Enhanced pulmonary and systemic response to endotoxin in transgenic sickle mice
Enhanced pulmonary and systemic response to endotoxin in transgenic sickle mice
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DOI：
10.1164/rccm.200302-224oc
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发表时间：
2004-03-15
影响因子：
24.7
通讯作者：
Hsu, LL
中科院分区：
文献类型：
--
作者：
Holtzclaw, JD;Jack, D;Hsu, LL
一些人认为镰状细胞病（SCD）与“促炎状态”有关，在触发因素的背景下，该状态使患者易患急性胸综合征。当SCD中的炎症标志物与健康个体进行比较时，出现了相互矛盾的数据。因此，我们在基线和腹腔注射内毒素（LPS）的情况下对转基因镰状小鼠和对照小鼠进行了检测，以确定是否真的存在促炎状态。在基线时，镰状小鼠的循环白细胞和可溶性血管细胞粘附分子1 （sVCAM-1）水平升高。在基线或生理盐水反应中没有观察到其他差异。然而，唇部刺激与死亡率（p < 0.05）、气道张力（p < 0.03）、血清和支气管肺泡灌洗液中肿瘤坏死因子- α细胞因子水平的显著升高相关。（p < 0.03），白细胞介素-1 β (p < 0.02)和sVCAM-1 （p < 0.01）。此外，在lip治疗4小时后，微阵列分析发现镰状小鼠（n = 5）中有413个基因差异表达，而对照组（n = 5）中只有7个基因差异表达。光镜下肺实质无明显差异。这种对LPS的增强反应表明镰状红细胞赋予亚临床“促炎状态”。这种对炎症损伤的增强反应，特别是对黏附分子如sVCAM-1的增强反应，可能在SCD临床观察到的肺功能障碍易感性增加中发挥作用。
Some suggest that sickle cell disease (SCD) is associated with a "proinflammatory state" that predisposes patients to acute chest syndrome in the setting of triggering factors. Conflicting data emerged when inflammation markers in SCD were compared with healthy individuals. Therefore, we examined transgenic sickle and control mice at baseline and with endotoxin (LPS) intraperitoneal injection to determine whether a proinflammatory state truly exists. At baseline, sickle mice had elevated levels of circulating leukocytes and soluble vascular cell adhesion molecule 1 (sVCAM-1). No other differences were observed at baseline or in response to saline. However, LIPS challenge was associated with significant increases in mortality (p < 0.05), airway tone (p < 0.03), serum and broncho-alveolar lavage levels of cytokines tumor necrosis factor-alpha. (p < 0.03), interieukin-1beta (p < 0.02), and sVCAM-1 (p < 0.01) in sickle mice compared with control subjects. Furthermore, 4 hours after LIPS, microarray analysis identified 413 genes differentially expressed in the sickle mice (n = 5) compared with only 7 in the control subjects (n = 5). No difference in lung parenchyma was observed by light microscopy. This enhanced response to LPS suggests that the sickle red blood cell confers a subclinical "proinflammatory state." This enhanced response to inflammatory insult, particularly by adhesion molecules such as sVCAM-1, could play a role in the increased susceptibility to pulmonary dysfunction that has been observed clinically in SCD.