Apoptosis in sepsis: a new target for therapeutic exploration

The treatment of sepsis and septic shock remains a clinical conundrum, and recent prospective trials with biological response modifiers aimed at the i nflammatory response have shown only modest clinical benefit. Recently, int erest has shifted toward therapies aimed at reversing the accompanying peri ods of immune suppression. Studies in experimental animals and critically i ll patients have demonstrated that increased apoptosis of lymphoid organs a nd some parenchymal tissues contributes to this immune suppression, anergy, and organ system dysfunction, During sepsis syndromes, lymphocyte apoptosi s can be triggered by the absence of IL-2 or by the release of glucocortico ids, granzymes, or the so-called 'death' cytokines: tumor necrosis factor a lpha or Fas ligand, Apoptosis proceeds via auto-activation of cytosolic and /or mitochondrial caspases, which can be influenced by the pro- and anti-ap optotic members of the Bcl-2 family, In experimental animals, not only can treatment with inhibitors of apoptosis prevent lymphoid cell apoptosis; it may also improve outcome. Although clinical trials with anti-apoptotic agen ts remain distant due in large part to technical difficulties associated wi th their administration and tissue targeting, inhibition of lymphocyte apop tosis represents an attractive therapeutic target for the septic patient.