significant improvements in oxygenation, thrombocytopenia, and multiple organ dysfunction score. The number of ventilator days (6.6 ± 6.1 versus 11.1 ± 8.4 days; P = 0.034) and length of stay in the intensive care unit (8.5 ± 6.2 versus 13.3 ± 9.5 days; P = 0.036) were significantly lower in the sivelestat group. The hospital mortality rate decreased by half in the sivelestat group, but was not significantly different between the two groups.ConclusionAdministration of sivelestat to patients with ALI/ARDS following surgery for abdominal sepsis resulted in early improvements of oxygenation and multiple organ dysfunction score, early ventilator weaning, and early discharge from the intensive care unit.

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The prostaglandin (PG) E2 receptor subtype EP4 has been found to mediate regulation of inflammatory cytokines in macrophages and neutrophils in vitro by PGE2. Yet the role of EP4 receptors in endotoxin shock in vivo and whether EP4 activation is a beneficial treatment are not clear. We tested the effect of an EP4 agonist on hemodynamic changes and production of inflammatory cytokines in a rat endotoxin-induced shock model. In rats under pentobarbital anesthesia, lipopolysaccharide (LPS) was injected, and an EP4 agonist (ONO-AE1-329) was administered at one of three concentrations (1, 3, or 10 microg/kg bolus i.v. hourly). Mean arterial pressure (MAP) was monitored throughout the experiment, and pressor responses to norepinephrine were determined 6 h after LPS injection. Serum tumor necrosis factor (TNF)-alpha and serum interleukin (IL)-6 were measured 1 h and 6 h after LPS injection. Venous nitrosyl hemoglobin (NO-Hb) concentration was measured by electron spin resonance. Expression of mRNAs encoding TNF-alpha and inducible nitric oxide synthase (iNOS) in the left ventricle and descending aorta was determined with a real-time reverse transcription polymerase chain reaction. As time progressed, LPS significantly depressed MAP and decreased reactivity to norepinephrine. Infusion of higher doses of the EP4 agonist at 3 and 10 microg/kg/h attenuated LPS-induced hypotension and hyporeactivity to norepinephrine. LPS significantly increased serum concentrations of TNF-alpha and IL-6, and higher doses of EP4 agonist significantly attenuated these increases. Left ventricular and aortic expression of mRNAs encoding TNF-alpha and iNOS was increased by LPS; again, EP4 agonist at higher doses attenuated the increases. LPS-induced production of inflammatory mediators and cardiovascular depression were attenuated by EP4 agonist administration in an in vivo endotoxin shock model. Anti-inflammatory effects thus would be involved in protection by EP4 agonist against cardiovascular depression in endotoxin shock.

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