重组人粒细胞集落刺激因子对急性肝衰竭大鼠模型的作用
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摘要
目的评价重组人粒细胞集落刺激因子(rhG-CSF)对于D-氨基半乳糖(D-GalN)诱导的急性肝衰竭大鼠模型的作用。方法将105只雄性SD大鼠随机分为正常对照组、肝衰竭模型组、rhG-CSF组,每组35只。采用腹腔内注射D-GalN (1400mg/kg)建立急性肝衰竭模型。观察建立模型后12、24、48、72及120 h的肝脏ALT、TBil水平、外周血白细胞计数、肝脏组织病理变化;测定TNFα阳性细胞率。并观察建立模型后120 h生存率。计量资料多组间比较用单因素方差分析,进一步两两比较采用LST-t检验。结果 rhG-CSF组与肝衰竭模型组相比,肝脏HE染色提示除造模后120 h外,其余各个时间点肝细胞变性坏死均更严重;造模后120 h rhG-CSF组的肝脏HE染色提示肝小叶结构恢复相对更完全。rhG-CSF组在5个时间点TNFα阳性细胞率较肝衰竭模型组均有增高趋势。rhG-CSF组ALT及TBil水平在5个时间点均有高于肝衰竭模型组的趋势,两组内比较,ALT水平在造模后24 h差异有统计学意义(P <0. 05),TBil水平在造模后24、48、120 h差异有统计学意义(P <0. 05)。在5个时间点,rhG-CSF组外周血白细胞计数水平均高于肝衰竭模型组,差异均有统计学意义(P值均<0. 05)。rhG-CSF组和肝衰竭模型组相比,120 h生存率差异无统计学意义(P> 0. 05)。结论在急性肝衰竭的急性炎症反应期应用rhG-CSF可能加重肝脏炎症反应。
Objective To investigate the effect of recombinant human granulocyte colony-stimulating factor( rhG-CSF) on acute liver failure( ALF) induced by D-galactosamine( D-GalN) in rats. Methods A total of 105 male Sprague-Dawley rats were randomly divided into healthy control group,liver failure model group,and rhG-CSF group,with 35 rats in each group. A rat model of ALF was established by intraperitoneal injection of D-GalN( 1400 mg/kg). Alanine aminotransferase( ALT) level in the liver,total bilirubin( TBil),peripheral blood leukocyte count,and liver pathological changes were observed at 12,24,48,72,and 120 hours after modeling,and survival rate was observed at 120 hours after modeling. A one-way analysis of variance was used for comparison of continuous data between multiple groups,and the LST-t test was used for further comparison between two groups. Results Compared with the liver failure model group,the rhG-CSF group had a significantly higher degree of hepatocyte degeneration and necrosis at all time points except 120 hours after modeling,and compared with the liver failure model group at 120 hours after modeling,the rhG-CSF group had better recovery of lobular structure on HE staining. Compared with the liver failure model group,the rhG-CSF group had a tendency of increase in the percentage of cells with positive tumor necrosis factor-α at the five time points after modeling. Compared with the liver failure model group,the rhG-CSF group had significantly higher levels of ALT and TBil at all five time points. Both groups had a significant change in ALT level at 24 hours after modeling( P < 0. 05),as well as a significant change in TBil at 24,48,and 120 hours after modeling( P < 0. 05). The rhG-CSF group had a significantly higher peripheral blood leukocyte count than the liver failure model group at all five time points( all P <0. 05). There was no significant difference in survival rate at 120 hours after modeling between the two groups( P > 0. 05). Conclusion Application of rhG-CSF during the stage of acute inflammatory reaction of ALF may aggravate liver inflammatory response.
Objective To investigate the effect of recombinant human granulocyte colony-stimulating factor( rhG-CSF) on acute liver failure( ALF) induced by D-galactosamine( D-GalN) in rats. Methods A total of 105 male Sprague-Dawley rats were randomly divided into healthy control group,liver failure model group,and rhG-CSF group,with 35 rats in each group. A rat model of ALF was established by intraperitoneal injection of D-GalN( 1400 mg/kg). Alanine aminotransferase( ALT) level in the liver,total bilirubin( TBil),peripheral blood leukocyte count,and liver pathological changes were observed at 12,24,48,72,and 120 hours after modeling,and survival rate was observed at 120 hours after modeling. A one-way analysis of variance was used for comparison of continuous data between multiple groups,and the LST-t test was used for further comparison between two groups. Results Compared with the liver failure model group,the rhG-CSF group had a significantly higher degree of hepatocyte degeneration and necrosis at all time points except 120 hours after modeling,and compared with the liver failure model group at 120 hours after modeling,the rhG-CSF group had better recovery of lobular structure on HE staining. Compared with the liver failure model group,the rhG-CSF group had a tendency of increase in the percentage of cells with positive tumor necrosis factor-α at the five time points after modeling. Compared with the liver failure model group,the rhG-CSF group had significantly higher levels of ALT and TBil at all five time points. Both groups had a significant change in ALT level at 24 hours after modeling( P < 0. 05),as well as a significant change in TBil at 24,48,and 120 hours after modeling( P < 0. 05). The rhG-CSF group had a significantly higher peripheral blood leukocyte count than the liver failure model group at all five time points( all P <0. 05). There was no significant difference in survival rate at 120 hours after modeling between the two groups( P > 0. 05). Conclusion Application of rhG-CSF during the stage of acute inflammatory reaction of ALF may aggravate liver inflammatory response.
引文
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[12]YA JC,SHIH LH,YI TL,et al.Gallic acid induces necroptosis via TNF-αsignaling pathway in activated hepatic stellate cells[J].PLo S One,2015,10(3):e0120713.
[13]TOGEL F,ISAAC J,WESTENFELDER C.Hematopoietic stem cell mobilization-associated granulocytosis severely worsens acute renal failure[J].J Am Soc Nephrol,2004,15(5):1261-1267.
[14]KANA S,TAKAAKI O,YU M,et al.Therapy with granulocyte colony-stimulating factor in the chronic stage,but not in the acute stage,improves experimental autoimmune myocarditis in rats via nitric oxide[J].J Mol Cell Cardiol,2010,49(3):469-481.
[15]WINSTON S,ASHISH M,SZE YL,et al.G-CSF for stem cell therapy in acute myocardial infarction:Friend or foe?[J].Cardiovasc Res,2011,89(1):20-30.
[16]MAGGIOLINI S,LENATTI L,MALAFRONTE C,et al.G-CSFadministration in acute myocardial infarction:What is the best timing?[J].Cardiovasc Res,2011,91(1):180-182.
[2]MARIA JT,MARCELINO A,JESU'S MC,et al.An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure[J].World J Gastroenterol,2009,15(25):3086-3098.
[3]VIEYRA DS,JACKSON KA,GOODELL MA.Plasticity and tissue regenerative potential of bone marrow-derived cells[J].Stem Cell Rev,2005,1(1):65-69.
[4]JANG YY,COLLECTOR MI,BAYLIN SB,et al.Hematopoietic stem cells convert into liver cells within days without fusion[J].Nat Cell Biol,2004,6(6):532-539.
[5]VALFRE DBL,FERRERO I,CRAVANZOLA C,et al.Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine:Engraftment and hepatocyte differentiation versus profibrogenic potential[J].Gut,2007,57(2):223-231.
[6]CASHEN AF,LINK D,DEVINE S,et al.Cytokines and stem cell mobilization for autologous and allogeneic transplantation[J].Curr Hematol Rep,2004,3(6):406-412.
[7]MARK AL,SUN Z,WARREN DS,et al.Stem cell mobilization is life saving in an animal model of acute liver failure[J].Ann Surg,2010,252(4):591-596.
[8]KIMURA M,YAMADA T,IWATA H,et al.Preoperative granulocyte-colony stimulating factor(G-CSF)treatment improves congested liver regeneration[J].J Surg Res,2010,158(1):132-137.
[9]ZHANG L,KANG W,LEI Y,et al.Granulocyte colony-stimulating factor treatment ameliorates liver injury and improves survival in rats with d-galactosamine-induced acute liver failure[J].Toxicol Lett,2011,204(1):92-99.
[10]TERBLANCHE J,HICKMAN R.Animal models of fulminant hepatic failure[J].Dig Dis Sci,1991,36(6):770-774.
[11]TUNON MJ,ALVAREZ M,CULEBRAS JM,et al.An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure[J].World J Gastroenterol,2009,15(25):3086-3098.
[12]YA JC,SHIH LH,YI TL,et al.Gallic acid induces necroptosis via TNF-αsignaling pathway in activated hepatic stellate cells[J].PLo S One,2015,10(3):e0120713.
[13]TOGEL F,ISAAC J,WESTENFELDER C.Hematopoietic stem cell mobilization-associated granulocytosis severely worsens acute renal failure[J].J Am Soc Nephrol,2004,15(5):1261-1267.
[14]KANA S,TAKAAKI O,YU M,et al.Therapy with granulocyte colony-stimulating factor in the chronic stage,but not in the acute stage,improves experimental autoimmune myocarditis in rats via nitric oxide[J].J Mol Cell Cardiol,2010,49(3):469-481.
[15]WINSTON S,ASHISH M,SZE YL,et al.G-CSF for stem cell therapy in acute myocardial infarction:Friend or foe?[J].Cardiovasc Res,2011,89(1):20-30.
[16]MAGGIOLINI S,LENATTI L,MALAFRONTE C,et al.G-CSFadministration in acute myocardial infarction:What is the best timing?[J].Cardiovasc Res,2011,91(1):180-182.