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The review by Looney and Matthay summarized recent progress in basic and preclinical research of activated protein C (APC), a novel therapeutic agent for the treatment of severe sepsis [1]. APC is traditionally an anticoagulant and profibrinolytic agent, and has been appreciated to possess anti-inflammatory and anti-apoptotic properties, yet the exact mechanisms by which APC executes its clinical effects in sepsis are not defined [2]. Emerging evidence has suggested that APC might exert its clinical benefit, at least in part, by maintaining endothelial barrier function [3,4]. The authors reviewed conflicting results of endothelial barrier protection of APC in the literature and pointed out that caution must be taken to interpret cell culture experiments and their relationship to in vivo conditions. Indeed, one should exercise caution while reviewing controversial data.  Looney and Matthay stated that 'in two different in vitro investigations [3,4], APC promoted endothelial barrier protection in a PAR-1- and S1P1-dependent mechanism', which represents a misinterpretation. These two papers did conclude that APC enhanced endothelial barrier function in different cell lines by a sphingosine 1-phosphate receptor-1 (S1P1)-dependent signaling pathway, but it is still arguable whether this is protease activated receptor-1 (PAR-1) dependent. Finigan and colleagues showed that anti-PAR-1 blocking antibody did not interfere with either APC-mediated myosin light-chain phosphorylation or S1P1 receptor phosphorylation/activation, and concluded that it was endothelial protein C receptor (EPCR) ligation with APC and the resulting S1P1 transactivation that led toendothelial cell cytoskeletal rearrangement and barrier protection [4]. There is therefore no evidence so far to support the notion that the 'APC ... effect on endothelial cytoskeletal rearrangement ... appears to operate in a PAR-1- ... dependent manner' [1].

To be or not to be protease activated receptor-1 in activated protein C-initiated endothelial barrier protection?