调控凝血活性对老年大鼠肺组织炎症反应的影响

目的 通过调控凝血活性,观察老年大鼠肺组织凝血酶受体(PAR-1)表达和纤维蛋白沉积变化与炎症反应之间的关系,探讨高凝状态对老年大鼠肺组织炎症反应的促进机制.方法 雌性Wistar大鼠3月龄(青年鼠)和27月龄(老年鼠)均随机分组,以脂多糖(LPS)腹腔注射诱导大鼠肺组织炎症反应,分别给予氨甲环酸、肝素或尿激酶调控凝血活性,检测PAR-1、细胞间黏附分子1(ICAM-1)表达及单核巨噬细胞浸润、纤维蛋白沉积水平的变化.结果 (1)氨甲环酸可使肺组织纤维蛋白沉积增加,而PAR-1表达无明显变化,浸润的炎细胞数目、ICAM-1的蛋白质表达水平较单独给予脂多糖显著上调(P＜0.05);(2)肝素和尿激酶均可使有炎症反应的肺组织纤维蛋白沉积显著减少,但仅有肝素能使PAR-1表达下调,肝素和尿激酶均可显著减少浸润的炎细胞数目及ICAM-1的蛋白质表达(P＜0.05),且两组下降程度差异无统计学意义(P＞0.05);(3)与相同处理的青年鼠比较,老年鼠肺组织纤维蛋白沉积、PAR-1表达显著增多(P＜0.05),浸润的炎细胞数目、ICAM-1的蛋白质表达水平亦显著增加(P＜0.05).结论 (1)凝血系统激活导致的纤维蛋白沉积和PAR-1表达上调,能够诱导黏附分子表达上调,促进炎症反应,增龄所导致的高凝状态能够促进肺组织纤维蛋白沉积及PAR-1表达,从而加重炎症反应;(2)纤维蛋白与PAR-1相比较,在凝血系统参与调节炎症反应的机制中,可能起着更主要的调节作用.     

纤维蛋白沉积对老年急性肺损伤大鼠肺组织内皮细胞功能的影响

目的 探讨纤维蛋白沉积对不同鼠龄大鼠肺组织血管内皮细胞功能的影响.方法 青年及老年大鼠均随机分为4组,对照组（NC）腹腔注射生理盐水;脂多糖组（L）腹腔注射脂多糖;氨甲环酸组（LT）注射脂多糖加氨甲环酸;尿激酶组（LTU）注射脂多糖及氨甲环酸加尿激酶.应用免疫组化分析纤维蛋白沉积;应用Western blot和Northern blot分别检测肺组织血栓调节蛋白（TM）、细胞间黏附分子-1（ICAM-1）、纤溶酶原激活剂抑制物-1（PAI-1）的表达.结果 （1）正常青年和老年大鼠肺组织内均无纤维蛋白沉积,脂多糖刺激后纤维蛋白沉积增多,加用氨甲环酸纤维蛋白沉积更加明显（P＜0.01）,应用尿激酶后纤维蛋白沉积明显减轻（P＜0.05）;老年大鼠L组、LT组和LTU组均比相同干预组的青年大鼠肺组织纤维蛋白沉积明显（P＜0.05）.（2）青年和老年大鼠给与脂多糖刺激后,ICAM-1和PAI-1表达明显上调（P＜0.05）,TM表达显著下降（P＜0.01）;加用氨甲环酸后ICAM-1和PAI-1表达上调更加明显（P＜0.01）,TM几乎无表达;给予尿激酶处理后,ICAM-1和PAI-1表达与LT组比较明显下调（P＜0.05）,TM表达增多（P＜0.05）;老年大鼠L组、LT组和LTU组Ⅰ CAM-1和PAI-1的表达均较青年大鼠相同干预组显著增多（P＜0.05）,TM表达则显著减少.（3）经纤维蛋白沉积量校正后,老年大鼠肺组织ICAM-1和PAI-1的表达量仍显著高于青年大鼠（P＜0.05）.结论 增龄能够促进脂多糖诱导的急性肺损伤大鼠肺组织纤维蛋白沉积,增强纤维蛋白的内皮细胞损伤作用.     

增龄对纤维蛋白急性肺损伤大鼠肺组织单核巨噬细胞趋化因子-1表达的影响

目的研究增龄对纤维蛋白诱导急性肺损伤大鼠肺组织单核巨噬细胞趋化因子-1 (MCP-1)表达的影响,探讨老年大鼠对炎性刺激易感的可能机制。方法青年及老年大鼠均根据腹腔注射不同的药物随机分为4组:对照组、脂多糖组、氨甲环酸组、肝素组。应用免疫组化分析纤维蛋白沉积;应用Western blot和Northern blot方法分别检测肺组织MCP-1蛋白质和基因表达。结果(1)青年和老年对照组大鼠肺组织内均无纤维蛋白沉积,老年大鼠脂多糖组、氨甲环酸组和肝素组均比青年大鼠相同干预组纤维蛋白沉积明显,差别均有统计学意义(18．5％±3．1％对12．3％±2．1％,32．5％±5．4％对24．1％±4．5％和20．8％±3．6％对12．6％±1．8％,均为P<0．05);(2)青年和老年对照组大鼠肺组织内几乎无MCP-1表达,老年大鼠脂多糖组、氨甲环酸组和肝素组的MCP-1表达均较青年大鼠相同干预组上调,差异有统计学意义(0．40±0．02对0．20±0．03,0．60±0．05对0．25±0．04和0．30±0．01对0．20±0．04,均为P<0．05);(3)经纤维蛋白沉积增加量校正后,老年氨甲环酸组大鼠肺组织MCP-1的表达量仍显著高于青年大鼠氨甲环酸组(P<0．05)。结论纤维蛋白可上调急性肺损伤肺组织MCP-1基因及蛋白质表达,促进肺组织炎症反应;增龄能够促进肺组织纤维蛋白沉积,增强其上调肺组织MCP-1表达的作用。     

低分子肝素和尿激酶对老年大鼠肾小球内皮细胞损伤保护作用的比较

目的探讨炎症状态下增龄对肾小球内皮损伤的影响，比较低分子肝素和尿激酶对损伤的保护作用。方法3月龄及27月龄雌性Wistar大鼠各40只，随机分为正常对照组（NC组）、脂多糖（LPS）组（L组）、LPS＋氨甲环酸组（LT组）、LPS＋氨甲环酸＋低分子量肝素组（LTH组）及LPS＋氨甲环酸＋尿激酶组（LTUU组）。采用直接免疫荧光检测肾小球纤维蛋白沉积，Western印迹法检测血管内皮血栓调节蛋白（TM），纤溶酶原激活物抑制物1（PAI-1）蛋白质表达。结果（1）LPS刺激后纤维蛋白沉积增多（P〈0．05），TM几乎无表达（P〈0．01），PAI-1表达明显上调（P〈0．05）；（2）加用氨甲环酸后，PAI-1表达进一步上调（P〈0．05）；（3）应用低分子肝素和尿激酶后纤维蛋白沉积明显减轻（P〈0．05），PAI-1表达与LT组比较明显下调（P〈0．05），TM表达增多（P〈0．05），两组之间无统计学差异。（4）老年大鼠各组肾小球纤维蛋白沉积均比相同干预组的青年大鼠明显，PAI-1的表达均较青年大鼠相同干预组显著增多，TM表达则显著减少，差别均有统计学意义（P〈0．05）。结论增龄可加重LPS诱导的肾小球内皮损伤；低分子肝素与尿激酶均能有效保护老年大鼠肾小球血管内皮损伤，两者无明显差别，但增龄可减弱低分子肝素和尿激酶对血管内皮的保护作用。     

Ghrelin对脓毒症小鼠肺脏炎症及JAK/STAT通路的影响

目的 通过观察生长素释放肽(ghrelin)对脓毒症小鼠肺组织炎症反应、肺组织janus激酶/信号转导通路和转录激活因子mRNA、STAT3蛋白及肺组织炎细胞因子肿瘤细胞α(TNF-α)、IL-6的表达水平的影响,探讨ghrelin在脓毒症炎症反应中的调节作用及可能的分子机制.方法 选用腹腔注射脂多糖的方法制作小鼠脓毒性模型:选取雌性小鼠54只,随机分为对照组、模型组及ghrelin干预组,对照组经腹腔注射等量生理盐水;模型组经腹腔内注射脂多糖(6 mg/kg);干预组先经腹腔注射ghrelin(200 μg/kg),30 min后再经腹腔注射脂多糖(6 mg/kg);各组分别于3、9、18h随机处死小鼠各6只,光镜下观察肺组织炎症改变;反转录聚合酶链反应(RT-PCR)法检查肺组织STAT3mRNA的基因转录水平;酶联免疫吸附测定(ELISA)法测定肺组织STAT3、TNF-α、IL-6的表达量.结果 Ghrelin可抑制肺组织STAT3mRNA基因转录活性,从而降低STAT3蛋白表达、减少炎症因子TNF-α、IL-6的分泌(P值均＜0.05);改善脓毒症小鼠肺组织病理结构损伤(充血、水肿、炎症细胞浸润).结论 ghrelin可减轻脓毒症小鼠肺脏炎症反应,其作用机制可能与抑制了janus激酶/信号转导和转录激活因子(JAK/STAT通路)、下调TNF-α和IL-6的表达有关.     

老年人全膝关节置换围术期使用氨甲环酸对术后深静脉血栓形成发生率的影响

目的探究老年人全膝关节置换(TKA)围术期使用氨甲环酸对术后深静脉血栓形成(DVT)发生率的影响。方法行TKA术的老年患者135例,根据给药方式不同将其分为静脉联合关节腔内注射氨甲环酸的患者34例(A组),静脉注射氨甲环酸的患者34例(B组),关节腔内注射氨甲环酸的患者34例(C组),未使用氨甲环酸的患者33例(D组)。比较4组手术前后血小板参数、凝血功能指标的差异,并记录术后2个月内DVT发生率。结果相较于术前,A、B、C、D组术后6 h的D-二聚体(D-D)、凝血酶原时间(PT)、纤维蛋白原(FIB)、活化部分凝血酶时间(APTT)均出现显著降低,凝血酶原时间显著升高且PT、APTT水平依次减少,D-D、FIB水平依次增加,各组间比较差异有统计学意义(P0.05);A、B、C、D组血小板分布宽度(PDW)、血小板压积(PCT)、血小板平均体积(MPV)水平均较术前显著升高,血小板计数(PLT)显著降低,PDW、PCT、MPV依次增加,PLT依次减少,各组间比较差异有统计学意义(P0.05)。此外,4组患者术后7 d行下肢血管多普勒超声检查均未发现DVT形成,术后2个月内4组均未发现症状性DVT病例。结论于TKA围术期,采用静脉联合关节腔内注射氨甲环酸可有效避免老年患者出现高凝状态及血小板活化现象,并且不增加DVT形成发生的风险,较单独使用氨甲环酸效果更好。     

老年全膝关节置换患者术后静脉注射不同剂量氨甲环酸效果对比

目的 对比不同剂量氨甲环酸用于老年全膝关节置换患者术后的临床效果。方法 选取60例行膝关节双间室置换术患者,采用掷硬币法分为观察组和对照组各30例。对照组术后即刻静脉注射1.0 g氨甲环酸,观察组术后即刻静脉注射2.0 g氨甲环酸,两组术后均行抗感染、止痛等治疗。术后3 d,统计两组出血量;比较两组术前、术后1 d时凝血功能[纤维蛋白原(FIB)、凝血原酶时间(PT)、活化部分凝血活酶时间(APTT)]、炎症指标[C反应蛋白(CRP)、白细胞介素(IL)-6]及术后不良反应。结果 观察组引流血量、显性失血量、隐性失血量、总失血量均少于对照组,差异有统计学意义(P<0.001)。术后1 d,两组FIB水平较术前升高,PT、APTT较术前延迟,但观察组FIB水平较对照组高,PT、APTT较对照组短,差异有统计学意义(P<0.05)。术后1 d,两组血清CRP、IL-6水平均较术前明显升高,但观察组升高水平低于对照组,差异有统计学意义(P<0.05)。两组不良反应总发生率差异无统计学意义(P>0.05)。结论 老年全膝关节置换患者术后静脉注射2.0 g氨甲环酸可进一步...     

甲状腺素对幼鼠脑TNF-α和TNFR1基因表达的影响

目的研究甲状腺素(T4)对幼鼠脑TNF-α和TNFR1基因表达的影响.方法采用丙基硫氧嘧啶灌胃制备甲状腺功能低下(甲低)孕鼠模型,出生后小鼠为先天性甲低鼠,另一组出生后即日起用腹腔注射T4,剂量为20 μg/(kg*d)(替代组),采用逆转录-聚合酶链反应检测出生后1,5,10 d幼鼠TNF-α和TNFR1基因的表达.结果在出生后第1 d甲低幼鼠脑TNF-α和TNFR1基因表达最高,随着鼠龄增长,表达降低;正常出生后第1 d幼鼠及替代组TNF-α和TNFR1基因表达较甲低组低.结论甲状腺素对TNF-α和TNFR1基因表达的影响在脑细胞凋亡中有重要的作用.     

LPS刺激对老年Balb／c小鼠血浆IL—1β，IL—6水平的影响

目的：研究在小剂量LPS刺激下老年机体血浆IL－1β，IL－6的变化情况。方法：8只老年Balb/c小鼠和10只青年Balb/c小鼠腹腔注射5ugLPS，对照动物注射生理盐水，注射后4h杀发产取血，ELISA方法测血浆中细胞因了水平，结果，老年小鼠血浆基因IL－β明显高于年青少鼠（P＜0．01），LPS 刺激后，老年鼠IL－1β无明显上升，而青年组IL－1β明显上升（P＜0．05），LPS刺激后老年，青年小鼠血浆IL－6水平均升高，但老年组上升幅度低于年青组，其IL－6水平也明显较青年小鼠（P＜0．05）。结论：老年机体IL－01β，IL－6的产生紊乱可能与老年期革蓝氏阴性细菌感染致死率高有关。     

老年大鼠内毒素血症时心肌血红素氧合酶1和一氧化碳系统变化分析

目的探讨内毒素血症时老年大鼠心肌血红素氧合酶1(HO-1)和CO系统的变化。方法 39只SD大鼠分为老年对照组7只、青年对照组12只、老年内毒素组8只、青年内毒素组12只。采用尾静脉注射脂多糖(3 mg/kg)制备内毒素模型,4 h后取血及心脏,检测血浆CO水平;光镜及电镜观察心肌病理改变;免疫组织化学法检测心肌HO-1的表达。结果与老年对照组和青年对照组比较,老年内毒素组和青年内毒素组CO水平明显升高(P<0.05);与老年内毒素组比较,青年内毒素组CO水平明显降低(P<0.05)。注射脂多糖后,老年和青年内毒素组大鼠均出现心肌细胞变性,间质毛细血管轻度扩张充血等病变,但老年组较青年组更严重。与青年内毒素组比较,老年内毒素组HO-1 A值明显升高(P<0.05)。结论内毒素血症时,老年大鼠心肌更容易受到损伤。HO-1/CO系统在老年内毒素组的表达更加明显,可能与其心肌细胞内蛋白变性严重、存在更加强烈的氧化应激有关。     

Effects of alterations of glomerular fibrin deposition on renal inflammation in rats at different age stages

Recent data indicated that aging accelerated glomerular fibrin deposition induced by lipopolysaccharide (LPS) in mice. Our hypothesis was that aging may exacerbate glomerular inflammatory responses induced by glomerular fibrin deposition. Both young and aged rats with glomerular fibrin deposition induced by LPS were treated with tranexamic acid (TA) and TA plus urokinase (UK). Infiltrating inflammatory cells and expressions of monocyte chemoattractant protein 1, intercellular adhesion molecule 1, and vascular endothelial-cadherin were markedly upregulated in the LPS+TA group compared with the LPS group. Reduction of fibrin deposition in the LPS+TA+UK group was associated with downregulation of the above indices (p < .05), whereas the alteration of vascular endothelial-cadherin protein expression was negatively correlated with the fibrin deposition. There were also significant differences in increased expressions of monocyte chemoattractant protein 1 and intercellular adhesion molecule 1 between young and aged rats. These in vivo data demonstrated that fibrin deposition contributed to glomerular inflammatory responses, which could be exacerbated by aging.     

Significance of Decreased Plasma D-Dimer Levels following Lipopolysaccharide-Induced Disseminated Intravascular Coagulation in Rats

Plasma D-dimer (DD) is considered to be one of the most useful markers in the diagnosis and assessment of disseminated intravascular coagulation (DIC). The present study was performed to clarify the role of DD in a rat model of lipopolysaccharide (LPS)-induced DIC in which low-molecular-weight heparin (LMWH) and tranexamic acid (TA) were used. We investigated whether a relationship exists between plasma DD levels and severity of DIC. Experimental DIC was induced in rats by a sustained 4-hour infusion of 30 mg/kg LPS administered via the tail vein (LPS group). Rats received either LPS alone (LPS group) or LPS combined with 200 U/kg LMWH (LPS+LMWH group) or 50 mg/kg TA (LPS+TA group) from -30 minutes to 4 hours. Blood was drawn from each rat at 4, 8, and 12 hours. Plasma levels of thrombin-antithrombin complex (TAT) and creatinine were suppressed in the LPS+LMWH group, and less glomerular fibrin deposition was observed compared with the LPS group. On the other hand, an increased level of creatinine and increased glomerular fibrin deposition were observed in the LPS+TA group compared with the LPS group. LMWH demonstrated a protective effect against LPS-induced DIC, resulting in increased survival at 12 hours, whereas TA had the opposite effect. From these results, it appears that LMWH protects against LPS-induced DIC, but TA exacerbates LPS-induced DIC. It was interesting that plasma levels of DD were almost completely suppressed by concurrent administration of either TA or LMWH in this LPS-induced DIC model. This finding suggested that plasma levels of DD were suppressed by inhibition of coagulation (reduced deposition of fibrin) in the LPS+LMWH group and that DD levels were also suppressed by inhibition of fibrinolysis (reduced degradation of fibrin by plasmin) in the LPS+TA group. Thus care should be taken when evaluating the significance of plasma DD levels, because suppressed levels can occur with progressive fibrin deposition and worsening organ dysfunction or improvement in the course of DIC.     

Enhancement of the activation of Glu-plasminogen by urokinase in the simultaneous presence of tranexamic acid or fibrin

The activation rate of Glu-plasminogen (Glu-plg) by urokinase (UK) was enhanced in the presence of either tranexamic acid or fibrin with an increase in the catalytic rate constant (kcat). The maximum increase in kcat was obtained at 0.5 mM of tranexamic acid and 0.1 microM of fibrin. Km did not change. The addition of fibrin to 1 mM tranexamic acid resulted in a further increase in kcat of the UK activation of Glu-plg. On the other hand, the addition of tranexamic acid to 0.1 microM fibrin further increased kcat of the UK activation of Glu-plg. Thus, stimulatory effects were observed on the activation of Glu-plg by UK in the simultaneous presence of tranexamic acid and fibrin. Fibrin-binding sites on the kringle 5 of Glu-plg may be involved in the further increase in the activation rate of Glu-plg by UK in the presence of both fibrin and tranexamic acid in comparison to that in the presence of tranexamic acid alone. Possibly, the Glu-plg binding with both tranexamic acid and fibrin (at kringle 5) may be most effectively activated by UK. It is also suggested that two molecules of Glu-plg bind to one molecule of fibrin monomer.     

Preventive effects of sevoflurane treatment on lung inflammation in rats

ObjectiveTo observe the effects of sevoflurane treatment on lung inflammation in rats with lipopoIysaccharide-induced acute lung injury (ALI).MethodsThe rat model of ALI was established by intratracheal instillation of lipopolysaccharide (LPS). 45 infantile SD rats [body weight (272±15) g] were randomly divided into 3 groups (n=15): control group, LPS group, sevoflurane group. NS (1 mL/kg) was instillated in rats' airways of control group; LPS (5 mg/kg) was instillated in rats' airways of LPS group. Sevoflurane group rats received sevoflurane (2.4%) inhalation for a hour after LPS was instillated in rats' airways. Six hours after NS or LPS instillation, all rats were exsanguinated. Lung tissues were examined by HE staining. Expressions of TNF-α and ICAM1 mRNA were detected by semiquantitative RT-PCR techniques. The protein level of TNF-α and ICAM1 were assessed by western blot techniques.ResultsIn LPS group the permeability of lung tissues increased, organizational structure severely damaged and the alveolar wall tumed thick, with interstitial edema and Europhiles infiltrated increasingly. The LPS group had higher mRNA expressions of TNF-α and ICAM1 than control group and sevoflurane group (P<0.05), and LPS group had higher protein level of TNF-α and ICAM1 than control group and sevoflurane group (P<0.05).ConclusionsSevoflurane treatment can attenuate lung inflammation in rats with lipopolysaccharide-induced acute lung injury.     

The immunopathology of the aging rat kidney.

Immunofluorescence studies of rat kidneys from 3-24 mo. of age demonstrated deposition of immunoglobulins, predominately IgM, within the glomerular mesangium by age 3 mo. Immunoglobulins eluted in acid buffer, did not fix complement, were not associated with inflammatory changes, and increased markedly with the onset of proteinuria at about 12 mo. Rats 24 mo. old also had mesangial deposits of IgG and fibrin. No basement membrane deposits were seen, and autoantibodies to antigens in normal kidney, liver, spleen, and skeletal muscle were not demonstrable in serum or eluates of kidneys from aged animals. The focal and segmental glomerular sclerosis which develops in aged rats does not appear to be mediated by glomerular deposition of auto-antibody or immune complexes. Mesangial accumulation of macro-molecular material, perhaps as a consequency of the age-associated increase in glomerular permeability, may contribute to the development of the glomerular sclerosis of aging in the rat by impairing mesangial phagocytic or clearing mechanisms rather than through immunologically mediated tissue injury.     

Thrombin modulates synthesis of plasminogen activator inhibitor type 2 by human peripheral blood monocytes

Fibrin deposition is characteristic of inflammatory diseases. The monocytes is central to the inflammatory response and can affect fibrinolysis by expression of urokinase (u-PA) and plasminogen activator inhibitor types 1 and 2 (PAI-1 and PAI-2, respectively). This study examines whether thrombin, which promotes fibrin deposition, can contribute to fibrin persistence by modulating expression of proteins of the fibrinolytic system. Monocytes were isolated from human peripheral blood and analyzed for PAI-2, PAI-1, and u-PA antigens by enzyme-linked immunosorbent assay (ELISA). Monocytes responded to thrombin by increased expression of PAI-2 in a dose- and time-dependent manner, with maximal synthesis at a concentration of 1 U/mL to 10 U/mL. This trend was also evident for PAI-1, which was present at much lower levels. Thrombin and lipopolysaccharide (LPS) stimulated comparable levels of PAI-2, studied at the antigen and mRNA level. The dose effet of LPS on PAI-2 and PAI-1 was found to differ from that of thrombin. The level of u-PA was undetectable by ELISA and zymography in all samples. Thrombin stimulates PAI-2 synthesis by human monocytes, therefore creating an imbalance in the fibrinolytic system. This may contribute to persistence of fibrin, deposited during inflammation.     

Increased expression of plasminogen activator inhibitor-1 with fibrin deposition in a murine model of aging, "Klotho" mouse

Although aging accompanies specific pathological changes, including thrombosis and organ sclerosis, the underlying mechanisms of these processes remain to be elucidated. In the present study, we analyzed the gene expression of plasminogen activator inhibitor-1 (PAI-1), a key molecule in the development of thrombosis, in a murine model of aging, klotho mutant ( kl/kl) mice. Active PAI-1 antigen in plasma and PAI-1 mRNA in several tissues were strikingly elevated in kl/kl mice as compared with wild-type mice. This increased PAI-1 expression was age dependent and linked to the development of ectopic calcification and glomerular fibrin deposition in the kidneys. In situ hybridization analysis of kl/kl mice demonstrated that strong signals for PAI-1 mRNA were localized in renal tubular epithelial cells, cardiomyocytes, adrenal medullar cells, and smooth muscle and endothelial cells in M?nckeberg's arteriosclerotic vessels. Renal glomerular fibrin deposition, as evaluated immunohistochemically, was occasionally observed only in kl/kl mice, and the number of fibrin-positive glomeruli increased as the kl/kl mice aged. These observations suggest that in the process of aging the PAI-1 gene expression is increased, contributing to the development of thrombosis.     

Plasminogen-plasmin system IX. Specific binding of tranexamic acid to plasmin.

Interactions between tranexamic acid and protein were studied in respect of the antifibrinolytic actions of tranexamic acid. Tranexamic acid did neither show any interaction with fibrinogen or fibrin, nor was incorporated into cross-linked fibrin structure by the action of factor XIII. On the other hand, tranexamic acid bound to human plasmin with a dissociation constant of 3.5 X 10-5 M, which was very close to the inhibition constatn (3.6 X 10-5 M1 for this compound in inhibiting plasmin-induced fibrinolysis. The binding site of tranexamic acid on plasmin was not the catalytic site of plasmin, because TLCK-blocked plasmin also showed a similar affinity to tranexamic acid (the dissociation constant, 2.9-4.8 x 10-5m). in the binding studies with the highly purified plasminogen and TLCK-plasmin preparations which were obtained by affinity chromatography on lysine-substituted Sepharose, the molar binding ratio was shown to be 1.5-1.6 moles tranexamic acid per one mole protein. On the basis of these and other findings, a model for the inhibitory mechanism of tranexamic acid is presented.     

Antithrombin III injection via the portal vein suppresses liver damage

AIM: To investigate the effects of antithrombin III (AT III) injection via the portal vein in acute liver failure.METHODS: Thirty rats were intraperitoneally challenged with lipopolysaccharide (LPS) and D-galactosamine (GalN) and divided into three groups: a control group; a group injected with AT III via the tail vein; and a group injected with AT III via the portal vein. AT III (50 U/kg body weight) was administrated 1 h after challenge with LPS and GalN. Serum levels of inflammatory cytokines and fibrin degradation products, hepatic fibrin deposition, and hepatic mRNA expression of hypoxia-related genes were analyzed.RESULTS: Serum levels of alanine aminotransferase, tumor necrosis factor-α and interleukin-6 decreased significantly following portal vein AT III injection compared with tail vein injection, and control rats. Portal vein AT III injection reduced liver cell destruction and decreased hepatic fibrin deposition. This treatment also significantly reduced hepatic mRNA expression of lactate dehydrogenase and heme oxygenase-1.CONCLUSION: A clinically acceptable dose of AT III injection into the portal vein suppressed liver damage, probably through its enhanced anticoagulant and anti-inflammatory activities.