We have shown that HS-induced PMN NAD(P)H oxidase activation is mediated by HMGB1-TLR4 signaling. HMGB1 was originally defined as a nuclear protein that functions to stabilize nucleosome formation, and it also acts as a transcription factor that regulates the expression of several genes (71) . HMGB1 can be secreted by innate immune cells in response to microbial products or other inflammatory stimuli (123, 124) . HMGB1 is also released by injured cells and is known as one of the main prototypes of the emerging DAMPs (125) (126) (127) . HMGB1 was initially identified as an inflammatory cytokine that is a late mediator of lethality in sepsis (123, 124) . However, recent studies suggest that HMGB1 acts as an early mediator of inflammation, contributing to the development of ALI after hemorrhage (128) , and hepatic injury after liver ischemia-reperfusion (129) .