Deficiency of Bid protein reduces sepsis-induced apoptosis and inflammation, while improving septic survival.

Increased apoptotic cell death is believed to play a pathological role in septic patients and experimental animals. Apoptosis can be induced by either a cell death receptor (extrinsic) or mitochondrial (intrinsic) pathway. Bid, a pro-apoptotic member of the Bcl-2 family, is thought to mediate cross talk between the extrinsic and intrinsic pathways of apoptosis; however, little is known about the action of Bid in the development of apoptosis and organ specific tissue damage/cell death as seen in polymicrobial sepsis. Our results show that following the onset of sepsis, tBid (the active form of Bid) is significantly increased in mitochondrial fractions of the thymus, spleen, Peyer’s patches and liver and that Fas or FasL deficiency blocks Bid activation in various tissues after septic challenge. Increased Bid activation is correlated with increased active caspase-3, -9 and apoptosis during sepsis. Bid deficient mice exhibit significantly reduced apoptosis in the thymus, spleen and Peyer’s patches compared with background mice after sepsis. Furthermore, Bid deficient mice had significantly reduced systemic and local inflammatory cytokine levels and improved survival after sepsis. These data support not only the contribution of Bid to sepsis-induced apoptosis and the onset of septic morbidity/mortality, but also the existence of a bridge between extrinsic apoptotic signals, e.g., FasL:Fas, TNF:TNFR, etc., and the intrinsic mitochondrial pathway via Bid-tBid activation during sepsis.