Angus and colleagues studied serum HMGB1 levels in a subgroup of 122 patients with CAP and observed elevated levels more than a week after presentation with high circulating levels associated with greater mortality [19] . These data differ from Sunden-Cullberg et al., who found lower HMGB1 serum levels in non-survivors of severe sepsis [20] . There have also been studies evaluating the role of HMGB-1's receptor, the receptor for advanced glycation end products (RAGE) [21] . Experimental studies demonstrate that RAGE-dependent activation of nuclear factor-kappa B (NF-B) plays a central role in modulating mortality after cecal ligation and puncture [22] . RAGE possesses a secretory isoform known as soluble RAGE (sRAGE), which maintains the extracellular ligand-binding domain but lacks the cytosolic and transmembrane domains. sRAGE has the same ligand binding specificity and competes with cell-bound RAGE, serving as a decoy that abolishes cell activation. In sepsis models, the administration of exogenous sRAGE slightly improved survival [22] . Evidence suggests that human endogenous sRAGE is generated by alternative splicing of RAGE mRNA, or alternatively, by proteolytic cleavage from membranous RAGE [23] . This former mechanism was considered to be a cell regulating mechanism, permitting restoration of homeostasis and survival.