Effects selleck bio of sedation on apoptosis in sepsisApoptotic (or programmed) cell death occurs in physiological conditions; for example, it is an important mechanism by which immune responses are controlled via activated cell death of lymphocytes. Sepsis induces apoptosis in lymphocytes, dendritic cells and enterocytes and death of these cells appear pivotal to the pathogenesis of the hypo-inflammatory phase of the condition [2,3]. Prevention of this apoptotic injury with inhibitors of the caspase enzymes [47], regarded as the final executioners in apoptosis or of over expression of anti-apoptotic proteins, has been shown to improve survival in animal models of less acute sepsis.[2,3] Critical mediators of this septic apoptotic injury include pro-apoptotic proteins such as BAX and activated caspase-3 [2,3].

Both midazolam and dexmedetomidine reduced the burden of splenic caspase-3 expression indicating that they may exert some anti-apoptotic effects in the presence of severe sepsis. It is possible that in the present model, TNF-�� binding stimulated the extrinsic apoptotic cascade. Thus the observed inhibition of apoptotic markers may be, in part, due to suppression of the inflammatory response. This would account for why both sedatives showed some anti-apoptotic ability. Interestingly, midazolam was only capable of reducing the 19 KDa fragment of cleaved caspase-3; why it had such an effect is currently unclear. Nonetheless, dexmedetomidine exhibited significantly superior anti-apoptotic effects, consistent with previous reports demonstrating that dexmedetomidine could prevent apoptotic injury from hypoxia and isoflurane in neurons [26,48].

��2 adrenoceptor stimulation reduces pro-apoptotic proteins such as BAX and increases anti-apoptotic Bcl-2 signaling [49], indicating activity against the intrinsic apoptotic cascade. As apoptotic mechanisms are highly conserved and therefore anti-apoptotic agents are likely to work in different tissue types we hypothesized that stimulation of ��2 adrenoceptors by dexmedetomidine may inhibit septic apoptosis. Indeed activation of AKT/protein kinase B, extracellular regulated signalling kinase and Bcl-2 improves survival in sepsis [2,3] and these effectors are upregulated by dexmedetomidine [49,50]. Therefore, the reduction in sepsis-induced splenic apoptosis is plausible (Figure (Figure33).

The consequences Batimastat of apoptosis may be more relevant in clinical sepsis and in the less acute phase of sepsis in animal models. Also, in acute severe sepsis apoptosis of cells may have a protective effect by dampening the immune response; improved mortality has been noted from endotoxic shock in animals treated with apoptotic cells [51]. This suggests a complex and dynamic set of circumstances pertain during sepsis expressed in apoptotic and inflammatory responses that are observed at different times.

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