Centre for Critical Illness Research, London, Ontario, Canada.
Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.
Crit Care. 2017 Aug 8;21(1):210. doi: 10.1186/s13054-017-1783-1.
Despite many animal studies and clinical trials, mortality in sepsis remains high. This may be due to the fact that most experimental studies of sepsis employ young animals, whereas the majority of septic patients are elderly (60 - 70 years). The objective of the present study was to examine the sepsis-induced inflammatory and pro-coagulant responses in aged mice. Since running exercise protects against a variety of diseases, we also examined the effect of voluntary running on septic responses in aged mice.
Male C57BL/6 mice were housed in our institute from 2-3 to 22 months (an age mimicking that of the elderly). Mice were prevented from becoming obese by food restriction (given 70-90% of ad libitum consumption amount). Between 20 and 22 months, a subgroup of mice ran voluntarily on wheels, alternating 1-3 days of running with 1-2 days of rest. At 22 months, mice were intraperitoneally injected with sterile saline (control) or 3.75 g/kg fecal slurry (septic). At 7 h post injection, we examined (1) neutrophil influx in the lung and liver by measuring myeloperoxidase and/or neutrophil elastase in the tissue homogenates by spectrophotometry, (2) interleukin 6 (IL6) and KC in the lung lavage by ELISA, (3) pulmonary surfactant function by measuring percentage of large aggregates, (4) capillary plugging (pro-coagulant response) in skeletal muscle by intravital microscopy, (5) endothelial nitric oxide synthase (eNOS) protein in skeletal muscle (eNOS-derived NO is putative inhibitor of capillary plugging) by immunoblotting, and (6) systemic blood platelet counts by hemocytometry.
Sepsis caused high levels of pulmonary myeloperoxidase, elastase, IL6, KC, liver myeloperoxidase, and capillary plugging. Sepsis also caused low levels of surfactant function and platelet counts. Running exercise increased eNOS protein and attenuated the septic responses.
Voluntary running protects against exacerbated sepsis-induced inflammatory and pro-coagulant responses in aged mice. Protection against pro-coagulant responses may involve eNOS upregulation. The present discovery in aged mice calls for clinical investigation into potential beneficial effects of exercise on septic outcomes in the elderly.
尽管有许多动物研究和临床试验，但脓毒症的死亡率仍然很高。这可能是因为大多数关于脓毒症的实验研究都使用年轻动物，而大多数脓毒症患者是老年人（60-70 岁）。本研究的目的是研究衰老小鼠中脓毒症引起的炎症和促凝反应。由于跑步运动可以预防多种疾病，我们还研究了自愿跑步对衰老小鼠脓毒症反应的影响。
雄性 C57BL/6 小鼠从 2-3 个月到 22 个月（模拟老年人的年龄）在我们的研究所中饲养。通过食物限制（给予 70-90%的自由摄入量）防止小鼠肥胖。在 20 到 22 个月之间，一组小鼠自愿在轮子上跑步，1-3 天跑步和 1-2 天休息交替进行。在 22 个月时，小鼠通过腹腔内注射无菌生理盐水（对照）或 3.75g/kg 粪便浆（脓毒症）。在注射后 7 小时，我们通过分光光度法测量组织匀浆中的髓过氧化物酶和/或中性粒细胞弹性蛋白酶来检查（1）肺和肝中的中性粒细胞浸润，（2）肺灌洗中的白细胞介素 6（IL6）和 KC 通过 ELISA，（3）肺表面活性剂功能通过测量大聚集体的百分比，（4）骨骼肌中的毛细血管堵塞（促凝反应）通过活体显微镜检查，（5）骨骼肌中的内皮型一氧化氮合酶（eNOS）蛋白（由 eNOS 衍生的 NO 是毛细血管堵塞的假定抑制剂）通过免疫印迹，和（6）通过血细胞计数的全血细胞血小板计数。
脓毒症导致肺髓过氧化物酶、弹性蛋白酶、IL6、KC、肝髓过氧化物酶和毛细血管堵塞水平升高。脓毒症还导致表面活性剂功能和血小板计数降低。自愿跑步可增强衰老小鼠的炎症和促凝反应。
自愿跑步可防止衰老小鼠脓毒症引起的炎症和促凝反应加重。对促凝反应的保护可能涉及 eNOS 的上调。本研究在衰老小鼠中的发现呼吁对运动对老年人脓毒症结局的潜在有益影响进行临床研究。
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