Li Bin, Li Yu Min, Li Xun, Shi Bin, He Ming Yan, Zhu Xiao Liang, Zhou Wen Ce, Wachtel Mitchell S, Frezza Eldo
Department of General Surgery, The First Hospital of Lanzhou University, Gansu, China.
J Surg Res. 2009 Nov;157(1):43-7. doi: 10.1016/j.jss.2008.12.020. Epub 2009 Jan 10.
To evaluate cyclooxygenase-2 (COX-2) inhibition by NS-398 in septic rats with respect to immunologic derangements and hepatic damage.
Six sham rats (Sham), 24 rats that underwent experimentally induced sepsis using cecal ligation and puncture (CLP), and 24 rats that underwent induced sepsis after treatment with NS-398 (NS-398), were compared. Sham rats were immediately sacrificed. Six each of CLP and NS-398 animals were sacrificed at 3, 6, 12, and 24 h after induction of sepsis. From each rat was obtained liver for COX-2 mRNA copy number determination and blood for quantification of alanine transaminase (ALT), aspartate aminotransferase (AST), interleukin 10 (IL-10), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNFalpha) levels, and CD4:CD8 ratios.
Sham rats had a lower COX-2 mRNA copy number than NS-398 rats, which had a lower copy number than CLP rats. CLP and NS-938 rats had IL-10 and IL-6 levels above Sham levels. NS-938 rat IL-10 levels were greater and IL-6 levels less than those of CLP rats. For CLP rats, TNF production sharply declined and then increased above Sham levels; NS-398 rat TNF production was consistently mildly elevated above Sham levels. CD4:CD8 ratios sharply dropped over time; NS-398 showed a more modest decline. CLP rats showed unrelenting climbs in AST and ALT values; NS-398 rat levels peaked at 6 h and returned to normal after 12 h; the biochemical evidence of protection against septic liver damage was also seen morphologically, with ultrastructural and histologic normalization of nuclear appearances 12 h after sepsis induction with NS-398 pretreatment.
Septic rats given the COX-2 inhibitor NS-398 showed amelioration of cytokine and cellular immunologic imbalances and decreased liver injury.
评估NS - 398对脓毒症大鼠环氧化酶 - 2（COX - 2）的抑制作用及其对免疫紊乱和肝损伤的影响。
比较6只假手术大鼠（假手术组）、24只通过盲肠结扎和穿刺（CLP）诱导实验性脓毒症的大鼠以及24只在接受NS - 398治疗后诱导脓毒症的大鼠（NS - 398组）。假手术大鼠立即处死。CLP组和NS - 398组各6只大鼠在诱导脓毒症后3、6、12和24小时处死。从每只大鼠获取肝脏用于测定COX - 2 mRNA拷贝数，采集血液用于定量丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、白细胞介素10（IL - 10）、白细胞介素6（IL - 6）和肿瘤坏死因子α（TNFα）水平以及CD4:CD8比值。
假手术大鼠的COX - 2 mRNA拷贝数低于NS - 398组大鼠，而NS - 398组大鼠的拷贝数又低于CLP组大鼠。CLP组和NS - 398组大鼠的IL - 10和IL - 6水平高于假手术组。NS - 398组大鼠的IL - 10水平高于CLP组大鼠，而IL - 6水平低于CLP组大鼠。对于CLP组大鼠，TNF生成急剧下降，然后升高至高于假手术组水平；NS - 398组大鼠的TNF生成持续轻度高于假手术组水平。CD4:CD8比值随时间急剧下降；NS - 398组下降幅度较小。CLP组大鼠的AST和ALT值持续升高；NS - 398组大鼠的水平在6小时达到峰值，12小时后恢复正常；在形态学上也观察到了预防脓毒症肝损伤的生化证据，NS - 398预处理诱导脓毒症12小时后，细胞核的超微结构和组织学表现恢复正常。
给予COX - 2抑制剂NS - 398的脓毒症大鼠细胞因子和细胞免疫失衡得到改善，肝损伤减轻。
