Hotchkiss R S, Swanson P E, Knudson C M, Chang K C, Cobb J P, Osborne D F, Zollner K M, Buchman T G, Korsmeyer S J, Karl I E
Department of Anesthesiology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Immunol. 1999 Apr 1;162(7):4148-56.
In sepsis there is extensive apoptosis of lymphocytes, which may be beneficial by down-regulating the accompanying inflammation. Alternatively, apoptosis may be detrimental by impairing host defense. We studied whether Bcl-2, a potent antiapoptotic protein, could prevent lymphocyte apoptosis in a clinically relevant model of sepsis. Transgenic mice in which Bcl-2 was overexpressed in T cells had complete protection against sepsis-induced T lymphocyte apoptosis in thymus and spleen. Surprisingly, there was also a decrease in splenic B cell apoptosis in septic Bcl-2 overexpressors compared with septic HeJ and HeOuJ mice. There were marked increases in TNF-alpha, IL-1beta, and IL-10 in thymic tissue in sepsis in the three species of mice, and the increase in TNF-alpha and IL-10 in HeOuJ mice was greater than that in Bcl-2 mice. Mitotracker, a mitochondrial membrane potential indicator, demonstrated a sepsis-induced loss of membrane potential in T cells in HeJ and HeOuJ mice but not in Bcl-2 mice. Importantly, Bcl-2 overexpressors also had improved survival in sepsis. To investigate the potential impact of loss of lymphocytes on survival in sepsis, Rag-1-/- mice, which are totally deficient in mature T and B cells, were also studied. Rag-1-/- mice had decreased survival compared with immunologically normal mice with sepsis. We conclude that overexpression of Bcl-2 provides protection against cell death in sepsis. Lymphocyte death may be detrimental in sepsis by compromising host defense.
在脓毒症中，淋巴细胞会发生广泛凋亡，这可能通过下调伴随的炎症反应而有益。或者，凋亡也可能因损害宿主防御而有害。我们研究了一种强效抗凋亡蛋白Bcl-2是否能在脓毒症的临床相关模型中预防淋巴细胞凋亡。T细胞中Bcl-2过表达的转基因小鼠对脓毒症诱导的胸腺和脾脏T淋巴细胞凋亡具有完全保护作用。令人惊讶的是，与脓毒症HeJ和HeOuJ小鼠相比，脓毒症Bcl-2过表达小鼠的脾脏B细胞凋亡也有所减少。三种小鼠脓毒症时胸腺组织中TNF-α、IL-1β和IL-10均显著增加，且HeOuJ小鼠中TNF-α和IL-10的增加幅度大于Bcl-2小鼠。线粒体膜电位指示剂Mitotracker显示，HeJ和HeOuJ小鼠的T细胞中存在脓毒症诱导的膜电位丧失，而Bcl-2小鼠中则没有。重要的是，Bcl-2过表达小鼠在脓毒症中的存活率也有所提高。为了研究淋巴细胞缺失对脓毒症存活率的潜在影响，还研究了完全缺乏成熟T和B细胞的Rag-1-/-小鼠。与患有脓毒症的免疫正常小鼠相比，Rag-1-/-小鼠的存活率降低。我们得出结论，Bcl-2过表达可提供针对脓毒症细胞死亡的保护。淋巴细胞死亡可能通过损害宿主防御而在脓毒症中有害。
