凝血酶促人肺成纤维细胞增殖及其机制的研究
|
摘要
研究背景
各种急慢性呼吸系统疾病常存在病原体感染、内毒素产生、炎性介质和炎性因子释放、缺氧、缺血、酸中毒等诸多因素中的一种或多种,这些因素可导致血管内皮受损和组织因子释放,激活各种凝血因子,使血液呈高凝状态或(和)血栓形成。凝血酶是参与此过程中的重要凝血因子之一。已有研究资料证实,除发挥凝血功能外,凝血酶还具有重要的非凝血功能,即通过与细胞膜表面的蛋白酶激活受体-1(PAR1)结合,激活一系列下游信号通路,在细胞的生长、增殖、分泌,粘附等方面发挥重要作用。在急性肺损伤和各种慢性肺部疾病如慢性阻塞性肺病(COPD)、肺间质性疾病中,肺泡灌洗液中的凝血酶浓度显著升高,其与PAR1结合,产生各种病理生理作用,如促进各类炎症因子IL-6、IL-8、PGE2、GM-CSF的释放,调控肺部的炎症反应及修复增殖。另有研究表明凝血酶可通过激活NADPH氧化酶亚单位p47(phox)和p67 (phox)诱导多种细胞如血管平滑肌细胞、血管内皮细胞、海马神经元细胞等产生以活性氧(ROS)为主的自由基。ROS对细胞的作用具有两面性,一方面,高浓度下具有损伤作用,参与促进细胞的凋亡、坏死过程；另一方面,低浓度可作为重要的信号分子,参与细胞信号转导,主要激活MAPK通路,通过激活转录因子,影响基因的表达,促进细胞增殖、分化等。核因子NF-κB是重要的转录因子之一,在氧化应激、感染、炎症反应、细胞凋亡及异常增殖等病理过程中,因调节多种靶基因的表达而发挥重要作用。肺成纤维细胞是肺组织重要结构细胞,占肺间质全部常驻细胞的95%以上,也是参与肺损伤修复的主要细胞。在损伤后的修复过程中,成纤维细胞表现出极高增殖反应。各种损害因子导致肺部毛细血管通透性增加,血浆成分渗漏到毛细血管外并与肺成纤维细胞接触,刺激该细胞的增殖修复反应。推测凝血酶可能在其中发挥一定作用。
研究目的
凝血酶作用于肺成纤维细胞,检测细胞产生ROS情况及产生途径,观察ROS是否可以活化MAPK信号系统,进而影响核转录因子NF-κB,调控生长基因的表达。
研究方法
选择人肺成纤维细胞(HLF)作为体外研究对象,一定浓度的凝血酶作用于该细胞。MTT法和流式细胞Brdu掺入法检测凝血酶促人肺成纤维细胞增殖现象；利用化学荧光法、流式细胞检测技术和GSH检测试剂盒检测活性氧的产生；Western blot法检测PAR1, NADPH氧化酶、ERK1/2及p38MAPK信号蛋白的表达；激光共聚焦显微扫描技术观察NF-κB中亚单位p65向核内转移情况。
研究结果
1.在0.1U/ml-20U/ml浓度范围内,凝血酶对细胞的增殖能力随浓度递增而增强。在10 U/ml及以上时,与对照组比较,可显著促进HLF细胞的增殖(P<0.05),但当浓度超过20U/ml,增殖作用不再增强；20 U/ml的凝血酶分别作用HLF 24 h、36 h、48 h、60h、72h,从36h时间点开始,与对照组比较,凝血酶组细胞增殖能力显著增强(P<0.05)；BrdU掺入增殖实验结果显示,凝血酶浓度在10 U/ml及以上时,较对照组可显著促进HLF细胞增殖(P<0.05),并随浓度增加而增强,但当凝血酶浓度超过20U/ml,增殖作用不再更强。
2.5U/ml及以上浓度的凝血酶可显著增加HLF内的活性氧数量(P<0.05),并呈剂量依赖关系,但当浓度大于20U/ml,活性氧的量不再增加；20U/ml凝血酶作用HLF细胞30min,流式检测显示细胞内ROS产生量较对照组增加64.7%,作用1h时细胞内ROS量较对照组增加138.8%,而加入凝血酶拮抗剂水蛭素组细胞内ROS量与对照组比较,差异无统计学意义(P>0.05)；10U/ml和20 U/ml的凝血酶作用HLF细胞,细胞内GSH/GSSG比值较对照组显著降低(P<0.05),而加入水蛭素或氧自由基拮抗剂NAC组,GSH/GSSG之比与对照组无统计学差异(P>0.05)。
3.20 U/ml凝血酶作用于HLF细胞10min和30min,胞浆内NADPH氧化酶亚单位p47phox和Rac2表达显著降低(P<0.05),1h后几乎无蛋白表达。加入水蛭素组与对照组比较,p47phox和Rac2表达无统计学意义(P>0.05)。
4.凝血酶作用于HLF细胞10min到2h,细胞内磷酸化ERK1/2表达水平较对照组显著升高(P<0.05),而提前加入NAC或水蛭素组则无表达；细胞内p38MAPK磷酸化不受凝血酶影响,即凝血酶作用HLF细胞10min到2h,蛋白磷酸化水平较对照组无统计学差异(P>0.05)。
5.凝血酶分别作用HLF细胞5min、10min、30min、1h和2h,各时间点细胞核内代表p65的荧光含量与对照组比较,差异无统计学意义(P>0.05),而佛波酯组荧光含量明显增加,差异有统计学意义(P<0.05)。
6.支气管上皮细胞和肺成纤维细胞均有PAR1蛋白表达,肺成纤维细胞受体表达更明显(P<0.05)。
结论
1.凝血酶具有促进人肺成纤维细胞HLF增殖的能力。
2.凝血酶促进HLF细胞增殖机制包括如下。
2.1凝血酶受体PAR1在HLF中有较高表达。
2.2凝血酶通过与PAR1受体结合,激活NADPH氧化酶,诱导细胞产生活性氧。
2.3凝血酶通过磷酸化ERK1/2而不是p38MAPK,激活生长信号转导通路。
2.4凝血酶促进HLF增殖过程中,无核因子NF-κB参与。
意义
凝血酶通过与肺成纤维细胞上的受体PAR1结合,激活NADPH氧化酶,诱导细胞产生活性氧,活性氧激活MAPK信号通路中的ERK1/2信号途径,实现促人肺成纤维细胞增殖过程。该研究初步探讨了凝血酶对人肺成纤维细胞的促增殖作用机理,为寻找凝血功能紊乱相关肺部疾病的新的防治靶点提供依据。
Background
Various acute or chronic lung diseases commonly exist diversity infections, endotoxin, inflammatory media and inflammatory factors, ischemia, acidosis. The factors can result in the vascular endothelium damage and tissue factor releasing, activating various coagulation factors, making blood in the condition of high coagulation or thrombogenesis. Thrombin is one of the key coagulation factors. In addition, it is confirmed that thrombin has important non-coagulation functions, including promoting cells growth, proliferation, secretion, adhere, and so on through binding to protease activated receptor (PAR) in cell membrane and activating a series of downstream signal pathways. The concentration of thrombin was high significantly in lung alveoli in acute lung injury and chronic lung diseases such as COPD, lung interstitial diseases. Thrombin binding to PAR1 results in many kinds of effects including promoting various kinds inflammation factors such as IL-6、IL-8、PGE2、GM-CSF releasing, regulating the lung inflammation reaction and recovery. Another reseach indicates that thrombin stimulates various cells such as vascular smooth muscle, vascular endothelia cells, hippocampus neuron to produce ROS through activating NADPH oxidase subunit p47(phox) and p67(phox). ROS have two sides effects, one is injury effect via participating cell apoptosis and necrosis at the middle to high concentrations of ROS. Another side is participating cells signal transduction, activating MAPK pathway mainly at the lower concentration of ROS, finally to activate transcription factor and impact gene expression, resulting in cells proliferation and differentiation. NF kappa B is an important transcription factor and has the extensive biological effects and has the important roles in the pathological process such as oxidative stress, infection, inflammation reaction, cell apoptosis and abnormal proliferation.
As we know lung fibroblast is the important structure cell in lung tissue and more than 95 percent of all lung interstitial cells in quantity. It is the main cell which participates the injury recovery process and manifestes higher proliferation activation. A great deal of damage factors make the capillary permeability increase and the plasm fractions leak into the outer of blood capillary. The leakage substances can touch fibroblast and then make cell proliferate. We presume that thrombin as one of the leakage substances could play a certain role in the recovery process.
Objective
Thrombin stimulated lung fibroblast and cell were detected to generate reactive oxygen series(ROS) and the produce pathway. ROS were investigated to activate MAPK signal pathway as the second messager, even more it has the effect on NF kappa B, regulating growth gene expression.
Methods
HLF cells were chosen as the research object in vitro, a certain concentration of thrombin was added to cells. MTT method and Brdu incorporation assay were used to observe thrombin promoting HLF proliferation. Chemiluminescence method, flow cytometry and GSH detection kit were used to detect ROS in HLF. Western blot method was used to detect PAR1, NADPH oxidase, ERK1/2 and P38MAPK protein expression. Laser copolymerization technology was used to detect the p65 translation from kytoplasm to nucleus.
Results
1. Thrombin had reproductive activity with concentration dependence during the concentration of 0.1U/ml-20U/ml.Compared with control group, thrombin could significantly facilitate HLF to proliferate at the concentration of 10 U/ml or above (P<0.05), but there was no more proliferation effect when thrombin concentration was more than 20U/ml. Thrombin at the concentration of 20U/ml for 24h,36h,48h,60h,72h,respectively, compared with the control group, had significant enhance in proliferation from 36h to 60h (P<0.05).Brdu incorporation assay showed that thrombin enhanced cells to proliferate significantly above the concentration of lOU/ml, compared with control group (P<0.05), and it was a dose-response relationship. But there was no more proliferation ability when thrombin's concentration was above 20U/ml.
2. Thrombin significantly increased the amount of ROS at the concentration of 5U/ml compared with control group (P<0.05), showing a dose-response relationship. ROS did not increase more when the concentration was more than 40U/ml. Thrombin at the concentration of 20 U/ml for 30 minutes increased intracellular ROS (mean value 298.0) by 64.7% compared with the control (mean value 180.6). The same concentration of thrombin for 1 hour caused the increase ROS (mean value 431.2) by 138.8% compared with the control. ROS generation in HLF pretreated with hirudin (20 U/ml) for 30 minutes had no significant change (mean value 171.2) compared with the control.Ratio of GSH/GSSG had a significant decrease in HLF treated with thrombin at the concentration of 10U/ml,20U/ml(2.1、1.7 respectively) compared with the control group(5.2) (P<0.05). The ratio was no significant change (5.0,4.9) compared with the control group (5.2) when pretreated with hirudin or NAC (P> 0.05)
3.Subunits p47phox and Rac2 specific bands markedly decreased in cytosol following treatment with thrombin(20 U/ml) at 10 minutes and 30 minutes time points(P<0.05). There was little protein expression at 1h time point (P<0.05). But there was no significant change between the control group and hirudin+thrombin group (P> 0.05)
4.p-ERK1/2 protein expressing increased significantly from 10 minutes to 2 hours time points with thrombin treatment compared with control (P<0.05). There was little protein expression in the cells pretreated with NAC and hirudin. Thrombin did not affect the change of p-p38 expression at all from 10 minutes to 2 hours time point (P >0.05)
5. Thrombin stimulated HLF at 5min,10min,30min,1h and 2h respectively. The fluorescence contents representing p65 at different time points in nucleus had no statistical difference compared with control group (P>0.05). The fluorescence contents in cells stimulated with TPA had the significantly increase and there was a statistical difference (P<0.05)
6. The protein expression of PAR1 was found in both bronchial epithelial cell and human lung fibroblast and there was more in the later (P<0.05)
Conclusion
1. Thrombin promotes human lung fibroblast to proliferation.
2. The mechanism of promoting proliferation is as follows.
2.1 PAR1 is expressed higher in HLF than that in bronchial epithelial cell.
2.2 Thrombin induced HLF generate ROS via activating NADPH oxidase.
2.3 Thrombin activated growth signal pathway via phosphorylating ERK1/2 but not p38MAPK.
2.4 NF kappa B was not activated in thrombin promoting proliferation process.
Significance
Thrombin activates protease activated receptor-PAR1, inducing NADPH oxidase generate ROS and ROS activate ERK1/2 signal pathway, resulting to HLF proliferation. Our study explore primarily the mechanism of thrombin on human lung fibroblast, which provides the theory evidence for blood coagulation disorder relative respiratory diseases revention and therapy.
各种急慢性呼吸系统疾病常存在病原体感染、内毒素产生、炎性介质和炎性因子释放、缺氧、缺血、酸中毒等诸多因素中的一种或多种,这些因素可导致血管内皮受损和组织因子释放,激活各种凝血因子,使血液呈高凝状态或(和)血栓形成。凝血酶是参与此过程中的重要凝血因子之一。已有研究资料证实,除发挥凝血功能外,凝血酶还具有重要的非凝血功能,即通过与细胞膜表面的蛋白酶激活受体-1(PAR1)结合,激活一系列下游信号通路,在细胞的生长、增殖、分泌,粘附等方面发挥重要作用。在急性肺损伤和各种慢性肺部疾病如慢性阻塞性肺病(COPD)、肺间质性疾病中,肺泡灌洗液中的凝血酶浓度显著升高,其与PAR1结合,产生各种病理生理作用,如促进各类炎症因子IL-6、IL-8、PGE2、GM-CSF的释放,调控肺部的炎症反应及修复增殖。另有研究表明凝血酶可通过激活NADPH氧化酶亚单位p47(phox)和p67 (phox)诱导多种细胞如血管平滑肌细胞、血管内皮细胞、海马神经元细胞等产生以活性氧(ROS)为主的自由基。ROS对细胞的作用具有两面性,一方面,高浓度下具有损伤作用,参与促进细胞的凋亡、坏死过程；另一方面,低浓度可作为重要的信号分子,参与细胞信号转导,主要激活MAPK通路,通过激活转录因子,影响基因的表达,促进细胞增殖、分化等。核因子NF-κB是重要的转录因子之一,在氧化应激、感染、炎症反应、细胞凋亡及异常增殖等病理过程中,因调节多种靶基因的表达而发挥重要作用。肺成纤维细胞是肺组织重要结构细胞,占肺间质全部常驻细胞的95%以上,也是参与肺损伤修复的主要细胞。在损伤后的修复过程中,成纤维细胞表现出极高增殖反应。各种损害因子导致肺部毛细血管通透性增加,血浆成分渗漏到毛细血管外并与肺成纤维细胞接触,刺激该细胞的增殖修复反应。推测凝血酶可能在其中发挥一定作用。
研究目的
凝血酶作用于肺成纤维细胞,检测细胞产生ROS情况及产生途径,观察ROS是否可以活化MAPK信号系统,进而影响核转录因子NF-κB,调控生长基因的表达。
研究方法
选择人肺成纤维细胞(HLF)作为体外研究对象,一定浓度的凝血酶作用于该细胞。MTT法和流式细胞Brdu掺入法检测凝血酶促人肺成纤维细胞增殖现象；利用化学荧光法、流式细胞检测技术和GSH检测试剂盒检测活性氧的产生；Western blot法检测PAR1, NADPH氧化酶、ERK1/2及p38MAPK信号蛋白的表达；激光共聚焦显微扫描技术观察NF-κB中亚单位p65向核内转移情况。
研究结果
1.在0.1U/ml-20U/ml浓度范围内,凝血酶对细胞的增殖能力随浓度递增而增强。在10 U/ml及以上时,与对照组比较,可显著促进HLF细胞的增殖(P<0.05),但当浓度超过20U/ml,增殖作用不再增强；20 U/ml的凝血酶分别作用HLF 24 h、36 h、48 h、60h、72h,从36h时间点开始,与对照组比较,凝血酶组细胞增殖能力显著增强(P<0.05)；BrdU掺入增殖实验结果显示,凝血酶浓度在10 U/ml及以上时,较对照组可显著促进HLF细胞增殖(P<0.05),并随浓度增加而增强,但当凝血酶浓度超过20U/ml,增殖作用不再更强。
2.5U/ml及以上浓度的凝血酶可显著增加HLF内的活性氧数量(P<0.05),并呈剂量依赖关系,但当浓度大于20U/ml,活性氧的量不再增加；20U/ml凝血酶作用HLF细胞30min,流式检测显示细胞内ROS产生量较对照组增加64.7%,作用1h时细胞内ROS量较对照组增加138.8%,而加入凝血酶拮抗剂水蛭素组细胞内ROS量与对照组比较,差异无统计学意义(P>0.05)；10U/ml和20 U/ml的凝血酶作用HLF细胞,细胞内GSH/GSSG比值较对照组显著降低(P<0.05),而加入水蛭素或氧自由基拮抗剂NAC组,GSH/GSSG之比与对照组无统计学差异(P>0.05)。
3.20 U/ml凝血酶作用于HLF细胞10min和30min,胞浆内NADPH氧化酶亚单位p47phox和Rac2表达显著降低(P<0.05),1h后几乎无蛋白表达。加入水蛭素组与对照组比较,p47phox和Rac2表达无统计学意义(P>0.05)。
4.凝血酶作用于HLF细胞10min到2h,细胞内磷酸化ERK1/2表达水平较对照组显著升高(P<0.05),而提前加入NAC或水蛭素组则无表达；细胞内p38MAPK磷酸化不受凝血酶影响,即凝血酶作用HLF细胞10min到2h,蛋白磷酸化水平较对照组无统计学差异(P>0.05)。
5.凝血酶分别作用HLF细胞5min、10min、30min、1h和2h,各时间点细胞核内代表p65的荧光含量与对照组比较,差异无统计学意义(P>0.05),而佛波酯组荧光含量明显增加,差异有统计学意义(P<0.05)。
6.支气管上皮细胞和肺成纤维细胞均有PAR1蛋白表达,肺成纤维细胞受体表达更明显(P<0.05)。
结论
1.凝血酶具有促进人肺成纤维细胞HLF增殖的能力。
2.凝血酶促进HLF细胞增殖机制包括如下。
2.1凝血酶受体PAR1在HLF中有较高表达。
2.2凝血酶通过与PAR1受体结合,激活NADPH氧化酶,诱导细胞产生活性氧。
2.3凝血酶通过磷酸化ERK1/2而不是p38MAPK,激活生长信号转导通路。
2.4凝血酶促进HLF增殖过程中,无核因子NF-κB参与。
意义
凝血酶通过与肺成纤维细胞上的受体PAR1结合,激活NADPH氧化酶,诱导细胞产生活性氧,活性氧激活MAPK信号通路中的ERK1/2信号途径,实现促人肺成纤维细胞增殖过程。该研究初步探讨了凝血酶对人肺成纤维细胞的促增殖作用机理,为寻找凝血功能紊乱相关肺部疾病的新的防治靶点提供依据。
Background
Various acute or chronic lung diseases commonly exist diversity infections, endotoxin, inflammatory media and inflammatory factors, ischemia, acidosis. The factors can result in the vascular endothelium damage and tissue factor releasing, activating various coagulation factors, making blood in the condition of high coagulation or thrombogenesis. Thrombin is one of the key coagulation factors. In addition, it is confirmed that thrombin has important non-coagulation functions, including promoting cells growth, proliferation, secretion, adhere, and so on through binding to protease activated receptor (PAR) in cell membrane and activating a series of downstream signal pathways. The concentration of thrombin was high significantly in lung alveoli in acute lung injury and chronic lung diseases such as COPD, lung interstitial diseases. Thrombin binding to PAR1 results in many kinds of effects including promoting various kinds inflammation factors such as IL-6、IL-8、PGE2、GM-CSF releasing, regulating the lung inflammation reaction and recovery. Another reseach indicates that thrombin stimulates various cells such as vascular smooth muscle, vascular endothelia cells, hippocampus neuron to produce ROS through activating NADPH oxidase subunit p47(phox) and p67(phox). ROS have two sides effects, one is injury effect via participating cell apoptosis and necrosis at the middle to high concentrations of ROS. Another side is participating cells signal transduction, activating MAPK pathway mainly at the lower concentration of ROS, finally to activate transcription factor and impact gene expression, resulting in cells proliferation and differentiation. NF kappa B is an important transcription factor and has the extensive biological effects and has the important roles in the pathological process such as oxidative stress, infection, inflammation reaction, cell apoptosis and abnormal proliferation.
As we know lung fibroblast is the important structure cell in lung tissue and more than 95 percent of all lung interstitial cells in quantity. It is the main cell which participates the injury recovery process and manifestes higher proliferation activation. A great deal of damage factors make the capillary permeability increase and the plasm fractions leak into the outer of blood capillary. The leakage substances can touch fibroblast and then make cell proliferate. We presume that thrombin as one of the leakage substances could play a certain role in the recovery process.
Objective
Thrombin stimulated lung fibroblast and cell were detected to generate reactive oxygen series(ROS) and the produce pathway. ROS were investigated to activate MAPK signal pathway as the second messager, even more it has the effect on NF kappa B, regulating growth gene expression.
Methods
HLF cells were chosen as the research object in vitro, a certain concentration of thrombin was added to cells. MTT method and Brdu incorporation assay were used to observe thrombin promoting HLF proliferation. Chemiluminescence method, flow cytometry and GSH detection kit were used to detect ROS in HLF. Western blot method was used to detect PAR1, NADPH oxidase, ERK1/2 and P38MAPK protein expression. Laser copolymerization technology was used to detect the p65 translation from kytoplasm to nucleus.
Results
1. Thrombin had reproductive activity with concentration dependence during the concentration of 0.1U/ml-20U/ml.Compared with control group, thrombin could significantly facilitate HLF to proliferate at the concentration of 10 U/ml or above (P<0.05), but there was no more proliferation effect when thrombin concentration was more than 20U/ml. Thrombin at the concentration of 20U/ml for 24h,36h,48h,60h,72h,respectively, compared with the control group, had significant enhance in proliferation from 36h to 60h (P<0.05).Brdu incorporation assay showed that thrombin enhanced cells to proliferate significantly above the concentration of lOU/ml, compared with control group (P<0.05), and it was a dose-response relationship. But there was no more proliferation ability when thrombin's concentration was above 20U/ml.
2. Thrombin significantly increased the amount of ROS at the concentration of 5U/ml compared with control group (P<0.05), showing a dose-response relationship. ROS did not increase more when the concentration was more than 40U/ml. Thrombin at the concentration of 20 U/ml for 30 minutes increased intracellular ROS (mean value 298.0) by 64.7% compared with the control (mean value 180.6). The same concentration of thrombin for 1 hour caused the increase ROS (mean value 431.2) by 138.8% compared with the control. ROS generation in HLF pretreated with hirudin (20 U/ml) for 30 minutes had no significant change (mean value 171.2) compared with the control.Ratio of GSH/GSSG had a significant decrease in HLF treated with thrombin at the concentration of 10U/ml,20U/ml(2.1、1.7 respectively) compared with the control group(5.2) (P<0.05). The ratio was no significant change (5.0,4.9) compared with the control group (5.2) when pretreated with hirudin or NAC (P> 0.05)
3.Subunits p47phox and Rac2 specific bands markedly decreased in cytosol following treatment with thrombin(20 U/ml) at 10 minutes and 30 minutes time points(P<0.05). There was little protein expression at 1h time point (P<0.05). But there was no significant change between the control group and hirudin+thrombin group (P> 0.05)
4.p-ERK1/2 protein expressing increased significantly from 10 minutes to 2 hours time points with thrombin treatment compared with control (P<0.05). There was little protein expression in the cells pretreated with NAC and hirudin. Thrombin did not affect the change of p-p38 expression at all from 10 minutes to 2 hours time point (P >0.05)
5. Thrombin stimulated HLF at 5min,10min,30min,1h and 2h respectively. The fluorescence contents representing p65 at different time points in nucleus had no statistical difference compared with control group (P>0.05). The fluorescence contents in cells stimulated with TPA had the significantly increase and there was a statistical difference (P<0.05)
6. The protein expression of PAR1 was found in both bronchial epithelial cell and human lung fibroblast and there was more in the later (P<0.05)
Conclusion
1. Thrombin promotes human lung fibroblast to proliferation.
2. The mechanism of promoting proliferation is as follows.
2.1 PAR1 is expressed higher in HLF than that in bronchial epithelial cell.
2.2 Thrombin induced HLF generate ROS via activating NADPH oxidase.
2.3 Thrombin activated growth signal pathway via phosphorylating ERK1/2 but not p38MAPK.
2.4 NF kappa B was not activated in thrombin promoting proliferation process.
Significance
Thrombin activates protease activated receptor-PAR1, inducing NADPH oxidase generate ROS and ROS activate ERK1/2 signal pathway, resulting to HLF proliferation. Our study explore primarily the mechanism of thrombin on human lung fibroblast, which provides the theory evidence for blood coagulation disorder relative respiratory diseases revention and therapy.
引文
1.Milbrandt EB, Reade MC, Lee M, Shook SL, Angus DC, Kong L, et al. Prevalence and significance of coagulation abnormalities in community-acquired pneumonia. Mol Med.2009;15(11-12):438-445.
2.Hofstra JJ, Haitsma JJ, Juffermans NP, Levi M, Schultz MJ.The role of bronchoalveolar hemostasis in the pathogenesis of acute lung injury. Semin Thromb Hemost.2008;34(5):475-484.
3.Ppova EN, Arkhipova DV, Kozlovskaia LV, Privalova EV, Bitsadze VO, Kornev BM. Role of endothelial dysfunction and coagulation disorders in the development of pulmonary fibrosis in patients with interstitial lung diseases. Klin Med (Mosk). 2004;82(6):38-42.
4.Idell S.Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med.2003;31(4 Suppl):S213-S220.
5.Wygrecka M, Jablonska E, Guenther A, Preissner KT, Markart P.Current view on alveolar coagulation and fibrinolysis in acute inflammatory and chronic interstitial lung diseases. Thromb Haemost.2008;99(3):494-501.
6. Ruppert C, Markart P, Wygrecka M, Preissner KT, Giinther A.Role of coagulation and fibrinolysis in lung and renal fibrosis. Hamostaseologie.2008;28(1-2):30-2,34-6.
7.Howell DC, Laurent GJ, Chambers RC. Role of thrombin and its major cellular receptor, protease-activated receptor-1, in pulmonary fibrosis. Biochem Soc Trans. 2002;30(2):211-216.
8.Shetty S, Padijnayayveetil J, Tucker T, Stankowska D, Idell S.The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability. Am J Physiol Lung Cell Mol Physiol.2008;295(6):L967-L975.
9. Chalmers JD, Singanayagam A, Scally C, Hill AT.Admission D-dimer can identify low-risk patients with community-acquired pneumonia. Ann Emerg Med. 2009;53(5):633-638.
lO.Ashitani J, Mukae H, Arimura Y, Matsukura S.Elevated plasma procoagulant and fibrinolytic markers in patients with chronic obstructive pulmonary disease. Intern Med.2002;41(3):181-185.
11. Tapson VF.The role of smoking in coagulation and thromboembolism in chronic obstructive pulmonary disease. Proc Am Thorac Soc.2005;2(1):71-77.
12. Agrawal DK, Bharadwaj A.Allergic airway inflammation. Curr Allergy Asthma Rep.2005;5(2):142-148.
13.Matthay MA, Clements JA.Coagulation-dependent mechanisms and asthma. J Clin Invest.2004;114(1):20-23.
H.Kawabata A, Kawao N. Physiology and pathophysiology of proteinase-activated receptors (PARs):PARs in the respiratory system:Cellular signaling and physiological/pathological roles. J Pharmacol Sci.2005;97(1):20-24.
15. Mousa SA.Role of current and emerging antithrombotics in thrombosis and cancer. Drugs Today (Bare).2006;42(5):331-350.
16.Kakkar AK, DeRuvo N, Chinswangwatanakul V, Tebbutt S, Williamson RC.Extrinsic-pathway activation in cancer with high factor VⅡa and tissue factor. Lancet.1995;346(8981):1004-1005.
17.Altiay G, Ciftci A, Demir M, Kocak Z, Sut N, Tabakoglu E, et al.High plasma D-dimer level is associated with decreased survival in patients with lung cancer. Clin Oncol (R Coll Radiol).2007;19(7):494-498.
18.Jin E, Fujiwara M, Pan X, Ghazizadeh M, Arai S, Ohaki Y,et al. Protease-activated receptor (PAR)-1 and PAR-2 participate in the cell growth of alveolar capillary endothelium in primary lung adenocarcinomas. Cancer.2003;97(3):703-713.
19.Kakkar AK.Low-molecular-weight heparins:beyond thrombosis in the management of the cancer patient. Semin Thromb Hemost.2003;29 Suppl 1:13-15.
20. Arora P, Ricks TK, Trejo J. Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer. J Cell Sci.2007;120(Pt 6):921-928.
21.Camerer E.Protease signaling in tumor progression. Thromb Res.2007; 120 Suppl 2:S75-S81.
22.Nierodzik ML, Karpatkin S.Thrombin induces tumor growth, metastasis, and angiogenesis:Evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell.2006;10(5):355-362.
23. Garcia-Lopez MT, Gutierrez-Rodriguez M, Herranz R.Thrombin-activated receptors:promising targets for cancer therapy? Curr Med Chem. 2010;17(2):109-128.
24.Sokolova E, Reiser G. A novel therapeutic target in various lung diseases:airway proteases and protease-activated receptors. Pharmacol Ther.2007;115(1):70-83.
25.Hernandez-Rodriguez NA, Cambrey AD, Harrison NK, Chambers RC, Gray AJ, Southcott AM, et al. Role of thrombin in pulmonary fibrosis. Lancet.1995;346(8982):1071-1073.
26.Ohba T, McDonald JK, Silver RM, Strange C, LeRoy EC, Ludwicka A.Scleroderma bronchoalveolar lavage fluid contains thrombin, a mediator of human lung fibroblast proliferation via induction of platelet-derived growth factor alpha-receptor. Am J Respir Cell Mol Biol.1994;10(4):405-412.
27.Djordjevic T, Pogrebniak A, BelAiba RS, Bonello S, Wotzlaw C, Acker H, et al. The expression of the NADPH oxidase subunit p22phox is regulated by a redox-sensitive pathway in endothelial cells. Free Radic Biol Med.2005;38 (5):616-630.
28.Park KW, Jin BK. Thrombin-induced oxidative stress contributes to the death of hippocampal neurons:role of neuronal NADPH oxidase. J Neurosci Res.2008;86 (5):1053-1063.
29.Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol.2007;39 (1):44-84.
30.Voeikov VL. Reactive oxygen species--(ROS) pathogens or sources of vital energy? Part 1. ROS in normal and pathologic physiology of living systems. J Altern Complement Med.2006; 12 (2):111-118
31.Matsuzawa A, Ichijo H. Stress-responsive protein kinases in redox-regulated apoptosis signaling. Antioxid Redox Signal.2005;7(3-4):472-481.
32. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res.2011;21(1):103-115.
33.海春旭,冯安吉等.自由基医学.第一版.第四军医大学出版社.2006.P125-130.
34.朱元珏,陈文彬.呼吸病学.第一版.人民卫生出版社.2004.199-208.
35.朱元珏,陈文彬.呼吸病学.第一版.人民卫生出版社.2004.P1074.
36.Hansel TT, Barnes PJ. New drugs for exacerbations of chronic obstructive pulmonary disease. Lancet.2009;374(9691):744-755.
37.Costa CH, Rufino R, Lapa E Silva JR. Inflammatory cells and their mediators in COPD pathogenesis.Rev Assoc Med Bras.2009;55(3):347-354.
38.Chambers RC.Procoagulant signaling mechanisms in lung inflammation and fibrosis:novel opportunities for pharmacological intervention? Br J Pharmacol.2008;153 Suppl 1:S367-S378.
39.Chambers RC. Role of coagulation cascade proteases in lung repair and fibrosis. Eur Respir J Suppl.2003,44:33s-35s.
40.Tani K, Yasuoka S, Ogushi F, Asada K, Fujisawa K, Ozaki T, et al.Thrombin enhances lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol.1991;5(1):34-40.
41.Dik WA, Zimmermann LJ, Naber BA, Janssen DJ, van Kaam AH, Versnel MA. Thrombin contributes to bronchoalveolar lavage fluid mitogenicity in lung disease of the premature infant.Pediatr Pulmonol.2003;35(1):34-41.
42. Darzynkiewicz Z, Gong J, Juan G, Ardelt B, Traganos F. Cytometry of cyclin proteins. Cytometry.1996;25(1):1-13.
43.Wu YF, Xu HM, Chen JQ.Relations of proliferative activities of gastric carcinoma cells to lymphatic involvement, venous invasion and prognosis. Chin Med J (Engl). 2004;117(10):1530-1535.
44.Agostini C, Gurrieri C. Chemokine/Cytokine Cocktail in Idiopathic Pulmonary Fibrosis. Proc Am Thoracic Soc.2006;3(4):357-363.
45.Daian T, Ohtsuru A, Rogounovitch T, Ishihara H, Hirano A, Akiyama-Uchida Y, et al.Insulin-like growth factor-I enhances transforming growth factor-beta-induced extracellular matrix protein production through the P38/activating transcription factor-2 signaling pathway in keloid fibroblasts. J Invest Dermatol. 2003;120(6):956-962.
46.White KE, Ding Q, Moore BB, Peters-Golden M, Ware LB, Matthay MA,et al.Prostaglandin E2 mediates IL-1 beta-related fibroblast mitogenic effects in acute lung injury through differential utilization of prostanoid receptors. J Immunol. 2008;180(1):637-646.
47.Kunzmann S, Schmidt-Weber C, Zingg JM, Azzi A, Kramer BW, Blaser K, et al.Connective tissue growth factor expression is regulated by histamine in lung fibroblasts:potential role of histamine in airway remodeling. J Allergy Clin Immunol. 2007;119(6):1398-1407.
48. Konigshoff M, Balsara N, Pfaff EM, Kramer M, Chrobak I, Seeger W, et al.Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS One. 2008;3(5):e2142.
49.Mandal SK, Rao LV, Tran TT, Pendurthi UR. A novel mechanism of plasmin-induced mitogenesis in fibroblasts. J Thromb Haemost.2005; 3(1):163-169.
50.Ossovskaya VS, Bunnett NW.Protease-activated receptors:contribution to physiology and disease. Physiol Rev.2004; 84:579-621.
51. Niu J, Profirovic J, Pan H, Vaiskunaite R, Voyno-Yasenetskaya T.G Protein betagamma subunits stimulate p114RhoGEF, a guanine nucleotide exchange factor for RhoA and Rac1:regulation of cell shape and reactive oxygen species production. Circ Res.2003;93(9):848-856.
52.Herkert O, Djordjevic T, BelAiba RS, Gorlach A. Insights into the redox control of blood coagulation:role of vascular NADPH oxidase-derived reactive oxygen species in the thrombogenic cycle.Antioxid Redox Signal.2004;6:765-776.
53.Madamanchi NR, Moon SK, Hakim ZS, Clark S, Mehrizi A, Patterson C,et al.Differential activation of mitogenic signaling pathways in aortic smooth muscle cells deficient in superoxide dismutase isoforms. Arterioscler Thromb Vase Biol. 2005;25(5):950-956.
54. Kamata H, Manabe T, Kakuta J, Oka S, Hirata H. Multiple redox regulation of the cellular signaling system linked to AP-1 and NFkappaB:effects of N-acetylcysteine and H2O2 on the receptor tyrosine kinases, the MAP kinase cascade, and IkappaB kinases. Ann N Y Acad Sci.2002;973:419-422.
55.Bian ZM, Elner SG, Elner VM. Thrombin-induced VEGF expression in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci.2007; 48:2738-2746.
56.Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med. 2001;30:1191-1212.
57.Nogueira CW, Zeni G, Rocha JB. Organoselenium and organotellurium compounds: toxicology and pharmacology. Chem Rev.2004; 104:6255-6285.
58.Hancock JT, Desikan R, Neill SJ. Role of reactive oxygen species in cell signalling pathways. Biochem Soc Trans.2001;29:345-350.
59.Nauseef WM.How human neutrophils kill and degrade microbes:an integrated view. Immunol Rev.2007; 219:88-102.
60.Chowdhury AK, Watkins T, Parinandi NL, Saatian B, Kleinberg ME, Usatyuk PV,et al.Src-mediated tyrosine phosphorylation of p47phox in hyperoxia-induced activation of NADPH oxidase and generation of reactive oxygen species in lung endothelial cells. J Biol Chem.2005; 280(21):20700-20711.
61. Zou T, Yang W, Hou Z, Yang J.Homocysteine enhances cell proliferation in vascular smooth muscle cells:role of p38 MAPK and p47phox. Acta Biochim Biophys Sin (Shanghai).2010; 42(12):908-915.
62.Brar SS, Kennedy TP, Sturrock AB, Huecksteadt TP, Quinn MT, Murphy TM, et al. NADPH oxidase promotes NF-kappaB activation and proliferation in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol.2002; 282:L782-L795.
63.E1-Benna J, Dang PM, Gougerot-Pocidalo MA, Elbim C. Phagocyte NADPH oxidase:a multicomponent enzyme essential for host defenses. Arch Immunol Ther Exp (Warsz).2005; 53:199-206.
64. Quinn MT, Ammons MC, Deleo FR. The expanding role of NADPH oxidases in health and disease:no longer just agents of death and destruction. Clin Sci (Lond).2006; 111(1):1-20.
65.Ushio-Fukai M. Redox signaling in angiogenesis:role of NADPH oxidase. Cardiovasc Res.2006;71:226-235.
66.Nitti M, Furfaro AL, Traverso N, Odetti P, Storace D, Cottalasso D, et al. PKC delta and NADPH oxidase in AGE-induced neuronal death.Neurosci Lett.2007;416:261-265.
67.Sumbayev VV, Yasinska IM. Regulation of MAP kinase-dependent apoptotic pathway:implication of reactive oxygen and nitrogen species. Arch Biochem Biophys.2005; 436:406-412.
68.Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation.Physiol Rev.2001;81:807-869.
69.O'Neill E, Kolch W. Conferring specificity on the ubiquitous Raf/MEK signalling pathway. Br J Cancer.2004;90:283-288.
70.杨雅茹,黄艳,李俊TGF-β1介导的Smads与ERK通路在肺纤维化中的作用及相互关系.中国药理学通报.2010；26：561-563.
71.Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P. Redox regulation of cell survival. Antioxid Redox Signal.2008; 10:1343-1374.
72.景亚武,易静,高飞,汤雪明。活性氧：从毒性分子到信号分子一活性氧与细胞的增殖、分化和凋亡及其信号转导途径。细胞生物学杂志.2003；4：197-202.
73.Colston JT, de la Rosa SD, Freeman GL. Impact of brief oxidant stress on primary adult cardiac fibroblasts. Biochem Biophys Res Commun.2004; 316:256-262.
74.Zhang H, Chalothorn D, Jackson LF, Lee DC, Faber JE. Transactivation of epidermal growth factor receptor mediates catecholamine-induced growth of vascular smooth muscle. Circ Res.2004;95:989-997.
75.McCubrey JA, Lahair MM, Franklin RA. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal.2006; 8:1775-1789.
76.Shen HM, Liu ZG JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species. Free Radic Biol Med.2006; 40: 928-939.
77.Han J, Lee JD, Bibbs L, Ulevitch RJ. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science.1994; 265:808-811.
78.Zatechka SD Jr, Lou MF. Studies of the mitogen-activated protein kinases and phosphatidylinositol-3 kinase in the lens.1. The mitogenic and stress responses. Exp Eye Res.2002;74:703-717.
79.Brandes RP, Viedt C, Nguyen K, Beer S, Kreuzer J, Busse R, et al. Thrombin-induced MCP-1 expression involves activation of the p22phox-containing NADPH oxidase in human vascular smooth muscle cells. Thromb Haemost.2001; 85:1104-1110.
80.Fubini B, Hubbard A. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis. Free Radic Biol Med. 2003; 34:1507-1516.
81. Fujimoto D, Hirono Y, Goi T, Katayama K, Matsukawa S, Yarhaguchi A.The activation of Proteinase-Activated Receptor-1 (PAR1) mediates gastric cancer cell proliferation and invasion. BMC Cancer.2010; 10:443.
82.Klatt P, Lamas S. Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. Eur J Biochem.2000; 267:4928-4944.
83.Pineda-Molina E, Klatt P, Vazquez J, Marina A, Garcia de Lacoba M, Perez-Sala D, et al. Glutathionylation of the p50 subunit of NF-kappaB:a mechanism for redox-induced inhibition of DNA binding. Biochemistry.2001;40:14134-14142.
84.Nick JA, Avdi NJ, Young SK, Lehman LA, McDonald PP, Frasch SC, et al. Selective activation and functional significance of p38alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils. J Clin Invest.1999; 103:851-858.
85.Jijon H, Allard B, Jobin C.NF-kappaB inducing kinase activates NF-kappaB transcriptional activity independently of IkappaB kinase gamma through a p38 MAPK-dependent RelA phosphorylation pathway. Cell Signal. 2004;16(9):1023-1032.
86.Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407:258-264.
[1]Sambola A, Osende J, Hathcock J,et al.Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity[J].Circulation,2003,107(7):973-977.
[2]Barua RS.Ambrose JA.Saha DC.et al. Smoking is associated with altered endothelial-derived fibrinolytic and antithrombotic factors:an in vitro demonstration[J].Circulation,2002,106:905-908.
[3]Ernst E. Haemorheological consequences of chronic cigarette smoking[J]. J Cardiovasc Risk 1995,2(5):435-439.
[4]Didilescu AC, Hanganu SC, Galie N,et al. The role of smoking in changing essential parameters in body homeostasis[J].Pneumologia,58(2):89-94.
[5]Hunter KA, Garlick PJ, Broom I, et al. Effects of smoking and abstention from smoking on fibrinogen synthesis in humans[J].Clin Sci (Lond)2001,100(4):459-465.
[6]Mendall MA, Patel P, Asante M,et al. Relation of serum cytokine concentrations to cardiovascular risk factors and coronary heart disease[J]. Heart,1997,78(3):273-277.
[7]Cesare Alessandri, Stefania Sasili,Francesco Violi, et al. Hypercoagulability state in patients with chronic obstructive pulmonary disease[J]. Thromb Haemost,1994, 72(3):343-346.
[8]Hioki H, Aoki N, Kawano K, et al.Acute effects of cigarette smoking on platelet-dependent thrombin generation[J]. Eur Heart J.2001,22(1):56-61.
[9]Roche N, Stirling RG, Lim S,et al.Effect of acute and chronic inflammatory stimuli on expression of protease-activated receptors 1 and 2 in alveolar macrophages[J]. J Allergy Clin Immunol.2003,111(2):367-373.
[10]Nystedt S.Ramakrishnan V.Sundelin J.The proteinase activated receptor 2 is induced by inflammatory mediators in human endothelial cells.Comparison with the thrombin receptor[J].J Biol Chem,1996,271(25):14910-14915
[11]Resendiz JC, Kroll MH, Lassila R. Protease-activated receptor-induced Akt activation--regulation and possible function[J].J Thromb Haemost,2007,5(12):2484-2493.
[12]Karimi M, Bereczky Z, Cohan N.et al. Factor ⅩⅢ Deficiency,2009,35(4):426-438.
[13]Ariens RAS.Kohler HP.Mansfield MW.et al.Subunit antigen and activity levels of blood coagulation factor XIII in healthy individuals relation to sex,age,smoking,and hypertention[J].Arterioscler Thromb Vase Bio,1999,19:2012-2016.
[14]Yi-Heng Li,Jyh-Hong Chen, Wei-Chuan Tsai.et al.Synergistic effect of thrombomodulin promoter-33G/A polymorphism and smoking on the onset of acute myocardial infarction[J].Thromb Haemost.2002,87 (1):86-91.
[15]Giannarelli C, De Negri F, Virdis A, et al. Nitric oxide modulates tissue plasminogen activator release in normotensive subjects and hypertensive patients[J]. Hypertension,2007, 49(4):878-884.
[16]Zidovetzki R.Chen P,Fisher M. Nicotine increases plasminogen activator inhibitor-1 production by human brain endothelial cells via protein kinase C-associated pathway[J].Stroke, 1999,30 (3):651-655.
[17]Opal SM.Phylogenetic and functional relationships between coagulation and the innate immune response[J].Crit Care Med,2000,28(9 suppl):S77-80.
[18]Wannamethee SG, Lowe GD, Shaper AG, et al. Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease[J]. Eur Heart J,2005,26:1765-1773.
[19]Lee AJ.Fowkes GR.Lowe GD.et al. Determinants of fibrin D-dimer in the Edinburgh Artery Study[J].Arterioscler Thromb Vasc Biol,1995,15 (8).1094-1097.
[20]Murohara T, Kugiyama K, Ohgushi M,et al. Cigarette smoke extract contracts isolated porcine coronary arteries by superoxide anion-mediated degradation of EDRF[J]. Am J Physiol, 1994,266(3 Pt 2):H874-880.
[21]Michaud SE, Dussault S, Groleau J,et al. Cigarette smoke exposure impairs VEGF-induced endothelial cell migration:role of NO and reactive oxygen species[J]. J Mol Cell Cardiol,2006,41(2):275-284.
[22]Vischer UM.von Willebrand factor, endothelial dysfunction, and cardiovascular disease[J]. J Thromb Haemost,2006,4(6):1186-1193.
[23]Kumari M,Marmot M.Brunner E. Social determinants of von Willebrand factor:The Whitehall II Study[J]. Arterioscler Thromb Vase boil,2000,20 (7):1842-1847.
[24]Polatli M, Cakir A, Cildag O, et al. Microalbuminuria, von Willebrand factor and fibrinogen levels as markers of the severity in COPD exacerbation[J]. J Thromb Thrombolysis,2008, 26(2):97-102.
[25]Kalra VK,Ying Y.Deemer K,et al. Mechanism of cigarette smoke condensate induced adhesion of human monocytes to cultured endothelial cells[J]. J Cell Physiol,1994;160 (1):154-162.
[26]Chen HW, Lii CK, Ku HJ, et al. Cigarette smoke extract induces expression of cell adhesion molecules in HUVEC via actin filament reorganization[J]. Environ Mol Mutagen, 2009,50(2):96-104.
[27]Mikhailidis DP, Barradas MA, Jeremy JY, et al. Cigarette smoking inhibits prostacyclin formation[J].Lancet,1983,2 (8350):627-628.
[28]Jeremy JY, Mikhailidis DP, Dandona P. Cigarette smoke extracts, but not nicotine, inhibit prostacyclin(PGI2)synthesis in human, rabbit and rat vascular tissue[J]. Prostaglandins Leukot,1985,19 (3):261-270.
[29]Goerre S, Staehli C, Shaw S, et al. Effect of cigarette smoking and nicotine on plasma endothelin-1 level[J]. J Cardiovase Pharmacol,1995,26(supple 3):S236-238.
[30]Fusegawa Y.Goto S.handa S,et al. Platelet spontaneous aggregation in platelet-rich plasma is increased in habitual smokers[J].Thromb Res,1999,93 (6):271-278
[31]Oksala NK, Heikkinen M, Mikkelsson J, et al. Smoking and the platelet fibrinogen receptor glycoprotein Ⅱb/ⅢA PIA1/A2 polymorphism interact in the risk of lacunar stroke and midterm survival[J]. Stroke,2007;38(1):50-55.
[32]Nair S,Kulkarni S,Camoens HM,et al. Changes in platelet glycoprotein receptors after smoking--Aflow cytometric study[J]. Platelets,2001,12(1):20-26.
[33]Lee DS, Larson MG, Lunetta KL.et al. Clinical and genetic correlates of soluble P-selectin in the community[J]. J Thromb Haemost,2008;6(1):20-31.
[34]Benowitz NL, Fitzgerald GA, Wilson M,et al. Nicotine effects on eicosanoid formation and hemostatic function:Comparison of transdermal nicotine and cigarette smoking[J]. J Am Coll Cardiol,1993,22(4):1159-1167.
[35]Benowitz NL, Hansson A, Jacob P 3rd. Cardiovascular effects of nasal and transdermal nicotine and cigarette smoking. Hypertension,2002,39(6):1107-1112.
[36]Yanbaeva DG, Dentener MA, Creutzberg EC.et al. Systemic effects of smoking[J]. Chest, 2007;131 (5):1557-1566.
[37]Smith CJ, Fischer TH. Particulate and vapor phase constituents of cigarette mainstream smoke and risk of myocardial infarction[J].Atherosclerosis,2001;158(2):257-267.
2.Hofstra JJ, Haitsma JJ, Juffermans NP, Levi M, Schultz MJ.The role of bronchoalveolar hemostasis in the pathogenesis of acute lung injury. Semin Thromb Hemost.2008;34(5):475-484.
3.Ppova EN, Arkhipova DV, Kozlovskaia LV, Privalova EV, Bitsadze VO, Kornev BM. Role of endothelial dysfunction and coagulation disorders in the development of pulmonary fibrosis in patients with interstitial lung diseases. Klin Med (Mosk). 2004;82(6):38-42.
4.Idell S.Coagulation, fibrinolysis, and fibrin deposition in acute lung injury. Crit Care Med.2003;31(4 Suppl):S213-S220.
5.Wygrecka M, Jablonska E, Guenther A, Preissner KT, Markart P.Current view on alveolar coagulation and fibrinolysis in acute inflammatory and chronic interstitial lung diseases. Thromb Haemost.2008;99(3):494-501.
6. Ruppert C, Markart P, Wygrecka M, Preissner KT, Giinther A.Role of coagulation and fibrinolysis in lung and renal fibrosis. Hamostaseologie.2008;28(1-2):30-2,34-6.
7.Howell DC, Laurent GJ, Chambers RC. Role of thrombin and its major cellular receptor, protease-activated receptor-1, in pulmonary fibrosis. Biochem Soc Trans. 2002;30(2):211-216.
8.Shetty S, Padijnayayveetil J, Tucker T, Stankowska D, Idell S.The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability. Am J Physiol Lung Cell Mol Physiol.2008;295(6):L967-L975.
9. Chalmers JD, Singanayagam A, Scally C, Hill AT.Admission D-dimer can identify low-risk patients with community-acquired pneumonia. Ann Emerg Med. 2009;53(5):633-638.
lO.Ashitani J, Mukae H, Arimura Y, Matsukura S.Elevated plasma procoagulant and fibrinolytic markers in patients with chronic obstructive pulmonary disease. Intern Med.2002;41(3):181-185.
11. Tapson VF.The role of smoking in coagulation and thromboembolism in chronic obstructive pulmonary disease. Proc Am Thorac Soc.2005;2(1):71-77.
12. Agrawal DK, Bharadwaj A.Allergic airway inflammation. Curr Allergy Asthma Rep.2005;5(2):142-148.
13.Matthay MA, Clements JA.Coagulation-dependent mechanisms and asthma. J Clin Invest.2004;114(1):20-23.
H.Kawabata A, Kawao N. Physiology and pathophysiology of proteinase-activated receptors (PARs):PARs in the respiratory system:Cellular signaling and physiological/pathological roles. J Pharmacol Sci.2005;97(1):20-24.
15. Mousa SA.Role of current and emerging antithrombotics in thrombosis and cancer. Drugs Today (Bare).2006;42(5):331-350.
16.Kakkar AK, DeRuvo N, Chinswangwatanakul V, Tebbutt S, Williamson RC.Extrinsic-pathway activation in cancer with high factor VⅡa and tissue factor. Lancet.1995;346(8981):1004-1005.
17.Altiay G, Ciftci A, Demir M, Kocak Z, Sut N, Tabakoglu E, et al.High plasma D-dimer level is associated with decreased survival in patients with lung cancer. Clin Oncol (R Coll Radiol).2007;19(7):494-498.
18.Jin E, Fujiwara M, Pan X, Ghazizadeh M, Arai S, Ohaki Y,et al. Protease-activated receptor (PAR)-1 and PAR-2 participate in the cell growth of alveolar capillary endothelium in primary lung adenocarcinomas. Cancer.2003;97(3):703-713.
19.Kakkar AK.Low-molecular-weight heparins:beyond thrombosis in the management of the cancer patient. Semin Thromb Hemost.2003;29 Suppl 1:13-15.
20. Arora P, Ricks TK, Trejo J. Protease-activated receptor signalling, endocytic sorting and dysregulation in cancer. J Cell Sci.2007;120(Pt 6):921-928.
21.Camerer E.Protease signaling in tumor progression. Thromb Res.2007; 120 Suppl 2:S75-S81.
22.Nierodzik ML, Karpatkin S.Thrombin induces tumor growth, metastasis, and angiogenesis:Evidence for a thrombin-regulated dormant tumor phenotype. Cancer Cell.2006;10(5):355-362.
23. Garcia-Lopez MT, Gutierrez-Rodriguez M, Herranz R.Thrombin-activated receptors:promising targets for cancer therapy? Curr Med Chem. 2010;17(2):109-128.
24.Sokolova E, Reiser G. A novel therapeutic target in various lung diseases:airway proteases and protease-activated receptors. Pharmacol Ther.2007;115(1):70-83.
25.Hernandez-Rodriguez NA, Cambrey AD, Harrison NK, Chambers RC, Gray AJ, Southcott AM, et al. Role of thrombin in pulmonary fibrosis. Lancet.1995;346(8982):1071-1073.
26.Ohba T, McDonald JK, Silver RM, Strange C, LeRoy EC, Ludwicka A.Scleroderma bronchoalveolar lavage fluid contains thrombin, a mediator of human lung fibroblast proliferation via induction of platelet-derived growth factor alpha-receptor. Am J Respir Cell Mol Biol.1994;10(4):405-412.
27.Djordjevic T, Pogrebniak A, BelAiba RS, Bonello S, Wotzlaw C, Acker H, et al. The expression of the NADPH oxidase subunit p22phox is regulated by a redox-sensitive pathway in endothelial cells. Free Radic Biol Med.2005;38 (5):616-630.
28.Park KW, Jin BK. Thrombin-induced oxidative stress contributes to the death of hippocampal neurons:role of neuronal NADPH oxidase. J Neurosci Res.2008;86 (5):1053-1063.
29.Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol.2007;39 (1):44-84.
30.Voeikov VL. Reactive oxygen species--(ROS) pathogens or sources of vital energy? Part 1. ROS in normal and pathologic physiology of living systems. J Altern Complement Med.2006; 12 (2):111-118
31.Matsuzawa A, Ichijo H. Stress-responsive protein kinases in redox-regulated apoptosis signaling. Antioxid Redox Signal.2005;7(3-4):472-481.
32. Morgan MJ, Liu ZG. Crosstalk of reactive oxygen species and NF-κB signaling. Cell Res.2011;21(1):103-115.
33.海春旭,冯安吉等.自由基医学.第一版.第四军医大学出版社.2006.P125-130.
34.朱元珏,陈文彬.呼吸病学.第一版.人民卫生出版社.2004.199-208.
35.朱元珏,陈文彬.呼吸病学.第一版.人民卫生出版社.2004.P1074.
36.Hansel TT, Barnes PJ. New drugs for exacerbations of chronic obstructive pulmonary disease. Lancet.2009;374(9691):744-755.
37.Costa CH, Rufino R, Lapa E Silva JR. Inflammatory cells and their mediators in COPD pathogenesis.Rev Assoc Med Bras.2009;55(3):347-354.
38.Chambers RC.Procoagulant signaling mechanisms in lung inflammation and fibrosis:novel opportunities for pharmacological intervention? Br J Pharmacol.2008;153 Suppl 1:S367-S378.
39.Chambers RC. Role of coagulation cascade proteases in lung repair and fibrosis. Eur Respir J Suppl.2003,44:33s-35s.
40.Tani K, Yasuoka S, Ogushi F, Asada K, Fujisawa K, Ozaki T, et al.Thrombin enhances lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol.1991;5(1):34-40.
41.Dik WA, Zimmermann LJ, Naber BA, Janssen DJ, van Kaam AH, Versnel MA. Thrombin contributes to bronchoalveolar lavage fluid mitogenicity in lung disease of the premature infant.Pediatr Pulmonol.2003;35(1):34-41.
42. Darzynkiewicz Z, Gong J, Juan G, Ardelt B, Traganos F. Cytometry of cyclin proteins. Cytometry.1996;25(1):1-13.
43.Wu YF, Xu HM, Chen JQ.Relations of proliferative activities of gastric carcinoma cells to lymphatic involvement, venous invasion and prognosis. Chin Med J (Engl). 2004;117(10):1530-1535.
44.Agostini C, Gurrieri C. Chemokine/Cytokine Cocktail in Idiopathic Pulmonary Fibrosis. Proc Am Thoracic Soc.2006;3(4):357-363.
45.Daian T, Ohtsuru A, Rogounovitch T, Ishihara H, Hirano A, Akiyama-Uchida Y, et al.Insulin-like growth factor-I enhances transforming growth factor-beta-induced extracellular matrix protein production through the P38/activating transcription factor-2 signaling pathway in keloid fibroblasts. J Invest Dermatol. 2003;120(6):956-962.
46.White KE, Ding Q, Moore BB, Peters-Golden M, Ware LB, Matthay MA,et al.Prostaglandin E2 mediates IL-1 beta-related fibroblast mitogenic effects in acute lung injury through differential utilization of prostanoid receptors. J Immunol. 2008;180(1):637-646.
47.Kunzmann S, Schmidt-Weber C, Zingg JM, Azzi A, Kramer BW, Blaser K, et al.Connective tissue growth factor expression is regulated by histamine in lung fibroblasts:potential role of histamine in airway remodeling. J Allergy Clin Immunol. 2007;119(6):1398-1407.
48. Konigshoff M, Balsara N, Pfaff EM, Kramer M, Chrobak I, Seeger W, et al.Functional Wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS One. 2008;3(5):e2142.
49.Mandal SK, Rao LV, Tran TT, Pendurthi UR. A novel mechanism of plasmin-induced mitogenesis in fibroblasts. J Thromb Haemost.2005; 3(1):163-169.
50.Ossovskaya VS, Bunnett NW.Protease-activated receptors:contribution to physiology and disease. Physiol Rev.2004; 84:579-621.
51. Niu J, Profirovic J, Pan H, Vaiskunaite R, Voyno-Yasenetskaya T.G Protein betagamma subunits stimulate p114RhoGEF, a guanine nucleotide exchange factor for RhoA and Rac1:regulation of cell shape and reactive oxygen species production. Circ Res.2003;93(9):848-856.
52.Herkert O, Djordjevic T, BelAiba RS, Gorlach A. Insights into the redox control of blood coagulation:role of vascular NADPH oxidase-derived reactive oxygen species in the thrombogenic cycle.Antioxid Redox Signal.2004;6:765-776.
53.Madamanchi NR, Moon SK, Hakim ZS, Clark S, Mehrizi A, Patterson C,et al.Differential activation of mitogenic signaling pathways in aortic smooth muscle cells deficient in superoxide dismutase isoforms. Arterioscler Thromb Vase Biol. 2005;25(5):950-956.
54. Kamata H, Manabe T, Kakuta J, Oka S, Hirata H. Multiple redox regulation of the cellular signaling system linked to AP-1 and NFkappaB:effects of N-acetylcysteine and H2O2 on the receptor tyrosine kinases, the MAP kinase cascade, and IkappaB kinases. Ann N Y Acad Sci.2002;973:419-422.
55.Bian ZM, Elner SG, Elner VM. Thrombin-induced VEGF expression in human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci.2007; 48:2738-2746.
56.Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med. 2001;30:1191-1212.
57.Nogueira CW, Zeni G, Rocha JB. Organoselenium and organotellurium compounds: toxicology and pharmacology. Chem Rev.2004; 104:6255-6285.
58.Hancock JT, Desikan R, Neill SJ. Role of reactive oxygen species in cell signalling pathways. Biochem Soc Trans.2001;29:345-350.
59.Nauseef WM.How human neutrophils kill and degrade microbes:an integrated view. Immunol Rev.2007; 219:88-102.
60.Chowdhury AK, Watkins T, Parinandi NL, Saatian B, Kleinberg ME, Usatyuk PV,et al.Src-mediated tyrosine phosphorylation of p47phox in hyperoxia-induced activation of NADPH oxidase and generation of reactive oxygen species in lung endothelial cells. J Biol Chem.2005; 280(21):20700-20711.
61. Zou T, Yang W, Hou Z, Yang J.Homocysteine enhances cell proliferation in vascular smooth muscle cells:role of p38 MAPK and p47phox. Acta Biochim Biophys Sin (Shanghai).2010; 42(12):908-915.
62.Brar SS, Kennedy TP, Sturrock AB, Huecksteadt TP, Quinn MT, Murphy TM, et al. NADPH oxidase promotes NF-kappaB activation and proliferation in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol.2002; 282:L782-L795.
63.E1-Benna J, Dang PM, Gougerot-Pocidalo MA, Elbim C. Phagocyte NADPH oxidase:a multicomponent enzyme essential for host defenses. Arch Immunol Ther Exp (Warsz).2005; 53:199-206.
64. Quinn MT, Ammons MC, Deleo FR. The expanding role of NADPH oxidases in health and disease:no longer just agents of death and destruction. Clin Sci (Lond).2006; 111(1):1-20.
65.Ushio-Fukai M. Redox signaling in angiogenesis:role of NADPH oxidase. Cardiovasc Res.2006;71:226-235.
66.Nitti M, Furfaro AL, Traverso N, Odetti P, Storace D, Cottalasso D, et al. PKC delta and NADPH oxidase in AGE-induced neuronal death.Neurosci Lett.2007;416:261-265.
67.Sumbayev VV, Yasinska IM. Regulation of MAP kinase-dependent apoptotic pathway:implication of reactive oxygen and nitrogen species. Arch Biochem Biophys.2005; 436:406-412.
68.Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation.Physiol Rev.2001;81:807-869.
69.O'Neill E, Kolch W. Conferring specificity on the ubiquitous Raf/MEK signalling pathway. Br J Cancer.2004;90:283-288.
70.杨雅茹,黄艳,李俊TGF-β1介导的Smads与ERK通路在肺纤维化中的作用及相互关系.中国药理学通报.2010；26：561-563.
71.Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P. Redox regulation of cell survival. Antioxid Redox Signal.2008; 10:1343-1374.
72.景亚武,易静,高飞,汤雪明。活性氧：从毒性分子到信号分子一活性氧与细胞的增殖、分化和凋亡及其信号转导途径。细胞生物学杂志.2003；4：197-202.
73.Colston JT, de la Rosa SD, Freeman GL. Impact of brief oxidant stress on primary adult cardiac fibroblasts. Biochem Biophys Res Commun.2004; 316:256-262.
74.Zhang H, Chalothorn D, Jackson LF, Lee DC, Faber JE. Transactivation of epidermal growth factor receptor mediates catecholamine-induced growth of vascular smooth muscle. Circ Res.2004;95:989-997.
75.McCubrey JA, Lahair MM, Franklin RA. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal.2006; 8:1775-1789.
76.Shen HM, Liu ZG JNK signaling pathway is a key modulator in cell death mediated by reactive oxygen and nitrogen species. Free Radic Biol Med.2006; 40: 928-939.
77.Han J, Lee JD, Bibbs L, Ulevitch RJ. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science.1994; 265:808-811.
78.Zatechka SD Jr, Lou MF. Studies of the mitogen-activated protein kinases and phosphatidylinositol-3 kinase in the lens.1. The mitogenic and stress responses. Exp Eye Res.2002;74:703-717.
79.Brandes RP, Viedt C, Nguyen K, Beer S, Kreuzer J, Busse R, et al. Thrombin-induced MCP-1 expression involves activation of the p22phox-containing NADPH oxidase in human vascular smooth muscle cells. Thromb Haemost.2001; 85:1104-1110.
80.Fubini B, Hubbard A. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis. Free Radic Biol Med. 2003; 34:1507-1516.
81. Fujimoto D, Hirono Y, Goi T, Katayama K, Matsukawa S, Yarhaguchi A.The activation of Proteinase-Activated Receptor-1 (PAR1) mediates gastric cancer cell proliferation and invasion. BMC Cancer.2010; 10:443.
82.Klatt P, Lamas S. Regulation of protein function by S-glutathiolation in response to oxidative and nitrosative stress. Eur J Biochem.2000; 267:4928-4944.
83.Pineda-Molina E, Klatt P, Vazquez J, Marina A, Garcia de Lacoba M, Perez-Sala D, et al. Glutathionylation of the p50 subunit of NF-kappaB:a mechanism for redox-induced inhibition of DNA binding. Biochemistry.2001;40:14134-14142.
84.Nick JA, Avdi NJ, Young SK, Lehman LA, McDonald PP, Frasch SC, et al. Selective activation and functional significance of p38alpha mitogen-activated protein kinase in lipopolysaccharide-stimulated neutrophils. J Clin Invest.1999; 103:851-858.
85.Jijon H, Allard B, Jobin C.NF-kappaB inducing kinase activates NF-kappaB transcriptional activity independently of IkappaB kinase gamma through a p38 MAPK-dependent RelA phosphorylation pathway. Cell Signal. 2004;16(9):1023-1032.
86.Coughlin SR. Thrombin signalling and protease-activated receptors. Nature. 2000;407:258-264.
[1]Sambola A, Osende J, Hathcock J,et al.Role of risk factors in the modulation of tissue factor activity and blood thrombogenicity[J].Circulation,2003,107(7):973-977.
[2]Barua RS.Ambrose JA.Saha DC.et al. Smoking is associated with altered endothelial-derived fibrinolytic and antithrombotic factors:an in vitro demonstration[J].Circulation,2002,106:905-908.
[3]Ernst E. Haemorheological consequences of chronic cigarette smoking[J]. J Cardiovasc Risk 1995,2(5):435-439.
[4]Didilescu AC, Hanganu SC, Galie N,et al. The role of smoking in changing essential parameters in body homeostasis[J].Pneumologia,58(2):89-94.
[5]Hunter KA, Garlick PJ, Broom I, et al. Effects of smoking and abstention from smoking on fibrinogen synthesis in humans[J].Clin Sci (Lond)2001,100(4):459-465.
[6]Mendall MA, Patel P, Asante M,et al. Relation of serum cytokine concentrations to cardiovascular risk factors and coronary heart disease[J]. Heart,1997,78(3):273-277.
[7]Cesare Alessandri, Stefania Sasili,Francesco Violi, et al. Hypercoagulability state in patients with chronic obstructive pulmonary disease[J]. Thromb Haemost,1994, 72(3):343-346.
[8]Hioki H, Aoki N, Kawano K, et al.Acute effects of cigarette smoking on platelet-dependent thrombin generation[J]. Eur Heart J.2001,22(1):56-61.
[9]Roche N, Stirling RG, Lim S,et al.Effect of acute and chronic inflammatory stimuli on expression of protease-activated receptors 1 and 2 in alveolar macrophages[J]. J Allergy Clin Immunol.2003,111(2):367-373.
[10]Nystedt S.Ramakrishnan V.Sundelin J.The proteinase activated receptor 2 is induced by inflammatory mediators in human endothelial cells.Comparison with the thrombin receptor[J].J Biol Chem,1996,271(25):14910-14915
[11]Resendiz JC, Kroll MH, Lassila R. Protease-activated receptor-induced Akt activation--regulation and possible function[J].J Thromb Haemost,2007,5(12):2484-2493.
[12]Karimi M, Bereczky Z, Cohan N.et al. Factor ⅩⅢ Deficiency,2009,35(4):426-438.
[13]Ariens RAS.Kohler HP.Mansfield MW.et al.Subunit antigen and activity levels of blood coagulation factor XIII in healthy individuals relation to sex,age,smoking,and hypertention[J].Arterioscler Thromb Vase Bio,1999,19:2012-2016.
[14]Yi-Heng Li,Jyh-Hong Chen, Wei-Chuan Tsai.et al.Synergistic effect of thrombomodulin promoter-33G/A polymorphism and smoking on the onset of acute myocardial infarction[J].Thromb Haemost.2002,87 (1):86-91.
[15]Giannarelli C, De Negri F, Virdis A, et al. Nitric oxide modulates tissue plasminogen activator release in normotensive subjects and hypertensive patients[J]. Hypertension,2007, 49(4):878-884.
[16]Zidovetzki R.Chen P,Fisher M. Nicotine increases plasminogen activator inhibitor-1 production by human brain endothelial cells via protein kinase C-associated pathway[J].Stroke, 1999,30 (3):651-655.
[17]Opal SM.Phylogenetic and functional relationships between coagulation and the innate immune response[J].Crit Care Med,2000,28(9 suppl):S77-80.
[18]Wannamethee SG, Lowe GD, Shaper AG, et al. Associations between cigarette smoking, pipe/cigar smoking, and smoking cessation, and haemostatic and inflammatory markers for cardiovascular disease[J]. Eur Heart J,2005,26:1765-1773.
[19]Lee AJ.Fowkes GR.Lowe GD.et al. Determinants of fibrin D-dimer in the Edinburgh Artery Study[J].Arterioscler Thromb Vasc Biol,1995,15 (8).1094-1097.
[20]Murohara T, Kugiyama K, Ohgushi M,et al. Cigarette smoke extract contracts isolated porcine coronary arteries by superoxide anion-mediated degradation of EDRF[J]. Am J Physiol, 1994,266(3 Pt 2):H874-880.
[21]Michaud SE, Dussault S, Groleau J,et al. Cigarette smoke exposure impairs VEGF-induced endothelial cell migration:role of NO and reactive oxygen species[J]. J Mol Cell Cardiol,2006,41(2):275-284.
[22]Vischer UM.von Willebrand factor, endothelial dysfunction, and cardiovascular disease[J]. J Thromb Haemost,2006,4(6):1186-1193.
[23]Kumari M,Marmot M.Brunner E. Social determinants of von Willebrand factor:The Whitehall II Study[J]. Arterioscler Thromb Vase boil,2000,20 (7):1842-1847.
[24]Polatli M, Cakir A, Cildag O, et al. Microalbuminuria, von Willebrand factor and fibrinogen levels as markers of the severity in COPD exacerbation[J]. J Thromb Thrombolysis,2008, 26(2):97-102.
[25]Kalra VK,Ying Y.Deemer K,et al. Mechanism of cigarette smoke condensate induced adhesion of human monocytes to cultured endothelial cells[J]. J Cell Physiol,1994;160 (1):154-162.
[26]Chen HW, Lii CK, Ku HJ, et al. Cigarette smoke extract induces expression of cell adhesion molecules in HUVEC via actin filament reorganization[J]. Environ Mol Mutagen, 2009,50(2):96-104.
[27]Mikhailidis DP, Barradas MA, Jeremy JY, et al. Cigarette smoking inhibits prostacyclin formation[J].Lancet,1983,2 (8350):627-628.
[28]Jeremy JY, Mikhailidis DP, Dandona P. Cigarette smoke extracts, but not nicotine, inhibit prostacyclin(PGI2)synthesis in human, rabbit and rat vascular tissue[J]. Prostaglandins Leukot,1985,19 (3):261-270.
[29]Goerre S, Staehli C, Shaw S, et al. Effect of cigarette smoking and nicotine on plasma endothelin-1 level[J]. J Cardiovase Pharmacol,1995,26(supple 3):S236-238.
[30]Fusegawa Y.Goto S.handa S,et al. Platelet spontaneous aggregation in platelet-rich plasma is increased in habitual smokers[J].Thromb Res,1999,93 (6):271-278
[31]Oksala NK, Heikkinen M, Mikkelsson J, et al. Smoking and the platelet fibrinogen receptor glycoprotein Ⅱb/ⅢA PIA1/A2 polymorphism interact in the risk of lacunar stroke and midterm survival[J]. Stroke,2007;38(1):50-55.
[32]Nair S,Kulkarni S,Camoens HM,et al. Changes in platelet glycoprotein receptors after smoking--Aflow cytometric study[J]. Platelets,2001,12(1):20-26.
[33]Lee DS, Larson MG, Lunetta KL.et al. Clinical and genetic correlates of soluble P-selectin in the community[J]. J Thromb Haemost,2008;6(1):20-31.
[34]Benowitz NL, Fitzgerald GA, Wilson M,et al. Nicotine effects on eicosanoid formation and hemostatic function:Comparison of transdermal nicotine and cigarette smoking[J]. J Am Coll Cardiol,1993,22(4):1159-1167.
[35]Benowitz NL, Hansson A, Jacob P 3rd. Cardiovascular effects of nasal and transdermal nicotine and cigarette smoking. Hypertension,2002,39(6):1107-1112.
[36]Yanbaeva DG, Dentener MA, Creutzberg EC.et al. Systemic effects of smoking[J]. Chest, 2007;131 (5):1557-1566.
[37]Smith CJ, Fischer TH. Particulate and vapor phase constituents of cigarette mainstream smoke and risk of myocardial infarction[J].Atherosclerosis,2001;158(2):257-267.