Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality.
Prevention of lymphocyte apoptosis in septic mice with cancer increases mortality.
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DOI：
10.4049/jimmunol.1003391
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发表时间：
2011-08-15
期刊：
影响因子：
--
通讯作者：
Coopersmith CM
中科院分区：
文献类型：
--
作者：
Fox AC;Breed ER;Liang Z;Clark AT;Zee-Cheng BR;Chang KC;Dominguez JA;Jung E;Dunne WM;Burd EM;Farris AB;Linehan DC;Coopersmith CM
淋巴细胞凋亡被认为在脓毒症的病理生理过程中起主要作用。然而，脓毒症的动物模型和患者之间存在着脱节，因为前者使用的是在感染发生之前是健康的受试者，而大多数患者都有潜在的合并症。这项研究的目的是确定淋巴细胞凋亡预防在预防已有癌症的脓毒症小鼠死亡率方面是否有效。给淋巴细胞Bcl2高表达(Bcl2-Ig)小鼠和野生型(WT)小鼠注射可移植的胰腺癌细胞系。三周后，在出现可触及的肿瘤后，所有动物都接受了气管内注射铜绿假单胞菌。尽管Bcl2-Ig小鼠减少了败血症诱导的T和B淋巴细胞凋亡，但与WT小鼠相比，Bcl2-Ig小鼠在铜绿假单胞菌肺炎后的死亡率显著增加(85%对44%的7天死亡率，p=0.004)。Bcl2-Ig组小鼠存活率下降与肺泡灌洗液中Th1型细胞因子肿瘤坏死因子α和干扰素γ增加，刺激脾细胞产生Th2型细胞因子IL-10有关。Bc l-2-Ig和WT小鼠在肿瘤大小和肺组织病理学方面无明显差异。为了验证死亡率的差异不是由于bcl2的过度表达，在Bim-/-小鼠身上进行了类似的实验。与患有癌症的WT败血症小鼠相比，患癌症的败血症Bim-/-小鼠的死亡率也有所增加。这些数据表明，尽管有压倒性的证据表明，预防淋巴细胞凋亡对没有共病的脓毒症宿主是有益的，但同样的策略会恶化患癌症的小鼠的存活率。
Lymphocyte apoptosis is thought to play a major role in the pathophysiology of sepsis. However, there is a disconnect between animal models of sepsis and patients with the disease, since the former use subjects that were healthy prior to the onset of infection while most patients have underlying comorbidities. The purpose of this study was to determine whether lymphocyte apoptosis prevention is effective in preventing mortality in septic mice with pre-existing cancer. Mice with lymphocyte Bcl-2 overexpression (Bcl-2-Ig) and wild type (WT) mice were injected with a transplantable pancreatic adenocarcinoma cell line. Three weeks later after development of palpable tumors, all animals received an intratracheal injection of Pseudomonas aeruginosa. Despite having decreased sepsis-induced T and B lymphocyte apoptosis, Bcl-2-Ig mice had markedly increased mortality compared to WT mice following Pseudomonas aeruginosa pneumonia (85% vs. 44% seven-day mortality, p=0.004). The worsened survival in Bcl-2-Ig mice was associated with increases in Th1 cytokines TNF-α and IFN-γ in bronchoalveolar lavage fluid and decreased production of the Th2 cytokine IL-10 in stimulated splenocytes. There were no differences in tumor size or pulmonary pathology between Bcl-2-Ig and WT mice. To verify the mortality difference was not specific to Bcl-2 overexpression, similar experiments were performed in Bim-/- mice. Septic Bim-/- mice with cancer also had increased mortality compared to septic WT mice with cancer. These data demonstrate that despite overwhelming evidence that prevention of lymphocyte apoptosis is beneficial in septic hosts without comorbidities, the same strategy worsens survival in mice with cancer that are given pneumonia.
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DOI：
10.1073/pnas.96.25.14541
发表时间：
1999-12-07
影响因子：
11.1
作者：
Hotchkiss, RS;Tinsley, KW;Karl, IE
通讯作者：
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影响因子：
20.3
作者：
Lamkanfi, Mohamed;Moreira, Lilian O.;Kanneganti, Thirumala-Devi
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DOI：
10.1073/pnas.1031788100
发表时间：
2003-05-27
影响因子：
11.1
作者：
Hotchkiss, RS;Chang, KC;Karl, IE
通讯作者：
Karl, IE
影响因子：
3.1
作者：
Husain, KD;Stromberg, PE;Coopersmith, CM
通讯作者：
Coopersmith, CM
影响因子：
7.5
作者：
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