Lyons John D, Mittal Rohit, Fay Katherine T, Chen Ching-Wen, Liang Zhe, Margoles Lindsay M, Burd Eileen M, Farris Alton B, Ford Mandy L, Coopersmith Craig M
Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA, United States of America.
Department of Internal Medicine and Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA, United States of America.
PLoS One. 2016 Mar 28;11(3):e0149069. doi: 10.1371/journal.pone.0149069. eCollection 2016.
Mortality is significantly higher in septic patients with cancer than in septic patients without a history of cancer. We have previously described a model of pancreatic cancer followed by sepsis from Pseudomonas aeruginosa pneumonia in which cancer septic mice have higher mortality than previously healthy septic mice, associated with increased gut epithelial apoptosis and decreased T cell apoptosis. The purpose of this study was to determine whether this represents a common host response by creating a new model in which both the type of cancer and the model of sepsis are altered.
C57Bl/6 mice received an injection of 250,000 cells of the lung cancer line LLC-1 into their right thigh and were followed three weeks for development of palpable tumors. Mice with cancer and mice without cancer were then subjected to cecal ligation and puncture and sacrificed 24 hours after the onset of sepsis or followed 7 days for survival.
Cancer septic mice had a higher mortality than previously healthy septic mice (60% vs. 18%, p = 0.003). Cancer septic mice had decreased number and frequency of splenic CD4+ lymphocytes secondary to increased apoptosis without changes in splenic CD8+ numbers. Intestinal proliferation was also decreased in cancer septic mice. Cancer septic mice had a higher bacterial burden in the peritoneal cavity, but this was not associated with alterations in local cytokine, neutrophil or dendritic cell responses. Cancer septic mice had biochemical evidence of worsened renal function, but there was no histologic evidence of renal injury.
Animals with cancer have a significantly higher mortality than previously healthy animals following sepsis. The potential mechanisms associated with this elevated mortality differ significantly based upon the model of cancer and sepsis utilized. While lymphocyte apoptosis and intestinal integrity are both altered by the combination of cancer and sepsis, the patterns of these alterations vary greatly depending on the models used.
患有癌症的脓毒症患者的死亡率显著高于无癌症病史的脓毒症患者。我们之前描述过一种胰腺癌模型，随后出现铜绿假单胞菌肺炎败血症，其中癌症败血症小鼠的死亡率高于先前健康的败血症小鼠，这与肠道上皮细胞凋亡增加和T细胞凋亡减少有关。本研究的目的是通过创建一个癌症类型和败血症模型均改变的新模型，来确定这是否代表一种常见的宿主反应。
C57Bl/6小鼠右大腿注射250,000个肺癌细胞系LLC-1，观察三周以确定是否出现可触及的肿瘤。然后对患有癌症的小鼠和未患癌症的小鼠进行盲肠结扎和穿刺，并在败血症发作后24小时处死，或观察7天以确定生存率。
癌症败血症小鼠的死亡率高于先前健康的败血症小鼠（60%对18%，p = 0.003）。癌症败血症小鼠脾脏CD4+淋巴细胞数量和频率减少，继发于凋亡增加，而脾脏CD8+数量无变化。癌症败血症小鼠的肠道增殖也减少。癌症败血症小鼠腹腔内细菌负荷更高，但这与局部细胞因子、中性粒细胞或树突状细胞反应的改变无关。癌症败血症小鼠有肾功能恶化的生化证据，但无肾损伤的组织学证据。
患有癌症的动物在败血症后的死亡率显著高于先前健康的动物。基于所使用的癌症和败血症模型不同，与这种死亡率升高相关的潜在机制有显著差异。虽然癌症和败血症共同作用会改变淋巴细胞凋亡和肠道完整性，但这些改变的模式因所使用的模型而异。
