Institute of Innovative Science and Technology, Tokai University, School of Medicine, Isehara, Kanagawa, Japan.
Shock. 2013 Mar;39(3):311-6. doi: 10.1097/SHK.0b013e3182845445.
Sepsis is primarily a disease of the aged, with 65% of sepsis cases reported in patients older than 65 years and 80% of deaths due to sepsis occurring in this age group. Klotho knockout mice (Klotho mice) are a mouse model of accelerated aging and shortened life span. The purpose of the study was to elucidate the immunological changes occurring in Klotho mice during sepsis. Five-week-old homozygous female Klotho knockout (Klotho) and wild-type (WT) mice were subjected to 1 × 27-gauge cecal ligation and puncture (CLP), and survival was compared after 4 days. Another set of mice was killed at 8 h after CLP or sham surgery, and the spleen, thymus, and serum were harvested. Apoptosis was measured by flow cytometry by using caspase 3. Serum cytokines and bacterial colony count in peritoneal lavage were also analyzed. Klotho septic mice started to die at 8 to 12 h after CLP, and the final survival of Klotho mice was significantly lower than that of WT mice (0% vs. 100%, P < 0.01). Increased bacterial count in the peritoneal cavity and decreased recruitment of neutrophils and macrophages to the peripheral cavity were observed in Klotho-CLP mice. Both flow cytometric and immunohistological analyses showed a dramatic increase in caspase 3-positive cells in the thymus and spleen of Klotho-CLP mice (P < 0.01). Serum concentrations of interleukin 6, tumor necrosis factor α, and interleukin 10 were higher in Klotho-CLP mice than in WT-CLP mice. Hypercytokinemia with impaired bacterial clearance and increased apoptosis of lymphocytes may be related to poor survival in Klotho-septic mice.
脓毒症主要是老年人的疾病，65%的脓毒症病例发生在 65 岁以上的患者中，80%的脓毒症死亡发生在该年龄组。Klotho 敲除小鼠（Klotho 小鼠）是一种加速衰老和缩短寿命的小鼠模型。本研究旨在阐明脓毒症过程中 Klotho 小鼠发生的免疫学变化。将 5 周龄的纯合雌性 Klotho 敲除（Klotho）和野生型（WT）小鼠进行 1×27 号肠结扎穿刺（CLP），并在 4 天后比较存活率。另一组小鼠在 CLP 或假手术后 8 小时处死，采集脾脏、胸腺和血清。通过使用 caspase 3 进行流式细胞术测量细胞凋亡。还分析了血清细胞因子和腹腔灌洗液中的细菌菌落计数。Klotho 脓毒症小鼠在 CLP 后 8 至 12 小时开始死亡，Klotho 小鼠的最终存活率明显低于 WT 小鼠（0%比 100%，P < 0.01）。在 Klotho-CLP 小鼠中观察到腹腔内细菌计数增加，中性粒细胞和巨噬细胞向外周腔的募集减少。流式细胞术和免疫组织化学分析均显示 Klotho-CLP 小鼠的胸腺和脾脏中 caspase 3 阳性细胞明显增加（P < 0.01）。Klotho-CLP 小鼠的血清白细胞介素 6、肿瘤坏死因子 α 和白细胞介素 10 浓度高于 WT-CLP 小鼠。细胞因子血症伴细菌清除受损和淋巴细胞凋亡增加可能与 Klotho 脓毒症小鼠的生存不良有关。
