Editors' ChoiceSepsis

Stirrings in the Graveyard

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Science Translational Medicine  19 Sep 2012:
Vol. 4, Issue 152, pp. 152ec171
DOI: 10.1126/scitranslmed.3004934

Severe sepsis is one of the most common causes of death worldwide and is responsible for health care costs approaching $15 billion per year in the United States alone. Despite the magnitude of the problem, there are no drugs that specifically treat this complex and frequently fatal syndrome beyond antibiotics. In fact, so many putative therapeutics for sepsis have failed in clinical trials that researchers refer to this drug discovery path as a drug-development “graveyard.” Translational scientists have continued to pursue a deeper understanding of the biology of sepsis in humans and animal models, with hopes that new mechanistic knowledge will lead to new therapeutic targets and treatment regimens. In particular, much recent interest has focused on the importance of endothelial permeability in driving the pathogenesis and severity of sepsis. Now, using mouse models and data from human patients, David et al. assess the role of the endothelial cell protein angiopoietin-2 (Angpt-2) in sepsis.

Known to be elevated in humans with severe sepsis, Angpt-2 is released from endothelial cells in the setting of inflammation and mediates increased endothelial permeability in animal models and cell culture. However, many questions about the role of Angpt-2 in human sepsis remain unanswered, including the potential efficacy of inhibiting its function in sepsis treatment. David and colleagues explored the potential of Angpt-2 as a therapeutic target, first by inducing experimental sepsis in mice that were heterozygous for the Angpt-2 allele and thus expressed lower-than-wild-type amounts of the Angpt-2 protein at baseline and after stimulation. The authors found that septic Angpt-2 heterozygotes had lower mortality, less severe end-organ injury, and less severe vascular leakage compared to septic wild-type mice. Moreover, they observed that the injury induced by serum from septic human subjects in cell-culture models of human endothelium was attenuated by simultaneous administration of a monoclonal antibody to human Angpt-2. In humans who went on to develop severe sepsis, the authors reported an elevation in plasma Angpt-2 concentrations on presentation to the emergency department very early in the course of the disease.

Although these findings suggest that Angpt-2 might be a feasible therapeutic target, it is unclear how often the elevation in plasma concentrations of Angpt-2 preceded the development of sepsis-induced organ failure in the patients assessed in the study by David et al. In addition, the optimal approach to Angpt-2 antagonism—for instance, via its physiological antagonist, angiopoietin-1, versus a neutralizing antibody—remains unknown. However, this study adds to the considerable volume of data suggesting that the vascular endothelium may be a useful therapeutic target in severe sepsis. Perhaps there is life after all in the sepsis drug-development graveyard.

S. David et al., Angiopoietin-2 may contribute to multiorgan dysfunction and death in sepsis. Crit. Care Med., published online 10 August 2012 (10.1097/CCM.0b013e31825fdc31). [Abstract]

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