博莱霉素致肺纤维化大鼠支气管肺泡灌洗液中蛋白C系统的研究
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摘要
目的:肺纤维化(pulmonary fibrosis,PF)是一种慢性间质性肺病,早期病理改变为肺泡炎,随着时间延长,纤维化逐渐加重,肺功能逐渐减退。预后非常差。有关间质性肺疾病的病因及发病机制目前仍未阐明,近年来研究发现,凝血系统的异常变化可能参与了间质性肺疾病患者肺纤维化的过程。本实验旨在观察博莱霉素致肺纤维化大鼠支气管肺泡灌洗液(BALF)中蛋白C(PC)、活化蛋白C-蛋白C抑制剂复合物(APC-PCI),血清中Ⅲ型前胶原(PCⅢ)的含量,探讨PC系统活性成分的变化及其对肺内凝血活性的升高及肺纤维化形成的影响。
方法:选择体重230g±10g SD清洁级健康雄性大鼠(河北省实验动物中心提供)48只,随机分为博来霉素(BLM)组和生理盐水对照组,每组各24只。博莱霉素组用10%水合氯醛(5mg/kg)腹腔内注射麻醉后,在无菌操作下作颈部正中切口,暴露气管,经穿刺向气管内注入博莱霉素(5mg/kg),于造模后3天、7天、14天、和28天各随机处死6只。对照组在同样条件下以同样方法向气管内注入等量的生理盐水(1.25ml/kg),于造模后3天、7天、14天、28天各随机处死6只。两组动物分别腹主动、静脉放血处死,收集血清保存到﹣70℃冰箱中待测Ⅲ型前胶原的含量。用4℃无菌生理盐水对左肺行肺泡灌洗,离心后保存到﹣70℃冰箱中备用。测定支气管肺泡灌洗液中蛋白C(PC)、活化蛋白C-蛋白C抑制剂复合物(APC-PCI)的含量。右肺下叶置于10%的中性福尔马林中固定,行常规病理切片,HE染色,观察肺内炎症,Masson染色,观察肺内胶原,并进行Szapiel病理分级,观察肺泡炎和肺纤维化的动态变化。实验结果及数据资料采用SPSS软件进行统计学分析。
结果:
1大鼠支气管肺泡灌洗液中蛋白C含量的变化:生理盐水对照组各时间点灌洗液中的蛋白C含量间无显著性差异(P>0.05)。博莱霉素组BALF中蛋白C含量3天时下降,为3.966±0.684,7天时下降最为明显,为1.423±0.799,与对照组比较均有显著性差异(P<0.01),14天较7天有所升高,为5.085±0.728,与对照组比较亦有显著性差异(P<0.05),28天为6.031±0.574,与对照组比较无显著性差异(P>0.05)。
2大鼠支气管肺泡灌洗液中活化蛋白C-蛋白C抑制剂复合物(APC-PCI)
含量的变化:生理盐水对照组各时间灌洗液中活化蛋白C-蛋白C抑制剂复合物的含量间无显著性差异(P>0.05),博莱霉素组BALF中蛋白C含量3天时下降,为55.855±8.555,7天时下降最明显,为31.971±8.296,与对照组比较均有显著性差异(P<0.05,P<0.01),14天较7天有所升高,为58.608±6.599,与对照组比较亦有显著性差异(P<0.05),28天为69.348±9.313,与对照组比较无显著性差异(P>0.05)。
3大鼠血清中Ⅲ型前胶原的含量的变化:生理盐水对照组各时间点Ⅲ型前
胶原的浓度间无显著性差异(P>0.05),博莱霉素组血清中Ⅲ型前胶原含量3天时有所升高,为31.804±5.155,但与对照组比较无显著性差异,7天时升高较明显,为44.209±7.299,与对照组比较有显著性差异(P<0.01),14天较7天有所下降,为33.941±4.384,与对照组比较亦有显著性差异(P<0.05),28天降至约正常水平,为30.239±6.811,与对照组比较无显著性差异(P>0.05)。
且Ⅲ型前胶原水平与活化蛋白C-蛋白C抑制剂复合物水平呈线性负相关(r =-0.633 , P<0.01)。Ⅲ型前胶原水平与蛋白C水平亦呈线性负相关(r=-0.455 , P<0.05)。
结论:
1肺间质纤维化存在血液的高凝状态。在肺泡炎期,支气管肺泡灌洗液中的抗凝活性下降;在肺纤维化期,抗凝活性无明显改变。即凝血活性的异常主要存在于肺泡炎阶段。
2肺内凝血活性的改变与肺内胶原代谢的活动性及肺纤维化的形成相关。PC系统活性的下降及PCⅢ水平的升高提示PC途径作用的减弱与凝血活性的升高及肺纤维化的形成有一定关系。凝血及纤溶系统的异常可能在肺纤维化的发生、发展中起了重要作用。
Objective: Pulmonary fibrosis is a chronic interstitial lung disease,the early pathological changes of alveolitis,with prolonged,ultimately developing pulmonary fibrosis, result in progressively loss of lung function.The prognosis is very poor. The etiology and pathogenesis of interstitial lung disease is still unknown.Resentely,studies suggested that disordered coagulation system may be involved in developmenting of pulmonary fibrosis in patients with interstitial lung disease.This study aimed to observe the changes of protein C、APC-PCI of bronchoalveolar lavage Fluid in Bleomycin-induced lung fibrosis in rats,PCⅢin serum, to investigate the changes of protein C system and the impact on contributing to the excessive procoagulation activity and developmenting of pulmonary fibrosis.
Methods: 48 healthy Sprague-Dawley male rats(provided by Center Experiment Animal of Hebei province) weighing 230g±10g were randomly divided into control group and Bleomycin(BLM) group,24 rats in each group.After intraperitoneal injection of anesthesia by 10% Chloral hydrate(5mg/kg),under sterile operation ,made the neck incision,exposed the bronchi.Lung fibrosis induced by intratracheal injection BLMA5(5mg/kg), on days 3,7,14 and 28,six rats were killed randomly from each group at each point. The control group animals were treated under the same conditions in the same way to the intratracheal injection of normal saline. On days 3,7,14 and 28,six rats were killed randomly from each group at each point.Rats were sacrificed with abdominal aorta depletion method,collected serum and stored at﹣70℃for later testing the content of PCⅢ. Left lung was lavaged by 4℃saline,after which the BALF was trifuged and stored at﹣70℃.The contents of PC、APC-PCI in BALF were measured.The inferior of right lung tissues were preserved in 10% formalin for histologic interpretation,HE staining was used to investigate alveolitis.Masson staining was used to investigate the extent of collagen deposition.To be classified by the method of Szapiel for studying the development alveolitis and lung fibrosis.The date were analyzed using the SPSS system.
Results:
1 The changs of protein C contents in bronchoalveolar lavage fluid in rats:The contents of protein C was no significant difference in control group(P>0.05). In BLM group,the levels of protein C in BALF became declined from 3rd,3.966±0.684,and on day 7 the difference were the most obvious, 1.423±0.799,there were both significant differences versus control group(P<0.01).On day 14,the contents showed an increasing tendency comprared with 7th,5.085±0.728,the difference was also significant versus control group.Accompanied with the time the content of protein C went on upregulating on day 28, 6.031±0.574, the differences were no significant(P>0.05).
2 The changs of APC-PCI complex contents in bronchoalveolar lavage fluid:The contents of APC-PCI was no significant difference in control group(P>0.05). In BLM group,the levels of protein C in BALF became declined from 3rd,55.855±8.555,and the differences were the most significant on day 7,31.971±8.296,there were both significant differences versus control group(P < 0.05,P < 0.01).On day 14,the contents showed an increasing tendency comprared with 7th,58.608±6.599,the differences were also significant versus control group.Accompanied with the time the contents of protein C went on upregulating on day 28, 69.348±9.313, the difference were no significant(P>0.05).
3 The changs of the contents of typeⅢprocollagen in Serum:The contents of PCⅢwere no difference in control group(P>0.05). In BLM group,the level of PCⅢin BALF had a little increase,but had no significant diffeence compared with control group from 3rd,31.804±5.155,and the difference were more significant on day 7, 44.208±7.299,there were significant differences versus control group(P<0.01).On day 14,the contents showed a declining tendency comprared with 7th, 33.941±4.384,the difference was also significant versus control group (P<0.05). Accompanied with the time the contents of protein C went on declining on day 28, 30.239±6.811, the difference were no significant(P > 0.05).And the levels of PCⅢwere negatively correlation with the levels of protein C.The levels of PCⅢwere also negatively correlation with the levels of APC-PCI.
Conclusions:
1 Excessive procoagulant activity exists in pulmonary interstitial fibrosis. In the alveolitis,the anticoagulation activity was declined in BALF;In the lung fibrosis,it was not obviously change.That is,the change of coagulation activity mainly exists in the alveolitis stage.
2 The change of coagulation activity in the alveolar space and lung interstitium may play a relevant role in the pathogenesis of pulmonary fibrosis. Decreased PC level and increased typeⅢprocollagen level were observed, showed that impairment of PC pathway was the reason for the excessive procoagulant activity and may promote pulmonary fibrosis.These results confirm that disordered coagulation and fibrinolysis system appeared to contribute to the development of pulmonary fibrosis.
方法:选择体重230g±10g SD清洁级健康雄性大鼠(河北省实验动物中心提供)48只,随机分为博来霉素(BLM)组和生理盐水对照组,每组各24只。博莱霉素组用10%水合氯醛(5mg/kg)腹腔内注射麻醉后,在无菌操作下作颈部正中切口,暴露气管,经穿刺向气管内注入博莱霉素(5mg/kg),于造模后3天、7天、14天、和28天各随机处死6只。对照组在同样条件下以同样方法向气管内注入等量的生理盐水(1.25ml/kg),于造模后3天、7天、14天、28天各随机处死6只。两组动物分别腹主动、静脉放血处死,收集血清保存到﹣70℃冰箱中待测Ⅲ型前胶原的含量。用4℃无菌生理盐水对左肺行肺泡灌洗,离心后保存到﹣70℃冰箱中备用。测定支气管肺泡灌洗液中蛋白C(PC)、活化蛋白C-蛋白C抑制剂复合物(APC-PCI)的含量。右肺下叶置于10%的中性福尔马林中固定,行常规病理切片,HE染色,观察肺内炎症,Masson染色,观察肺内胶原,并进行Szapiel病理分级,观察肺泡炎和肺纤维化的动态变化。实验结果及数据资料采用SPSS软件进行统计学分析。
结果:
1大鼠支气管肺泡灌洗液中蛋白C含量的变化:生理盐水对照组各时间点灌洗液中的蛋白C含量间无显著性差异(P>0.05)。博莱霉素组BALF中蛋白C含量3天时下降,为3.966±0.684,7天时下降最为明显,为1.423±0.799,与对照组比较均有显著性差异(P<0.01),14天较7天有所升高,为5.085±0.728,与对照组比较亦有显著性差异(P<0.05),28天为6.031±0.574,与对照组比较无显著性差异(P>0.05)。
2大鼠支气管肺泡灌洗液中活化蛋白C-蛋白C抑制剂复合物(APC-PCI)
含量的变化:生理盐水对照组各时间灌洗液中活化蛋白C-蛋白C抑制剂复合物的含量间无显著性差异(P>0.05),博莱霉素组BALF中蛋白C含量3天时下降,为55.855±8.555,7天时下降最明显,为31.971±8.296,与对照组比较均有显著性差异(P<0.05,P<0.01),14天较7天有所升高,为58.608±6.599,与对照组比较亦有显著性差异(P<0.05),28天为69.348±9.313,与对照组比较无显著性差异(P>0.05)。
3大鼠血清中Ⅲ型前胶原的含量的变化:生理盐水对照组各时间点Ⅲ型前
胶原的浓度间无显著性差异(P>0.05),博莱霉素组血清中Ⅲ型前胶原含量3天时有所升高,为31.804±5.155,但与对照组比较无显著性差异,7天时升高较明显,为44.209±7.299,与对照组比较有显著性差异(P<0.01),14天较7天有所下降,为33.941±4.384,与对照组比较亦有显著性差异(P<0.05),28天降至约正常水平,为30.239±6.811,与对照组比较无显著性差异(P>0.05)。
且Ⅲ型前胶原水平与活化蛋白C-蛋白C抑制剂复合物水平呈线性负相关(r =-0.633 , P<0.01)。Ⅲ型前胶原水平与蛋白C水平亦呈线性负相关(r=-0.455 , P<0.05)。
结论:
1肺间质纤维化存在血液的高凝状态。在肺泡炎期,支气管肺泡灌洗液中的抗凝活性下降;在肺纤维化期,抗凝活性无明显改变。即凝血活性的异常主要存在于肺泡炎阶段。
2肺内凝血活性的改变与肺内胶原代谢的活动性及肺纤维化的形成相关。PC系统活性的下降及PCⅢ水平的升高提示PC途径作用的减弱与凝血活性的升高及肺纤维化的形成有一定关系。凝血及纤溶系统的异常可能在肺纤维化的发生、发展中起了重要作用。
Objective: Pulmonary fibrosis is a chronic interstitial lung disease,the early pathological changes of alveolitis,with prolonged,ultimately developing pulmonary fibrosis, result in progressively loss of lung function.The prognosis is very poor. The etiology and pathogenesis of interstitial lung disease is still unknown.Resentely,studies suggested that disordered coagulation system may be involved in developmenting of pulmonary fibrosis in patients with interstitial lung disease.This study aimed to observe the changes of protein C、APC-PCI of bronchoalveolar lavage Fluid in Bleomycin-induced lung fibrosis in rats,PCⅢin serum, to investigate the changes of protein C system and the impact on contributing to the excessive procoagulation activity and developmenting of pulmonary fibrosis.
Methods: 48 healthy Sprague-Dawley male rats(provided by Center Experiment Animal of Hebei province) weighing 230g±10g were randomly divided into control group and Bleomycin(BLM) group,24 rats in each group.After intraperitoneal injection of anesthesia by 10% Chloral hydrate(5mg/kg),under sterile operation ,made the neck incision,exposed the bronchi.Lung fibrosis induced by intratracheal injection BLMA5(5mg/kg), on days 3,7,14 and 28,six rats were killed randomly from each group at each point. The control group animals were treated under the same conditions in the same way to the intratracheal injection of normal saline. On days 3,7,14 and 28,six rats were killed randomly from each group at each point.Rats were sacrificed with abdominal aorta depletion method,collected serum and stored at﹣70℃for later testing the content of PCⅢ. Left lung was lavaged by 4℃saline,after which the BALF was trifuged and stored at﹣70℃.The contents of PC、APC-PCI in BALF were measured.The inferior of right lung tissues were preserved in 10% formalin for histologic interpretation,HE staining was used to investigate alveolitis.Masson staining was used to investigate the extent of collagen deposition.To be classified by the method of Szapiel for studying the development alveolitis and lung fibrosis.The date were analyzed using the SPSS system.
Results:
1 The changs of protein C contents in bronchoalveolar lavage fluid in rats:The contents of protein C was no significant difference in control group(P>0.05). In BLM group,the levels of protein C in BALF became declined from 3rd,3.966±0.684,and on day 7 the difference were the most obvious, 1.423±0.799,there were both significant differences versus control group(P<0.01).On day 14,the contents showed an increasing tendency comprared with 7th,5.085±0.728,the difference was also significant versus control group.Accompanied with the time the content of protein C went on upregulating on day 28, 6.031±0.574, the differences were no significant(P>0.05).
2 The changs of APC-PCI complex contents in bronchoalveolar lavage fluid:The contents of APC-PCI was no significant difference in control group(P>0.05). In BLM group,the levels of protein C in BALF became declined from 3rd,55.855±8.555,and the differences were the most significant on day 7,31.971±8.296,there were both significant differences versus control group(P < 0.05,P < 0.01).On day 14,the contents showed an increasing tendency comprared with 7th,58.608±6.599,the differences were also significant versus control group.Accompanied with the time the contents of protein C went on upregulating on day 28, 69.348±9.313, the difference were no significant(P>0.05).
3 The changs of the contents of typeⅢprocollagen in Serum:The contents of PCⅢwere no difference in control group(P>0.05). In BLM group,the level of PCⅢin BALF had a little increase,but had no significant diffeence compared with control group from 3rd,31.804±5.155,and the difference were more significant on day 7, 44.208±7.299,there were significant differences versus control group(P<0.01).On day 14,the contents showed a declining tendency comprared with 7th, 33.941±4.384,the difference was also significant versus control group (P<0.05). Accompanied with the time the contents of protein C went on declining on day 28, 30.239±6.811, the difference were no significant(P > 0.05).And the levels of PCⅢwere negatively correlation with the levels of protein C.The levels of PCⅢwere also negatively correlation with the levels of APC-PCI.
Conclusions:
1 Excessive procoagulant activity exists in pulmonary interstitial fibrosis. In the alveolitis,the anticoagulation activity was declined in BALF;In the lung fibrosis,it was not obviously change.That is,the change of coagulation activity mainly exists in the alveolitis stage.
2 The change of coagulation activity in the alveolar space and lung interstitium may play a relevant role in the pathogenesis of pulmonary fibrosis. Decreased PC level and increased typeⅢprocollagen level were observed, showed that impairment of PC pathway was the reason for the excessive procoagulant activity and may promote pulmonary fibrosis.These results confirm that disordered coagulation and fibrinolysis system appeared to contribute to the development of pulmonary fibrosis.
引文
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12姚咏明,孟海东.进一步认识活化蛋白C在脓毒症治疗中的抗炎作用.武警医学,2007,11:805-808
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14 Esmon C.The protein C pathway.Crit CareM ed,2000,28 (Supp l): 44-48
15 Brueckmann M,Hoffmann U,De Rossi L,et al.Activated protein C inhibits the release of macrophage inflammatory protein-1-alpha from THP-1 cells and from human monocytes.Cytokine,2004,26(3):106-113
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1 Esmon CT.The protein C pathway.Chest.2003,124:26S–32S
2 Vande Wouwer M,Collen D,Conway EM.Thrombomdulin protein C- EP CR system .Biology,2004,24:1 374-385
3 Vincent JL.Microvascular endothelial dysfunction:a renewed appreciation of sepsis pathophysiology.Crit Care,2001,5(suppl 2):S1-S5
4 Sturn DH,Kaneider NC,Feist rizer C,et al.Expression and function of the endothelial cell protein C receptor in human neutrophils. Blood, 2003, 102: 1499-1505
5 Esmon CT.Structure and functions of the endothelial cell protein C recapt- or. Crit Care Med,2004,32:S298-S301
6 Hiroyasu Kobayashi, Gabazza E C,Osamu Taguchi, et al.Protein C antico- agulant system in patients with interstitial lung disease. Am J Respir Crit Care Med ,1998,157:1850-1854
7 Idell S (2003).Coagulation,fibrinolysis,and fibrin deposition in acute lung injury.Crit Care Med 31:S213–S220
8 Robert M.To clot or not to clot,that is the question in pulmonary fibrosis.Am J Respir Crit Care Med ,2003,167:1589-1590
9 Hataji O, Taguchi O,Gabazza EC,et al.Activation of protein C pathway in the airways.Lung,2002,180:47-59
10姚橹,王美堂,霍正禄.急性肺损伤/急性呼吸窘迫综合征血凝状态异常及抗凝治疗进展.中国急救医学,2007,27(5):460-464
11张健,霍正禄,何建.活化蛋白C与脓毒症. Chin J Crit Care Med,2006,1(11):56-58
12姚咏明,孟海东.进一步认识活化蛋白C在脓毒症治疗中的抗炎作用.武警医学,2007,11:805-808
13 Fisher C J Jr,Yan S B. Protein C levels as a prognostic indicator of outco- me in sepsis and related diseases.Crit Care Med,2000,28 (9 Supp l): S49- S56
14 Esmon C.The protein C pathway.Crit CareM ed,2000,28 (Supp l): 44-48
15 Brueckmann M,Hoffmann U,De Rossi L,et al.Activated protein C inhibits the release of macrophage inflammatory protein-1-alpha from THP-1 cells and from human monocytes.Cytokine,2004,26(3):106-113
16 White B,Schmidt M, Murphy C,et al.Activated protein C inhibits LPS ind- uced nuclear translocation of nuclear factor-κB and tumor necrosis factor-αproduction in the THP1 monocytic cell line.Br J Haematol, 2000, 10:130- 134
17 Esmon CT.Role of coagulation inhibitors in inflammation. Thromb Hae- most, 2001,86:51-56
18 Nick JA, Coldren CD, Geraci MW, et al.Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis.Blood,2004,31
19 Sturn DH,Kaneider NC,Feistritzer C et al.Expression and function of the endothelial protein C receptor in human neutrophils. Blood,2003,102:1499
20 Vincent JL.Microvascular endothelial dysfunction:a renewed appreciation of sepsis pathophysiology.Crit Care,2001,5(suppl 2):S1-S5
21 Esmon CT.The interactions between inflammation and coagulation. Br J Haematol,2005,131:417
22 Aird WC. Sepsis and coagulation. Crit Care Clin ,2005,21:417
23陈颖,代华平,王辰等.特发性肺纤维化患者蛋白C系统的研究.首都医科大学学报,2006,27(1):59-62
24 Shimizu S,Gabazza EC,Taguchi O,et al.Activated protein C inhibits the expression of platelet-derived growth factor in the lung. Am J Respir Crit Care Med ,2003,167:1416-1426