Prevention of lymphocyte cell death in sepsis improves survival in mice

TLDR

Sepsis induces extensive lymphocyte apoptosis, which may be protective by dampening inflammation or detrimental by compromising host defenses. The study aimed to assess whether inhibiting lymphocyte apoptosis in sepsis is beneficial or harmful by using a caspase inhibitor or Bcl‑2 transgenic mice. Lymphocyte apoptosis was blocked by administering the broad‑spectrum caspase inhibitor z‑VAD or by employing Bcl‑2 Ig transgenic mice that overexpress anti‑apoptotic Bcl‑2 in lymphoid tissues. Blocking apoptosis with z‑VAD or Bcl‑2 prevented lymphocyte loss, markedly improved survival, did not reduce TNF‑α production, and collectively demonstrates that lymphocyte depletion drives sepsis pathogenesis, suggesting caspase inhibitors as a potential therapy.

Abstract

Sepsis induces extensive lymphocyte apoptosis, a process which may be beneficial to host survival by down-regulating the inflammatory response or, alternatively, harmful by impairing host defenses. To determine the beneficial vs. adverse effects of lymphocyte apoptosis in sepsis, we blocked lymphocyte apoptosis either by N- benzyloxycarbonyl-Val-Ala-Asp( O -methyl) fluoromethyl ketone ( z -VAD), a broad-spectrum caspase inhibitor, or by use of Bcl-2 Ig transgenic mice that selectively overexpress the antiapoptotic protein Bcl-2 in a lymphoid pattern. Both z -VAD and Bcl-2 prevented lymphocyte apoptosis and resulted in a marked improvement in survival. z -VAD did not decrease lymphocyte tumor necrosis factor-α production. Considered together, these two studies employing different methods of blocking lymphocyte apoptosis provide compelling evidence that immunodepression resulting from the loss of lymphocytes is a central pathogenic event in sepsis, and they challenge the current paradigm that regards sepsis as a disorder resulting from an uncontrolled inflammatory response. Caspase inhibitors may represent a treatment strategy in this highly lethal disorder.