Grossie V B, Mailman D
University of Texas at Houston Medical School, Department of Integrative Biology, 77225, USA.
J Cancer Res Clin Oncol. 1997;123(4):189-94. doi: 10.1007/BF01240314.
Cachexia and a decreased immune function are negative prognostic factors for cancer patients. While the decreased immunity results in a greater susceptibility to bacterial infection, the response of the host to the resulting infection is not clear. The experiments reported here were designed to evaluate the toxicity of endotoxin to rats with a transplantable Ward colon tumor (WCT) and to evaluate the mechanism of the observed increase in lethal toxicity. The lethal toxicity of endotoxin (lipopolysaccharide, LPS) at 5 mg/kg, i.p. was evaluated in the first of two experiments. Rats received LPS and were observed for morbidity and weight loss for a period of 11 days. A second experiment was done to evaluate the effect of LPS on the plasma nitrate/nitrite concentrations and plasma indicators of host tissue dysfunction. LPS was administered as previously described but blood and tissues were collected 5 h after LPS administration. LPS resulted in the death of 1 of 12 nontumor-bearing (NTB) rats and a transient weight loss in the survivors. This same dose of LPS, however, resulted in death for 10 of 12 WCT rats with tumor burdens less than 4% of body weight. The response of WCT rats 5 h after LPS was then compared with that of age-matched NTB rats. Plasma albumin concentrations were not affected by LPS in NTB rats but were significantly decreased in WCT rats. Peripheral blood gases were not consistently affected by LPS in either group. Peripheral blood white cell counts, except monocytes, were significantly decreased by LPS in both groups. Monocyte counts in peripheral blood were further reduced in WCT rats compared with NTB rats receiving LPS. The presence of the WCT significantly enhanced the LPS-associated increase in spleen weight. Liver weights were lower in LPS rats but there was no effect of the presence of WCT. The LPS-associated increase in plasma nitrate/nitrite concentration was enhanced by the WCT. The plasma arginine and citrulline concentrations were altered in a manner consistent with an increase in nitric oxide synthesis. An increase in plasma ornithine concentration suggests an increase in arginine metabolism by arginase. The plasma concentration of alanine aminotransferase was significantly elevated when WCT rats received LPS, suggesting enhanced hepatic dysfunction. The plasma blood urea nitrogen concentration was elevated by LPS to a greater extent in the WCT rats than in the NTB controls, indicating increased renal dysfunction. These results demonstrate that the Ward colon tumor increases the host lethal response to the endotoxin, a toxic product of bacterial infections. The mechanisms of lethality may include an increased nitric oxide synthesis in WCT rats and enhanced liver and renal toxicity.
恶病质和免疫功能下降是癌症患者的不良预后因素。虽然免疫力下降会导致患者更易受到细菌感染，但宿主对由此引发感染的反应尚不清楚。本文报道的实验旨在评估内毒素对患有可移植Ward结肠癌（WCT）大鼠的毒性，并评估所观察到的致死毒性增加的机制。在两项实验的第一项中，评估了腹腔注射5mg/kg内毒素（脂多糖，LPS）的致死毒性。给大鼠注射LPS，并观察其发病情况和体重减轻情况，为期11天。第二项实验旨在评估LPS对血浆硝酸盐/亚硝酸盐浓度以及宿主组织功能障碍血浆指标的影响。LPS的给药方式如前所述，但在注射LPS后5小时采集血液和组织。LPS导致12只无肿瘤（NTB）大鼠中的1只死亡，幸存者出现短暂体重减轻。然而，相同剂量的LPS导致12只肿瘤负荷小于体重4%的WCT大鼠中的10只死亡。然后将LPS注射后5小时的WCT大鼠的反应与年龄匹配的NTB大鼠的反应进行比较。LPS对NTB大鼠的血浆白蛋白浓度没有影响，但对WCT大鼠的血浆白蛋白浓度有显著降低作用。两组中LPS对外周血气的影响并不一致。两组中，除单核细胞外，LPS均使外周血白细胞计数显著降低。与接受LPS的NTB大鼠相比，WCT大鼠外周血中的单核细胞计数进一步减少。WCT的存在显著增强了LPS相关的脾脏重量增加。LPS处理的大鼠肝脏重量较低，但WCT的存在对此没有影响。WCT增强了LPS相关的血浆硝酸盐/亚硝酸盐浓度升高。血浆精氨酸和瓜氨酸浓度的变化与一氧化氮合成增加一致。血浆鸟氨酸浓度升高表明精氨酸酶介导的精氨酸代谢增加。当WCT大鼠接受LPS时，血浆丙氨酸转氨酶浓度显著升高，表明肝功能障碍增强。LPS使WCT大鼠的血浆尿素氮浓度升高的程度大于NTB对照组，表明肾功能障碍增加。这些结果表明，Ward结肠癌增加了宿主对内毒素（一种细菌感染的毒性产物）的致死反应。致死机制可能包括WCT大鼠中一氧化氮合成增加以及肝脏和肾脏毒性增强。
