AM protected against hepatic and intestinal injury in VILI driven sepsis. These findings support previous studies in which AM protected from liver or gut injury in staphylococcal toxin induced shock, in polymicrobial sepsis or in gut ischemia and reperfusion. Again, in the majority of studies tissue protective order inhibitor effects of AM have been attributed to anti inflammatory properties, whereas anti inflammatory effects of AM where not detected in the current study. Apoptosis may be crucial for the development of organ failure in sepsis, and AM holds anti apoptotic properties. However, whether protection from apoptosis observed here and elsewhere is mechanism or consequence of other yet unknown underlying AM functions remains unclear.

The lower hematocrit in AM treated mice currently observed indicated Inhibitors,Modulators,Libraries intravascular plasma conservation due to systemic vascular barrier protection by AM, confirming previous studies demonstrating barrier protection in liver, ileum and kidney as central beneficial mechanism Inhibitors,Modulators,Libraries of AM in shock. Taken together, AM protected against hepatic and intestinal injury Inhibitors,Modulators,Libraries accompanied by anti apoptotic and barrier protective effects without modulating hyperinflammation in pneumonia associated VILI driven sepsis. Further Inhibitors,Modulators,Libraries characterization of this potent protective AM function downstream of injurious hyperinflammation warrants further investigation. One limitation of this study was that AM treatment could not be investigated in non ventilated mice as this requires vascular catheterization for continuous infusion due to the very short half life of AM.

This is not feasible in awake mice and anesthesia in spontaneously breathing mice placed in supine position Inhibitors,Modulators,Libraries for instrumentation likely results in hypoventilation thereby provoking major bias to the sensitive readout performed here. Conclusion In conclusion, this study provides evidence that MV with moderate tidal volumes aggravates lung injury and promotes progression of sepsis and multiple Z-VAD-FMK manufacturer organ failure in pneumococcal pneumonia. Exogenous AM, which has gained orphan drug status by the EMA for treatment of ARDS recently, protected against MV induced lung injury and sepsis related organ failure without suppression of the host immune response. These data further encourage current efforts to evaluate AM as adjuvant therapy for VILI in addition to protective ventilation strategies and for sepsis related organ failure in clinical trials. Key messages In mice with pneumococcal pneumonia, mechanical ventilation evoked lung injury and lead to the development of sepsis with multiple organ injury independent from bacterial translocation. Adrenomedullin infusion protected against lung injury and extrapulmonary organ failure in this condition.