Prevention of lymphocyte cell death in sepsis improves survival in mice
Prevention of lymphocyte cell death in sepsis improves survival in mice
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DOI：
10.1073/pnas.96.25.14541
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发表时间：
1999-12-07
影响因子：
11.1
通讯作者：
Karl, IE
中科院分区：
文献类型：
--
作者：
Hotchkiss, RS;Tinsley, KW;Karl, IE
脓毒症诱导广泛的淋巴细胞凋亡，这一过程可能通过下调炎症反应而有利于宿主的生存，或者通过损害宿主的防御而有害。为了确定脓毒症时淋巴细胞凋亡的利弊，我们用N-苄氧基甲酰基-Val-丙氨酸-天冬氨酸(O-甲基)氟甲基酮(z-VAD)阻断淋巴细胞的凋亡。一种广谱半胱氨酸天冬氨酸氨基转移酶抑制剂，或通过使用有选择地以淋巴模式过表达抗凋亡蛋白Bcl-2 Ig转基因小鼠。Z-VAD和Bc l-2均可抑制淋巴细胞凋亡，显著提高小鼠的存活率。Z-VAD不减少淋巴细胞肿瘤坏死因子-α的产生。综合考虑，这两项采用不同方法阻断淋巴细胞凋亡的研究提供了令人信服的证据，证明淋巴细胞丢失导致的免疫抑制是脓毒症的中心致病事件。他们挑战了目前的范式，即将脓毒症视为一种由不受控制的炎症反应引起的疾病。Caspase抑制剂可能是这种高度致命疾病的一种治疗策略。
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-alpha 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.