肝细胞生长因子对大鼠肺移植缺血再灌注损伤的保护作用
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摘要
肺移植已成为肺纤维化、原发性肺动脉高压、肺气肿、支气管扩张等慢性终末期肺病的最有效治疗措施,在肺移植中缺血再灌注所致肺损伤是移植失败和早期肺移植患者死亡的主要原因,因而如何减轻缺血再灌注损伤已成为现阶段研究的重要课题。缺血再灌注的病理生理过程中,氧自由基的快速大量产生及细胞间Ca2+积聚,这两种情况均可导致细胞凋亡的发生。肝细胞生长因子(hepatocyte growth factor HGF)具有很强的促进肺上皮细胞生长、抑制缺血-再灌注诱导的肺上皮细胞凋亡作用,故我们运用HGF的抗凋亡活性,起到减轻肺缺血再灌注的损伤的作用。课题分为以下两个部分:
第一部分:改良三袖套法建立大鼠左肺原位移植动物模型
目的探讨建立更稳定有效的大鼠原位左肺移植模型。
方法将40只SD大鼠随机配对,采用三袖套法建立大鼠肺移植模型。
结果进行大鼠左肺原位移植正式实验20例,手术平均时间(65±4)min。手术成功率85%。血气、病理学等检查证实成功复制了肺移植缺血再灌注模型。
讨论该方法操作成功率高,经济实用,高度模仿临床肺移植,可用于肺移植缺血再灌注损伤的实验研究。
第二部分:肝细胞生长因子对大鼠肺移植缺血再灌注损伤的保护作用
目的通过建立大鼠肺移植缺血再灌注模型,探讨肝细胞生长因子对大鼠肺移植缺血再灌注损伤的影响及其作用机制。
方法实验分3组,即假手术对照组(A组)、空白对照组(B组)和HGF组(C组),每组8例。B组用4℃LPDG液灌洗并保存供肺4h,C组用含HGF(10ug/100ml)的4℃LPDG液灌洗并保存供肺4h。移植肺再灌注2h后结束实验。测定肺组织湿-干重比、MPO活性,观察移植肺组织病理改变,ELISA测定TNF-α表达水平,免疫组化染色检测c-met表达,RT-PCR检测Bcl-2 mRNA的水平,TUNEL检测细胞凋亡。
结果与空白对照组比较,HGF组肺组织损伤程度明显减轻,肺组织湿干重比、MPO活性、TNF-α均有下降(P < 0.01)。c-met、Bcl-2 mRNA的表达水平较空白对照组明显增加(P < 0.01)。
讨论HGF能有效地减轻移植肺缺血再灌注损伤,明显改善移植肺功能,其保护作用可能与刺激c-met的表达,增加抗凋亡基因bcl-2的表达有关。
Lung transplantation has become the most effective therapeutic measure for chronicity pulmonary tuberculosis at the final stage, such as pulmonary fibrosis, primary pulmonary hypertension, emphysema, bronchiectasis and so on. While lung transplantation ischemia reperfusion injury(IRI) is the main cause of the transportation failure and patients’death at the earlier period. Therefore, how to lessen ischemical reperfusion injury has been the major point at the very present study period. During the patho and physio process of ischemia reperfusion, rapidly increasing oxyradicals and accumulation of Ca2 + among cells may lead to the apoptosis.Hepatocyte growth factor HGF has extreme effection on enhancement of pulmonary epithelial cells and suppression on IRI which leads to apoptosis pulmonary epithelial cells. Hence, we make full use of antiapoptosis of HGF which can alleviate the pulmonary I/R injury. This whole study consists of two parts as follows:
1. To establish rat orthotopic left pulmonary allograft transplantation by improving the“cuff-like”vessel anastomosis technique.
Objective To establish a more stable and effective rat orthotopic left pulmonary allograft transplantation models.
Methods 40 rats were randomly divided into two groups: donors group and recipients group. Pulmonary arteries and veins were anastomosed by traditional cuff technique.Bronchi was reconstructed by stent technique
Results 20 cases of rat orthotopic left pulmonary allograft transplantation was finished successfully. The total time of surgical procedure was (65±4)min. The operation successful rate was 85%. By blood gas and pathologic study we successfully found the typical lung ischemia reperfusion injury model.
Conclusion It is an economical and successful model in highly imitating clinic lung transplantation, which can be used in lung ischemia reperfusion injury,
2. Protection of Hepatocyte Growth Factor in Rat’s Lungs Preservation
Objective To establish a more stable and effective rat orthotopic left pulmonary allograft transplantation models. To discuss the protection and mechanisms of hepatocyte growth factor in transplantated rat’s lungs from ischemia reperfusion injury.
Methods This study was divided into three groups: sham operation control group(A group),empty control group(B group) and HGF group(C group). Every group had 8 cases.The harvested lung blocks were flushed and stored in 4℃low-potassium-dextran and glucose (LPDG) solution for 4 hours in B group. 4℃LPDG solution which contains HGF(10ug/100ml)was used in C group. The experiment was over after flushing the transplanted lung 2h. The transplanted lung tissue wet-to-dry (W/D) ratio and activity of myeloperoxidase (MPO) were measured. TNF-αwas detected by ELISA. C-met were detected by immunohistochemical staining. Bcl-2 mRNA was detected by RT-PCR. Apoptosis is detected by TUNEL.
Results Comparing with the empty control group, obviously, the degree of lung tissue injury in the HGF group reduces, and the lung tissue wet-dry weight ratio, MPO activity, TNF-αalso decrease (P <0.01). Moreover, the expression levels of c-met, Bcl-2 mRNA increased significantly (P <0.01), too.
Conclusion HGF can effectively reduce IRI and further improve transplanted lung functions.The protection mechanism is probably associated with the stimulation of c-met and bcl-2 expression.
第一部分:改良三袖套法建立大鼠左肺原位移植动物模型
目的探讨建立更稳定有效的大鼠原位左肺移植模型。
方法将40只SD大鼠随机配对,采用三袖套法建立大鼠肺移植模型。
结果进行大鼠左肺原位移植正式实验20例,手术平均时间(65±4)min。手术成功率85%。血气、病理学等检查证实成功复制了肺移植缺血再灌注模型。
讨论该方法操作成功率高,经济实用,高度模仿临床肺移植,可用于肺移植缺血再灌注损伤的实验研究。
第二部分:肝细胞生长因子对大鼠肺移植缺血再灌注损伤的保护作用
目的通过建立大鼠肺移植缺血再灌注模型,探讨肝细胞生长因子对大鼠肺移植缺血再灌注损伤的影响及其作用机制。
方法实验分3组,即假手术对照组(A组)、空白对照组(B组)和HGF组(C组),每组8例。B组用4℃LPDG液灌洗并保存供肺4h,C组用含HGF(10ug/100ml)的4℃LPDG液灌洗并保存供肺4h。移植肺再灌注2h后结束实验。测定肺组织湿-干重比、MPO活性,观察移植肺组织病理改变,ELISA测定TNF-α表达水平,免疫组化染色检测c-met表达,RT-PCR检测Bcl-2 mRNA的水平,TUNEL检测细胞凋亡。
结果与空白对照组比较,HGF组肺组织损伤程度明显减轻,肺组织湿干重比、MPO活性、TNF-α均有下降(P < 0.01)。c-met、Bcl-2 mRNA的表达水平较空白对照组明显增加(P < 0.01)。
讨论HGF能有效地减轻移植肺缺血再灌注损伤,明显改善移植肺功能,其保护作用可能与刺激c-met的表达,增加抗凋亡基因bcl-2的表达有关。
Lung transplantation has become the most effective therapeutic measure for chronicity pulmonary tuberculosis at the final stage, such as pulmonary fibrosis, primary pulmonary hypertension, emphysema, bronchiectasis and so on. While lung transplantation ischemia reperfusion injury(IRI) is the main cause of the transportation failure and patients’death at the earlier period. Therefore, how to lessen ischemical reperfusion injury has been the major point at the very present study period. During the patho and physio process of ischemia reperfusion, rapidly increasing oxyradicals and accumulation of Ca2 + among cells may lead to the apoptosis.Hepatocyte growth factor HGF has extreme effection on enhancement of pulmonary epithelial cells and suppression on IRI which leads to apoptosis pulmonary epithelial cells. Hence, we make full use of antiapoptosis of HGF which can alleviate the pulmonary I/R injury. This whole study consists of two parts as follows:
1. To establish rat orthotopic left pulmonary allograft transplantation by improving the“cuff-like”vessel anastomosis technique.
Objective To establish a more stable and effective rat orthotopic left pulmonary allograft transplantation models.
Methods 40 rats were randomly divided into two groups: donors group and recipients group. Pulmonary arteries and veins were anastomosed by traditional cuff technique.Bronchi was reconstructed by stent technique
Results 20 cases of rat orthotopic left pulmonary allograft transplantation was finished successfully. The total time of surgical procedure was (65±4)min. The operation successful rate was 85%. By blood gas and pathologic study we successfully found the typical lung ischemia reperfusion injury model.
Conclusion It is an economical and successful model in highly imitating clinic lung transplantation, which can be used in lung ischemia reperfusion injury,
2. Protection of Hepatocyte Growth Factor in Rat’s Lungs Preservation
Objective To establish a more stable and effective rat orthotopic left pulmonary allograft transplantation models. To discuss the protection and mechanisms of hepatocyte growth factor in transplantated rat’s lungs from ischemia reperfusion injury.
Methods This study was divided into three groups: sham operation control group(A group),empty control group(B group) and HGF group(C group). Every group had 8 cases.The harvested lung blocks were flushed and stored in 4℃low-potassium-dextran and glucose (LPDG) solution for 4 hours in B group. 4℃LPDG solution which contains HGF(10ug/100ml)was used in C group. The experiment was over after flushing the transplanted lung 2h. The transplanted lung tissue wet-to-dry (W/D) ratio and activity of myeloperoxidase (MPO) were measured. TNF-αwas detected by ELISA. C-met were detected by immunohistochemical staining. Bcl-2 mRNA was detected by RT-PCR. Apoptosis is detected by TUNEL.
Results Comparing with the empty control group, obviously, the degree of lung tissue injury in the HGF group reduces, and the lung tissue wet-dry weight ratio, MPO activity, TNF-αalso decrease (P <0.01). Moreover, the expression levels of c-met, Bcl-2 mRNA increased significantly (P <0.01), too.
Conclusion HGF can effectively reduce IRI and further improve transplanted lung functions.The protection mechanism is probably associated with the stimulation of c-met and bcl-2 expression.
引文
1.Hertz M,Taylor D,Trulock E,etal.The Registry of the International Society for Heart and Lung transplantation: nineteenth official report:2002. J Heart Lung Transplant 2002,21:950-970.
2.Fischer S,Cassivi SD, Xavier A,et al,Cell death in human lung transplantation:apoptosis induction in human lungs during ischemia and after transplantation.Ann Surg 2000,231:424-431.
3.Quadri SM,Segall L,de Perrot M, et al.Caspase inhibition improve ischemia-reperfusion injury after lung transplantation. Am J Transplant, 2005,5;292-299.
4.Nakagami H, Morishita R, Yamamoto K, et al. Hepatocyte growth factor prevents endothelial cell death through inhibition of bax transloction from cytosol to mitochondrial membrance. Diabetes, 2002 51 (8):2604-2611.
5.Akiko Makiuchi, Kazuhiro Yamaura, Shinya Mizuno, et al. Hepatocyte Growth Factor Prevents Pulmonary Ischemia–Reperfusion Injury in Mice.J Heart Lung Transplant 2007;26:935–943.
6.宫素岗,刘锦铭,贾向波,大鼠同种异体左肺原位移植模型的改进.同济大学学报,2007,28(1):93-95.
7.Mizuta T, Nakahara K, Shirakura R, et al.Total nonmicrosuturetechnique for rat lung transplantation J Thorac Cardiovasc Surg,1991,102:159-160.
8.Reis A,Giaid A,Serrick C,et al. Improved outcome of rat lung transplantation with modification of the non suture external cuff technique. J Heart Lung Transplant, 1995,14(2):274-279.
9.张新,陈如冲,高颖欣,等.一种新的大鼠肺移植模型.中华器官移植杂志,2005 ,26(3):178-179.
10.Mason RJ,Leslie CC, McCormick-Shannon K,et al. Hepatocyte growth factor is a growth factor for rat alveolar type II cells. Am J Respir Cell Mol Biol. 1994;11(5):561-567.
11.Cooper JD, Pearson FG, Patterson GA, et al. Technique of successful lung transplantation in humans. J Thorac Cardiovasc Surg, 1987, 93:173-181.
12.De Perrot M, Liu M, Waddell TK, Keshavjee S.Ischemia-reperfusion-induced lung injury.Am J Respir Crit Care Med, 2003,167(4):490-511.
13.McCord JM.Oxygen-derived free radicals in postischemic tissue injury.N Engl J Med, 1985,312(3):159-163.
14.Al-Mehdi AB,Shuman H,Fisher AB.Intracellular generation of reactive oxygen species during nonhypoxic lung ischemia.Am J Physiol,1997,272:L294-L300.
15.Yokomise H,Ueno T,Yamazaki F,et al.The effect and optimal time of administration of verapamil on lung preservation.Transplantation,1990,49:1039-1043.
16.Piekford MA,Gower JD,Dore C,et al.Lipid peroxidation and ultrastruetural changes in rat lung isografts after single-passage organ flush and 48-hour cold storage with and without one-hour reperfusion in vivo.Transplantation,1990,50:210-218.
17.Karek M,Haverich A,Nifedipine and diltiazem reduce pulmonary edema formation during postischemic reperfusion of the rabbit lung.Res Exp Med(Berl),1992,192:137-144.
18.Shimamatsu K, Wanless IR. Role of ischemia in causing apoptosis,atrophp,and nodular hyperplasia in human liver[J] Hepatology,1997,26﹙2﹚:343-350.
19.Dieperink HI, Blackwell TS, Prince LS. Hyperoxia and apoptosis in developing mouse lung mesenchyme. Pediatr Res. 2006;59(2):185-190.
20.Akiko Makiuchi, Kazuhiro Yamaura, Shinya Mizuno, et al. Hepatocyte Growth Factor Prevents Pulmonary Ischemia–Reperfusion Injury in Mice.J Heart Lung Transplant 2007;26:935–943.
21.UZ Stammberger, Ariana Gaspert,Sven Hillinger, et al. Apoptosis induced by ischemia and reperfusion in experimental lung transplantation.Ann Thorac Surg.2000;69:1532-1536.
22.谢东甫,秦雄,徐志飞.大鼠肺缺血再灌注损伤引起肺细胞的凋亡.第二军医大学学报,2004,25﹙3﹚:295-297
23.Barrington R,Zhang M, Fischer M, et al. The role of complement in inflammation and adaptive immunity.Immunol Rev.2001;180:5-15.
24.Mason RJ, Leslie CC, McCormick-Shannon K. Deterding RR, Nakamura T, Rubin JS,Shannon JM. Hepatocyte growth factor is a growth factor for rat alveolar type IIcells. Am J Respir Cell Mol Biol. 1994;11(5):561-567.
25.Thompson CB.Apoptosis in the pathogenesis and treatment of disease[J]science 1995.267:1456-1462.
26.Buttke TM.Sandstrom PA.Oxidative stress as a mediator of apoptosis[J]Immanol Today,l994,15﹙1﹚7-10.
27. Fischer S , Cassivi SD , Xavier A , et al , Cell death in human lung transplantation:apoptosis induction in human lungs during ischemia and after transplantation.Ann Surg 2000,231:424-431.
28.Quadri SM, Segall L, de Perrot M, et al. Caspase inhibition improve ischemia-reperfusion injury after lung transplantation. Am J Transplant, 2005,5;292-299.
29.Granville DJ, Cassidy BA,Ruehlmann D0, et al.Mitochondrial release of apoptosis-inducing factor and cytochrome c during smooth muscle cell apoptosis.Am J Pathol,2001,159,305-311.
30.Kamesaki S,Kamesaki H ,Jorgensen TJ,et al, Bcl-2 protein inhibit etopside induced apoptosis through its effects on events subsequent to topoisomerase induced DNA strand breaks and their repair.Cancer Res,1993,53﹙18﹚:4251-4256.
31.Akiko Makiuchi, Kazuhiro Yamaura, Shinya Mizuno, et al. Hepatocyte Growth Factor Prevents Pulmonary Ischemia–Reperfusion Injury in Mice.J Heart Lung Transplant 2007;26:935–943.
32. Hu Y, Benedict MA,Wu D, et al.Bcl-xl interacts with Apaf-1 and inhibits Apaf-l-dependent caspase-9 ctivation[J].Proc Natl Acad Sci USA , 1998 ,95(8):4386-4391.
33.Nakamura T Nawa K,Chihara A. Partial purification andcharacterization of hepatocyte growth factor from serum ofhepatectomized rats .Biochem Biophys Res Commun,1984,122(3):1450-1455.
34.Nakagami H, Morishita R, Yamamoto K, et al. Hepatocyte growth factor prevents endothelial cell death through inhibition of bax transloction from cytosol to mitochondrial membrance. Diabetes, 2002,51(8):2604-2611.
35.Tomita N,Morish ita R, Taniyama Y, et al. Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis, ets-1. Circulation, 2003,107(10):1411-1417.
36.Nakagami H,Morishita R, Yamamoto K, et al. Mitogenic and antiapoptotic action of hepatocyte growth factor through ERK,STAT3,and Akt in endothelial cells. Hypertension, 2001, 37 (part 2):581-586.
37.Wang X, Zhou Y, Kim HP,et al. Hepatocyte Growth Factor Protects against Hypoxia/ Reoxygenation-induced Apoptosis in Endothelial Cells.J Biol Chem ,2004 ,279:5237-5243.
38.Yamada T ,Hisanaga M ,Nakajima Y,et al. Enhanced expression of hepatocyte growth factor by pulmonary ischemia-reperfusion injury in the rat. Am J Respir Crit Care Med ,2000,162 ( 2 Pt I):707-715.
39.Akiko Makiuchi, Kazuhiro Yamaura, Shinya Mizuno, et al. Hepatocyte Growth Factor Prevents Pulmonary Ischemia–Reperfusion Injury in Mice.J Heart Lung Transplant 2007;26:935-943.
40.Nakagami H,Morishita R, Yamamoto K,et al, Mitogenic and antiapoptotic action of hepatocyte growth factor through ERK,STAT3,and Akt in endothelial cells.Hypertension, 2001,37 (part2):581-586.
41.Roggia C,Ukena C, Bohm M, et al. Hepatocyte growth factor enhances cardiac commitment of differentiating embryonic stem cells by activating PI3 kinase. Exp Cell Res. 2007;313(5):921-930.
42.Pugazhenthi S, Nesterova A, Sable C, et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem, 2000, 275(15):10761-10766.
43.Santangelo C, Matarrese P,Masella R, Di Carlo MC, Di Lillo A, Scazzocchio B,Vecci E, Malorni W,Perfetti R, Anastasi E. Hepatocyte growth factor protects rat RINm5F cell line against free fatty acid-induced apoptosis by counteracting oxidative stress. J Mol Endocrinol. 2007;38(1):147-158.
44,Sigaud S, Evelson P, Gonzalez-Flecha B. H202-induced proliferation of primary alveolar epithelial cells is mediated by MAP kinases.Antioxid RedoxSignal.2005;7(1-2):6-13.
45.Matthay MA, Folkesson HG, Clerici C. Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev 2002;82:569–600.
1.Ware LB,Golden JA,Finkbeiner WE,et al. Am J Respir Crit Care Med 1999 159.980-988.
2.Hosenpud JD, Bonnet LE, Keck BM, et al. J Heart Lung Transplant, 1998, 17: 656-668.
3.Haydock DA Trulock EP, Kaiser LR, et al. Ann Thorac Surg,1992, 53: 635-641.
4.King RC,Binns OA,Rodriguez F, et al. Ann Thorac Sure, 2000,69:1681-1685.
5.ChabotF,MitcheLL.JA,Gutteridge.JM,etal.EurRespir.J,1998,11:745-757.
6.A IMehdiAB,ShumanH,FisherAB. Am JPhysiol, 1997,272:L294-300.
7.MCGowan FX , Ikegam iM , PJ delNido, etal,Thorac Cardiovasc Surg1993.106:968-977.
8.ElliottSJ,Meszaros,JG,Schilling,WP:FreeRadBiolMed, 1992,13:635-650.
9.Saris NE, CarafoliE.Bicchem istry, 2005, 70 (2):187-194.
10.Leist,NE,Nicotera,P.Bicchem Biophys ResCommun, 1997;236(1):1-9.
11.SerrickC,AdoumieR,Giaid,etal.Transplantation,1994,58:1158-1162.
12.RolfeMW , KunkeISL , DeM eesterSR , etaL Am Rev Respir D is, 1993,147(4):1010-6.
13.de,PerrotM,Sekine,Y,Fischer,S,Waddell,TK,etaL,Am,JrespirCrit CareMed,2002. 165,211-215.
14.TomasdottirH , H jartarson H , Ricksten A , etal. A nesth Analg, 2003;97(4)944-949.
15.Hosenpud ,JD , Bennett LE,Keck BM,JHeart Lung Transp lant,2000,19:909-931.
16.SuM,ChiEY,Bishop,MJ,etaLl.Am RevRespirDis,l993,147:448-456.
17.BarrML,Carey JN,Nishanian GP,etal JThorac Cardiovasc Surg, 1998,115:631-636.
18.ZamoraCA,Baron DA,Heffner JE.JApplphysiol,1993,74:224-229.
19.Kimblad PO,Green K,Sjoberg,etal.JHeart Lung Transplant,1996,
15(10):999-1004.
20.SatoY,HoggJC,EnglishD,etal,Am,RespirCellMolBiol,2000,23:404-410.
21Abraham D,TaghaviS,Rim IP, etal.Transplantation, 2002, 73:1703-1706.
22.McMrllan,DM,Bekker,JM,parry AJ,etal. Circulation, 2000,3,172-178.
23.Le,Cras,TD,McMurtry ,IF.AmJPhysiolLungCellMolPhysiol,2001,280;L575-582.
24.LiuM,Tremblavl,CassiviSD,etal,AM,Jphvsio:LungCellMolPhysiol,2000,278; L1071-1081.
25. Lick SD , Brown PS,Jr, KuruszM , etal.Ann Thorac Surg, 2000,69, (3),910-910.
26.FemandezL,Heredia N,Grandel,etal,Hepatology, 2002,36: 562-572.
27.Ilhan Inci, Wei Zhai,etal. Ann Thorac Surg 2007;84:240–6.
28.朱红军、于曙东等,中华实验外科杂志,2007,23:277-279.
29.尤颢、廖崇先等,中华器官移植杂志,2004,25:212-214.
30 .Suda T, Mora BN,D Ovidio F,et al. J Thorac Cardiovasc Surg, 2000,119(2):297-304.
31.Itano H,Zhang W,Bitter ,JH,et al. J Thorac Cardiovasc Surg, 2000, 120: 947-956 .
32.康明强,林培裘,林若柏,中华医学杂志,2007, (87):3425-3429.
33. Murry CE et al.Cirulation,1986; 74(5): 1124-1136.
34.H. Burak Kandilci and Bulent Gumusel,Experimental Lung Research, 32:287–303, 2006.
35.Nakamura T Nawa K,I chihara A. Biochem Biophys Res Commun,1984,122 (3):1450-1455.
36.Nakagami H, Morishita R, Yamamoto K, et al. Diabetes, 2002 51 (8):2604-2611.
37.Tomita N , Morish ita R, Taniyama Y, et al. Circulation, 2003, 107 (10):1411-1417.
38.Nakagami H, Morishita R, Yamamoto K, et al. Hypertension, 2001, 37 (part 2):581-586.
39.丘玉昌,国外医学,生理病理科学与临床分册,1999,19(1):67-69.
40.Wang X, Zhou Y, Kim HP , Song R , et al. J Biol Chem ,2004 ,279 :5237-5243.
41.Yamada T ,Hisanaga M ,Nakajima Y,et al. Am J Respir Crit Care Med ,2000,162 ( 2 Pt I):707-715.
42.Akiko Makiuchi,Kazuhiro Yamaura, Shinya Mizuno, et al.J Heart Lung Transplant 2007;26:935–43.
43. HischerS,Liu M,Maclian AA,etal,Hum Gene THe,2001,12:1513-1526.
44.Nagase T, IshiiS, KumeK,eta1.JC lin Invest 1999,104:1071-1076.
2.Fischer S,Cassivi SD, Xavier A,et al,Cell death in human lung transplantation:apoptosis induction in human lungs during ischemia and after transplantation.Ann Surg 2000,231:424-431.
3.Quadri SM,Segall L,de Perrot M, et al.Caspase inhibition improve ischemia-reperfusion injury after lung transplantation. Am J Transplant, 2005,5;292-299.
4.Nakagami H, Morishita R, Yamamoto K, et al. Hepatocyte growth factor prevents endothelial cell death through inhibition of bax transloction from cytosol to mitochondrial membrance. Diabetes, 2002 51 (8):2604-2611.
5.Akiko Makiuchi, Kazuhiro Yamaura, Shinya Mizuno, et al. Hepatocyte Growth Factor Prevents Pulmonary Ischemia–Reperfusion Injury in Mice.J Heart Lung Transplant 2007;26:935–943.
6.宫素岗,刘锦铭,贾向波,大鼠同种异体左肺原位移植模型的改进.同济大学学报,2007,28(1):93-95.
7.Mizuta T, Nakahara K, Shirakura R, et al.Total nonmicrosuturetechnique for rat lung transplantation J Thorac Cardiovasc Surg,1991,102:159-160.
8.Reis A,Giaid A,Serrick C,et al. Improved outcome of rat lung transplantation with modification of the non suture external cuff technique. J Heart Lung Transplant, 1995,14(2):274-279.
9.张新,陈如冲,高颖欣,等.一种新的大鼠肺移植模型.中华器官移植杂志,2005 ,26(3):178-179.
10.Mason RJ,Leslie CC, McCormick-Shannon K,et al. Hepatocyte growth factor is a growth factor for rat alveolar type II cells. Am J Respir Cell Mol Biol. 1994;11(5):561-567.
11.Cooper JD, Pearson FG, Patterson GA, et al. Technique of successful lung transplantation in humans. J Thorac Cardiovasc Surg, 1987, 93:173-181.
12.De Perrot M, Liu M, Waddell TK, Keshavjee S.Ischemia-reperfusion-induced lung injury.Am J Respir Crit Care Med, 2003,167(4):490-511.
13.McCord JM.Oxygen-derived free radicals in postischemic tissue injury.N Engl J Med, 1985,312(3):159-163.
14.Al-Mehdi AB,Shuman H,Fisher AB.Intracellular generation of reactive oxygen species during nonhypoxic lung ischemia.Am J Physiol,1997,272:L294-L300.
15.Yokomise H,Ueno T,Yamazaki F,et al.The effect and optimal time of administration of verapamil on lung preservation.Transplantation,1990,49:1039-1043.
16.Piekford MA,Gower JD,Dore C,et al.Lipid peroxidation and ultrastruetural changes in rat lung isografts after single-passage organ flush and 48-hour cold storage with and without one-hour reperfusion in vivo.Transplantation,1990,50:210-218.
17.Karek M,Haverich A,Nifedipine and diltiazem reduce pulmonary edema formation during postischemic reperfusion of the rabbit lung.Res Exp Med(Berl),1992,192:137-144.
18.Shimamatsu K, Wanless IR. Role of ischemia in causing apoptosis,atrophp,and nodular hyperplasia in human liver[J] Hepatology,1997,26﹙2﹚:343-350.
19.Dieperink HI, Blackwell TS, Prince LS. Hyperoxia and apoptosis in developing mouse lung mesenchyme. Pediatr Res. 2006;59(2):185-190.
20.Akiko Makiuchi, Kazuhiro Yamaura, Shinya Mizuno, et al. Hepatocyte Growth Factor Prevents Pulmonary Ischemia–Reperfusion Injury in Mice.J Heart Lung Transplant 2007;26:935–943.
21.UZ Stammberger, Ariana Gaspert,Sven Hillinger, et al. Apoptosis induced by ischemia and reperfusion in experimental lung transplantation.Ann Thorac Surg.2000;69:1532-1536.
22.谢东甫,秦雄,徐志飞.大鼠肺缺血再灌注损伤引起肺细胞的凋亡.第二军医大学学报,2004,25﹙3﹚:295-297
23.Barrington R,Zhang M, Fischer M, et al. The role of complement in inflammation and adaptive immunity.Immunol Rev.2001;180:5-15.
24.Mason RJ, Leslie CC, McCormick-Shannon K. Deterding RR, Nakamura T, Rubin JS,Shannon JM. Hepatocyte growth factor is a growth factor for rat alveolar type IIcells. Am J Respir Cell Mol Biol. 1994;11(5):561-567.
25.Thompson CB.Apoptosis in the pathogenesis and treatment of disease[J]science 1995.267:1456-1462.
26.Buttke TM.Sandstrom PA.Oxidative stress as a mediator of apoptosis[J]Immanol Today,l994,15﹙1﹚7-10.
27. Fischer S , Cassivi SD , Xavier A , et al , Cell death in human lung transplantation:apoptosis induction in human lungs during ischemia and after transplantation.Ann Surg 2000,231:424-431.
28.Quadri SM, Segall L, de Perrot M, et al. Caspase inhibition improve ischemia-reperfusion injury after lung transplantation. Am J Transplant, 2005,5;292-299.
29.Granville DJ, Cassidy BA,Ruehlmann D0, et al.Mitochondrial release of apoptosis-inducing factor and cytochrome c during smooth muscle cell apoptosis.Am J Pathol,2001,159,305-311.
30.Kamesaki S,Kamesaki H ,Jorgensen TJ,et al, Bcl-2 protein inhibit etopside induced apoptosis through its effects on events subsequent to topoisomerase induced DNA strand breaks and their repair.Cancer Res,1993,53﹙18﹚:4251-4256.
31.Akiko Makiuchi, Kazuhiro Yamaura, Shinya Mizuno, et al. Hepatocyte Growth Factor Prevents Pulmonary Ischemia–Reperfusion Injury in Mice.J Heart Lung Transplant 2007;26:935–943.
32. Hu Y, Benedict MA,Wu D, et al.Bcl-xl interacts with Apaf-1 and inhibits Apaf-l-dependent caspase-9 ctivation[J].Proc Natl Acad Sci USA , 1998 ,95(8):4386-4391.
33.Nakamura T Nawa K,Chihara A. Partial purification andcharacterization of hepatocyte growth factor from serum ofhepatectomized rats .Biochem Biophys Res Commun,1984,122(3):1450-1455.
34.Nakagami H, Morishita R, Yamamoto K, et al. Hepatocyte growth factor prevents endothelial cell death through inhibition of bax transloction from cytosol to mitochondrial membrance. Diabetes, 2002,51(8):2604-2611.
35.Tomita N,Morish ita R, Taniyama Y, et al. Angiogenic property of hepatocyte growth factor is dependent on upregulation of essential transcription factor for angiogenesis, ets-1. Circulation, 2003,107(10):1411-1417.
36.Nakagami H,Morishita R, Yamamoto K, et al. Mitogenic and antiapoptotic action of hepatocyte growth factor through ERK,STAT3,and Akt in endothelial cells. Hypertension, 2001, 37 (part 2):581-586.
37.Wang X, Zhou Y, Kim HP,et al. Hepatocyte Growth Factor Protects against Hypoxia/ Reoxygenation-induced Apoptosis in Endothelial Cells.J Biol Chem ,2004 ,279:5237-5243.
38.Yamada T ,Hisanaga M ,Nakajima Y,et al. Enhanced expression of hepatocyte growth factor by pulmonary ischemia-reperfusion injury in the rat. Am J Respir Crit Care Med ,2000,162 ( 2 Pt I):707-715.
39.Akiko Makiuchi, Kazuhiro Yamaura, Shinya Mizuno, et al. Hepatocyte Growth Factor Prevents Pulmonary Ischemia–Reperfusion Injury in Mice.J Heart Lung Transplant 2007;26:935-943.
40.Nakagami H,Morishita R, Yamamoto K,et al, Mitogenic and antiapoptotic action of hepatocyte growth factor through ERK,STAT3,and Akt in endothelial cells.Hypertension, 2001,37 (part2):581-586.
41.Roggia C,Ukena C, Bohm M, et al. Hepatocyte growth factor enhances cardiac commitment of differentiating embryonic stem cells by activating PI3 kinase. Exp Cell Res. 2007;313(5):921-930.
42.Pugazhenthi S, Nesterova A, Sable C, et al. Akt/protein kinase B up-regulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem, 2000, 275(15):10761-10766.
43.Santangelo C, Matarrese P,Masella R, Di Carlo MC, Di Lillo A, Scazzocchio B,Vecci E, Malorni W,Perfetti R, Anastasi E. Hepatocyte growth factor protects rat RINm5F cell line against free fatty acid-induced apoptosis by counteracting oxidative stress. J Mol Endocrinol. 2007;38(1):147-158.
44,Sigaud S, Evelson P, Gonzalez-Flecha B. H202-induced proliferation of primary alveolar epithelial cells is mediated by MAP kinases.Antioxid RedoxSignal.2005;7(1-2):6-13.
45.Matthay MA, Folkesson HG, Clerici C. Lung epithelial fluid transport and the resolution of pulmonary edema. Physiol Rev 2002;82:569–600.
1.Ware LB,Golden JA,Finkbeiner WE,et al. Am J Respir Crit Care Med 1999 159.980-988.
2.Hosenpud JD, Bonnet LE, Keck BM, et al. J Heart Lung Transplant, 1998, 17: 656-668.
3.Haydock DA Trulock EP, Kaiser LR, et al. Ann Thorac Surg,1992, 53: 635-641.
4.King RC,Binns OA,Rodriguez F, et al. Ann Thorac Sure, 2000,69:1681-1685.
5.ChabotF,MitcheLL.JA,Gutteridge.JM,etal.EurRespir.J,1998,11:745-757.
6.A IMehdiAB,ShumanH,FisherAB. Am JPhysiol, 1997,272:L294-300.
7.MCGowan FX , Ikegam iM , PJ delNido, etal,Thorac Cardiovasc Surg1993.106:968-977.
8.ElliottSJ,Meszaros,JG,Schilling,WP:FreeRadBiolMed, 1992,13:635-650.
9.Saris NE, CarafoliE.Bicchem istry, 2005, 70 (2):187-194.
10.Leist,NE,Nicotera,P.Bicchem Biophys ResCommun, 1997;236(1):1-9.
11.SerrickC,AdoumieR,Giaid,etal.Transplantation,1994,58:1158-1162.
12.RolfeMW , KunkeISL , DeM eesterSR , etaL Am Rev Respir D is, 1993,147(4):1010-6.
13.de,PerrotM,Sekine,Y,Fischer,S,Waddell,TK,etaL,Am,JrespirCrit CareMed,2002. 165,211-215.
14.TomasdottirH , H jartarson H , Ricksten A , etal. A nesth Analg, 2003;97(4)944-949.
15.Hosenpud ,JD , Bennett LE,Keck BM,JHeart Lung Transp lant,2000,19:909-931.
16.SuM,ChiEY,Bishop,MJ,etaLl.Am RevRespirDis,l993,147:448-456.
17.BarrML,Carey JN,Nishanian GP,etal JThorac Cardiovasc Surg, 1998,115:631-636.
18.ZamoraCA,Baron DA,Heffner JE.JApplphysiol,1993,74:224-229.
19.Kimblad PO,Green K,Sjoberg,etal.JHeart Lung Transplant,1996,
15(10):999-1004.
20.SatoY,HoggJC,EnglishD,etal,Am,RespirCellMolBiol,2000,23:404-410.
21Abraham D,TaghaviS,Rim IP, etal.Transplantation, 2002, 73:1703-1706.
22.McMrllan,DM,Bekker,JM,parry AJ,etal. Circulation, 2000,3,172-178.
23.Le,Cras,TD,McMurtry ,IF.AmJPhysiolLungCellMolPhysiol,2001,280;L575-582.
24.LiuM,Tremblavl,CassiviSD,etal,AM,Jphvsio:LungCellMolPhysiol,2000,278; L1071-1081.
25. Lick SD , Brown PS,Jr, KuruszM , etal.Ann Thorac Surg, 2000,69, (3),910-910.
26.FemandezL,Heredia N,Grandel,etal,Hepatology, 2002,36: 562-572.
27.Ilhan Inci, Wei Zhai,etal. Ann Thorac Surg 2007;84:240–6.
28.朱红军、于曙东等,中华实验外科杂志,2007,23:277-279.
29.尤颢、廖崇先等,中华器官移植杂志,2004,25:212-214.
30 .Suda T, Mora BN,D Ovidio F,et al. J Thorac Cardiovasc Surg, 2000,119(2):297-304.
31.Itano H,Zhang W,Bitter ,JH,et al. J Thorac Cardiovasc Surg, 2000, 120: 947-956 .
32.康明强,林培裘,林若柏,中华医学杂志,2007, (87):3425-3429.
33. Murry CE et al.Cirulation,1986; 74(5): 1124-1136.
34.H. Burak Kandilci and Bulent Gumusel,Experimental Lung Research, 32:287–303, 2006.
35.Nakamura T Nawa K,I chihara A. Biochem Biophys Res Commun,1984,122 (3):1450-1455.
36.Nakagami H, Morishita R, Yamamoto K, et al. Diabetes, 2002 51 (8):2604-2611.
37.Tomita N , Morish ita R, Taniyama Y, et al. Circulation, 2003, 107 (10):1411-1417.
38.Nakagami H, Morishita R, Yamamoto K, et al. Hypertension, 2001, 37 (part 2):581-586.
39.丘玉昌,国外医学,生理病理科学与临床分册,1999,19(1):67-69.
40.Wang X, Zhou Y, Kim HP , Song R , et al. J Biol Chem ,2004 ,279 :5237-5243.
41.Yamada T ,Hisanaga M ,Nakajima Y,et al. Am J Respir Crit Care Med ,2000,162 ( 2 Pt I):707-715.
42.Akiko Makiuchi,Kazuhiro Yamaura, Shinya Mizuno, et al.J Heart Lung Transplant 2007;26:935–43.
43. HischerS,Liu M,Maclian AA,etal,Hum Gene THe,2001,12:1513-1526.
44.Nagase T, IshiiS, KumeK,eta1.JC lin Invest 1999,104:1071-1076.