中华实验外科杂志
中華實驗外科雜誌
중화실험외과잡지
CHINESE JOURNAL OF EXPERIMENTAL SURGERY
2012年
5期
861-864
,共4页
刘亮%徐华祥%武春涛%王文权%汤钊猷
劉亮%徐華祥%武春濤%王文權%湯釗猷
류량%서화상%무춘도%왕문권%탕쇠유
肝动脉断流%肝癌%炎症%塞来昔布
肝動脈斷流%肝癌%炎癥%塞來昔佈
간동맥단류%간암%염증%새래석포
Hepatic artery blocking%Hepatocellular carcinoma%Inflammation%Celecoxib
目的 观察肝动脉断流后肝癌局部或机体全身的炎症反应,以及非甾体类抗炎药物塞来昔布( Celecoxib)对断流术后残癌恶性潜能的影响.方法 建立具有自发转移潜能的肝癌原位移植+肝动脉结扎(HAL)模型.酶联免疫吸附试验(ELISA)检测HAL对荷瘤动物血清内炎症因子肿瘤坏死因子(TNF)-α、白细胞介素(IL)-6、肝细胞生长因子(HGF)表达的影响；免疫组织化学分析肝脏原发瘤及转移靶器官(肺部)的炎症反应及环氧合酶-2(COX-2)表达；继而不同剂量的Celecoxib 协同HAL处理荷瘤裸鼠,观察对上述炎症反应及转移的影响.结果 HAL显著上调荷瘤动物血清中TNF-α、IL.-6、HGF表达(3.78、2.91、1.82倍,P＜0.05),增加肝脏原发瘤局部坏死[HAL组(51.27±19.39)％比假手术组(19.69±5.49)％,P＜0.01]及组织内COX-2表达,引起转移靶器官(肺)明显炎症改变.协同使用高剂量Celecoxib(每天50 mg/kg)下调组织内COX-2表达,进一步减少移植瘤体积[(1091.81 ±870.14) mm3比( 2735.06±474.97) mm3,P＜0.01],并显著抑制肿瘤肺转移(0/6比8/10,P＜0.01),延长荷瘤裸鼠生存时间[(81.67±8.51)d比(60.17±5.42)d,P＜0.05]；小剂量Celecoxib(每天12.5 mg/kg)虽不能抑制原发瘤生长及组织内COX-2表达,但减少了肝癌肺转移(2/6比8/10,P ＞0.05).结论 肝动脉断流增加荷瘤裸鼠全身及原发瘤或转移靶器官局部炎症反应；抗炎药物Celecoxib 抑制炎症反应,通过依赖或不依赖COX-2的机制阻止断流后增强的残癌侵袭、转移.
目的 觀察肝動脈斷流後肝癌跼部或機體全身的炎癥反應,以及非甾體類抗炎藥物塞來昔佈( Celecoxib)對斷流術後殘癌噁性潛能的影響.方法 建立具有自髮轉移潛能的肝癌原位移植+肝動脈結扎(HAL)模型.酶聯免疫吸附試驗(ELISA)檢測HAL對荷瘤動物血清內炎癥因子腫瘤壞死因子(TNF)-α、白細胞介素(IL)-6、肝細胞生長因子(HGF)錶達的影響；免疫組織化學分析肝髒原髮瘤及轉移靶器官(肺部)的炎癥反應及環氧閤酶-2(COX-2)錶達；繼而不同劑量的Celecoxib 協同HAL處理荷瘤裸鼠,觀察對上述炎癥反應及轉移的影響.結果 HAL顯著上調荷瘤動物血清中TNF-α、IL.-6、HGF錶達(3.78、2.91、1.82倍,P＜0.05),增加肝髒原髮瘤跼部壞死[HAL組(51.27±19.39)％比假手術組(19.69±5.49)％,P＜0.01]及組織內COX-2錶達,引起轉移靶器官(肺)明顯炎癥改變.協同使用高劑量Celecoxib(每天50 mg/kg)下調組織內COX-2錶達,進一步減少移植瘤體積[(1091.81 ±870.14) mm3比( 2735.06±474.97) mm3,P＜0.01],併顯著抑製腫瘤肺轉移(0/6比8/10,P＜0.01),延長荷瘤裸鼠生存時間[(81.67±8.51)d比(60.17±5.42)d,P＜0.05]；小劑量Celecoxib(每天12.5 mg/kg)雖不能抑製原髮瘤生長及組織內COX-2錶達,但減少瞭肝癌肺轉移(2/6比8/10,P ＞0.05).結論 肝動脈斷流增加荷瘤裸鼠全身及原髮瘤或轉移靶器官跼部炎癥反應；抗炎藥物Celecoxib 抑製炎癥反應,通過依賴或不依賴COX-2的機製阻止斷流後增彊的殘癌侵襲、轉移.
목적 관찰간동맥단류후간암국부혹궤체전신적염증반응,이급비치체류항염약물새래석포( Celecoxib)대단류술후잔암악성잠능적영향.방법 건립구유자발전이잠능적간암원위이식+간동맥결찰(HAL)모형.매련면역흡부시험(ELISA)검측HAL대하류동물혈청내염증인자종류배사인자(TNF)-α、백세포개소(IL)-6、간세포생장인자(HGF)표체적영향；면역조직화학분석간장원발류급전이파기관(폐부)적염증반응급배양합매-2(COX-2)표체；계이불동제량적Celecoxib 협동HAL처리하류라서,관찰대상술염증반응급전이적영향.결과 HAL현저상조하류동물혈청중TNF-α、IL.-6、HGF표체(3.78、2.91、1.82배,P＜0.05),증가간장원발류국부배사[HAL조(51.27±19.39)％비가수술조(19.69±5.49)％,P＜0.01]급조직내COX-2표체,인기전이파기관(폐)명현염증개변.협동사용고제량Celecoxib(매천50 mg/kg)하조조직내COX-2표체,진일보감소이식류체적[(1091.81 ±870.14) mm3비( 2735.06±474.97) mm3,P＜0.01],병현저억제종류폐전이(0/6비8/10,P＜0.01),연장하류라서생존시간[(81.67±8.51)d비(60.17±5.42)d,P＜0.05]；소제량Celecoxib(매천12.5 mg/kg)수불능억제원발류생장급조직내COX-2표체,단감소료간암폐전이(2/6비8/10,P ＞0.05).결론 간동맥단류증가하류라서전신급원발류혹전이파기관국부염증반응；항염약물Celecoxib 억제염증반응,통과의뢰혹불의뢰COX-2적궤제조지단류후증강적잔암침습、전이.
Objective To investigate the local or systemic inflammatory reaction after hepatic artery ligation ( HAL),and to explore the therapeutic effect of celecoxib on HAL-enhanced metastatic potential of hepatocellular carcinoma (HCC).Methods The spontaneous metastatic model in nude mice was established with MHCC97 cells via orthotopic implantation and further to HAL.The proinflammatory cytokines such as tumor necrosis factor (TNF)-α,interleukin (IL)-6,and hepatocyte growth factor ( HGF ) in serum in HAL group were compared with those in sham-operation group by enzyme linked immunosorbent assay (ELISA).The signs of inflammation in primary tumor or the lung from two groups were observed by immunohistochemistry and the expression of cyclooxgenase 2 (COX-2) in xenografts was evaluated.The influence of celecoxib at different doses on tumor growth,pulmonary metastatic ratio,and COX-2 expression in tumor tissues due to HAL was investigated.Results The serum levels of proinflammatory cytokines (TNF-α,IL-6 and HGF) were elevated after HAL (3.78 times; 2.91 times; 1.82 times,P ＜ 0.05 ).Also the necrotic area in the xenograft as scored with hepatic replacement area (HRA) was increased by HAL [ HAL group:(5 1.27 ± 19.39 ) ％ vs.sham-operation group:( 19.69 ± 5.49 ) ％ ; P ＜ 0.01 ].Especially,the lungs of nude mice in the HAL group showed more inflammatory damage,characterized by intense inflammatory infiltration,thickening of alveolar walls,and severe vascular margination.As compared with normal saline (NS) treatment following HAL,HAL in combination with high dose of celecoxib (50 mg/kg every day) resulted in significantly reduced tumor size [( 1091.81 ± 870.14) mm3 vs. (2735.06 ±474.97 ) mm3,P ＜0.01 ],decreased pulmonary metastasis (0/6 vs.8/10,P ＜0.01 ),and prolonged survival [ ( 81.67 ± 8.51 ) days vs.( 60.17 ± 5.42 ) days,P ＜ 0.05 ].HAL followed by celecoxib at a dose of 12.5 mg/kg every day neither slowed down residual tumors growth nor prolonged survival,but inhibited the formation of pulmonary metastatic nodules though the difference (compared with sham operation) was not statistically significant (2/6 vs.8/10,P ＞0.05).Interestingly,as shown in supplementary study,we did not detect the conspicuous changes of COX-2 expression in tumor tissues-derived HAL with low dose celecoxib-trcated mice,while the striking decrease of COX-2 expression was observed in treatments by HAL combined with moderate or high dose celecoxib.Conclusion HLA leads to local or systemic inflammatory reaction,which is inhibited by celecoxib as accompanied with arrest of HAL-induced metastatic potential in residual HCC cells.
