Prevention of lymphocyte cell death in sepsis improves survival in mice

Sepsis induces extensive lymphocyte apoptosis, a process which may be benef icial to host survival by down-regulating the inflammatory response or, alt ernatively, harmful by impairing host defenses. To determine the beneficial vs. adverse effects of lymphocyte apoptosis in sepsis, we blocked lymphocy te apoptosis either by N-benzyloxycarbonyl-Val-Ala-Asp(O-methyl) fluorometh yl ketone (z-VAD). a broad-spectrum caspase inhibitor, or by use of Bcl-2 I g transgenic mice that selectively overexpress the antiapoptotic protein Bc l-2 in a lymphoid pattern. Both z-VAD and Bcl-2 prevented lymphocyte apopto sis and resulted in a marked improvement in survival. z-VAD did not decreas e lymphocyte tumor necrosis factor-alpha production. Considered together, t hese two studies employing different methods of blocking lymphocyte apoptos is provide compelling evidence that immunodepression resulting from the los s of lymphocytes is a central pathogenic event in sepsis. and they challeng e the current paradigm that regards sepsis as a disorder resulting from an uncontrolled inflammatory response. Caspase inhibitors may represent a trea tment strategy in this highly lethal disorder.