División Inmunología, Instituto de Medicina Experimental, CONICET, Academia Nacional de Medicina de Buenos Aires, Buenos Aires, Argentina.
Infect Immun. 2011 Mar;79(3):1280-8. doi: 10.1128/IAI.01127-10. Epub 2010 Dec 20.
Severe sepsis is associated with early release of inflammatory mediators that contribute to the morbidity and mortality observed during the first stages of this syndrome. Although sepsis is a deadly, acute disease, high mortality rates have been observed in patients displaying evidence of sepsis-induced immune deactivation. Although the contribution of experimental models to the knowledge of pathophysiological and therapeutic aspects of human sepsis is undeniable, most of the current studies using animal models have focused on the acute, proinflammatory phase. We developed a murine model that reproduces the early acute phases but also the long-term consequences of human sepsis. We induced polymicrobial acute peritonitis (AP) by establishing a surgical connection between the cecum and the peritoneum, allowing the exit of intestinal bacteria. Using this model, we observed an acute phase with high mortality, leukopenia, increased interleukin-6 levels, bacteremia, and neutrophil activation. A peak of leukocytosis on day 9 or 10 revealed the persistence of the infection within the lung and liver, with inflammatory hepatic damage being shown by histological examination. Long-term (20 days) derangements in both innate and adaptive immune responses were found, as demonstrated by impaired systemic tumor necrosis factor alpha production in response to an inflammatory stimulus; a decreased primary humoral immune response and T cell proliferation, associated with an increased number of myeloid suppressor cells (Gr-1(+) CD11b(+)) in the spleen; and a low clearance capacity. This model provides a good approach to attempt novel therapeutic interventions directed to augmenting host immunity during late sepsis.
严重脓毒症与炎症介质的早期释放有关，这些介质导致在该综合征的早期阶段观察到的发病率和死亡率。尽管脓毒症是一种致命的急性疾病，但在显示脓毒症引起免疫失活的证据的患者中观察到高死亡率。尽管实验模型对了解人类脓毒症的病理生理和治疗方面的贡献是不可否认的，但大多数使用动物模型的当前研究都集中在急性、促炎阶段。我们开发了一种能够重现人类脓毒症早期急性阶段和长期后果的小鼠模型。我们通过在盲肠和腹膜之间建立手术连接来诱导多微生物急性腹膜炎 (AP)，允许肠道细菌排出。使用这种模型，我们观察到了一个高死亡率、白细胞减少、白细胞介素-6 水平升高、菌血症和中性粒细胞活化的急性阶段。第 9 或 10 天的白细胞增多峰值表明感染在肺部和肝脏中持续存在，组织学检查显示肝脏炎症损伤。发现固有和适应性免疫反应的长期（20 天）失调，表现为对炎症刺激的全身性肿瘤坏死因子 alpha 产生受损；初级体液免疫反应和 T 细胞增殖减少，与脾中髓样抑制细胞（Gr-1(+) CD11b(+)）数量增加相关；以及清除能力降低。该模型为尝试新型治疗干预措施提供了一种很好的方法，旨在增强晚期脓毒症期间的宿主免疫力。
