Therapeutic effect of combined protein C pathway factors on acutelung injury

联合Protein C通路因子对急性肺损伤的治疗作用

• 批准号: 18590846
• 负责人: TAGUCHI Osamu
• 金额: $ 2.57万
• 依托单位: Mie University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590846/
• 关键词: Acute lung iniury; Combined therapy; Protein S; Protein C pathway; Cytokines; Sepsis; Activated protein C; Coagulation system; 併用治療; プロテインC制御機構; 敗血症状; 炎症性サイトカイン; 血液凝固系; 肺胞マクロファージ; 血液凝固制御機構; 急性肺傷害; 感染症

Background: Protein S (PS) and activated protein C (APC) have anticoagulant and anti-inflammatory activities. PS may exert anticoagulant activity by favoring the anticoagulant activity of APC and/or by directly inhibiting the prothrombinase complex. The role of PS and the combination of PS and APC on acute lung injury have not been as yet appraised.Objective : The aim of this present study was to evaluate the effect of PS and APC plus PS on acute lung injury in the mouse.Methods : Acute lung injury was induced in C57/BL6 mice by intratracheal instillation of lipopolysaccharide(LPS)(5mg/kg). Mice treated with saline served as controls. To evaluate the therapeutic effect of PS and APC plus PS, the animals were treated with PS alone, a combination of PS and APC or saline by intraperitoneal injection one hour before LPS instillation. These animals were sacrificed 24 hours after LPS injection and sampling of bronchoalveolar lavage fluid and lung tissue were performed. The in vitro effect of PS on secretion of inflammatory cytokines from alveolar epithelial cells was also assessed.Results : The total cell count and the bronchoalveolar lavage fluid level of total protein, interleukin-6 and monocyte chemoattractant protein-1 were significantly increased in LPS-treated mice compared with controls. Mice with acute lung injury treated with PS and combined therapy of PS plus APC had significantly decreased concentration of interleukin-6 and monocyte chemoattractant protein-1 in bronchoalveolar lavage fluid as compared to untreated animals. Treatment with protein C pathway factors also improved lung pathological changes. PS alone significantly abated the expression of inflammatory cytokines from alveolar epithelial cells.Conclusions : These results suggest that combined administration of protein C pathway factors may be a potential therapeutic strategy for the therapy of acute lung injury.

背景：蛋白S（PS）和活化蛋白C（APC）具有抗凝和抗炎活性。 PS可以通过促进APC的抗凝血活性和/或通过直接抑制凝血酶原酶复合物来发挥抗凝血活性。 PS以及PS与APC联用对急性肺损伤的作用尚未得到评价。 目的：本研究的目的是评价PS和APC加PS对小鼠急性肺损伤的作用。方法：通过气管内滴注脂多糖（LPS）（5mg/kg）诱导C57/BL6小鼠急性肺损伤。用盐水处理的小鼠作为对照。为了评价PS和APC加PS的治疗效果，在LPS滴注前1小时通过腹腔注射单独用PS、PS和APC的组合或盐水对动物进行治疗。注射LPS 24小时后处死这些动物，并对支气管肺泡灌洗液和肺组织进行取样。还评估了PS对肺泡上皮细胞分泌炎性细胞因子的体外影响。结果：与对照组相比，LPS处理的小鼠的总细胞计数和支气管肺泡灌洗液中总蛋白、白细胞介素6和单核细胞趋化蛋白1的水平显着增加。与未治疗的动物相比，接受 PS 治疗以及 PS 加 APC 联合治疗的急性肺损伤小鼠支气管肺泡灌洗液中白细胞介素 6 和单核细胞趋化蛋白 1 的浓度显着降低。蛋白C途径因子治疗也改善了肺部病理变化。单独使用PS可显着降低肺泡上皮细胞炎症细胞因子的表达。结论：这些结果表明，蛋白C途径因子的联合给药可能是治疗急性肺损伤的潜在治疗策略。

项目成果

Decreased protein C activation in patients with fulminant hepatic failure.

暴发性肝衰竭患者的蛋白 C 激活减少。

• 发表时间: 2006
• 期刊: Scand J Gastroenterol 41
• 作者: S.Kuno;E.Mizuta;S.Yamasaki;I.Araki;Yamauchi M
• 通讯作者: Yamauchi M

Protective role of thrombin activatable fibrinolysis inhibitor in obstructive nephropathy-associated tubulointerstitial fibrosis.

凝血酶可激活纤溶抑制剂在梗阻性肾病相关肾小管间质纤维化中的保护作用。

• 发表时间: 2008
• 期刊: J Thromb Haemost 6
• 作者: Terada K;Ogawa E;et.al.;Bruno N
• 通讯作者: Bruno N

Role of Thrombin in interleukin-5 secretion from basophils

凝血酶在嗜碱性粒细胞分泌白细胞介素 5 中的作用

• 发表时间: 2007
• 作者: Sato;K.;Sano;C.;Shimizu;T.;Tomioka;H;Yamaguchi A
• 通讯作者: Yamaguchi A

Lipopolysaccharide-induced decreased protein S expression in liver cells is mediated by MEK/ERK signaling and NFkappaB activation : involvement of membrane-bound CD 14 and toll-like receptor-4.

脂多糖诱导的肝细胞中蛋白 S 表达减少是由 MEK/ERK 信号传导和 NFkappaB 激活介导的：膜结合 CD 14 和 Toll 样受体 4 的参与。

• 发表时间: 2006
• 期刊: J Thromb Haemost 4
• 作者: Nakahara;H;Gabazza;EC;Fujimoto;H;Nishii;Y;D'Alessandro-Gabazza;CN;Bruno;NE;Takagi;T;Hayashi;T;Maruyama;J;Maruyama;K;Imanaka-Yoshida;K;Suzuki;K;Yoshida;T;Adachi;Y;Taguchi;O;Hayashi T
• 通讯作者: Hayashi T

Protective role of protein C inhibitor in monocrotaline-induced pulmonary hypertension

• DOI: 10.1111/j.1538-7836.2006.02174.x
• 发表时间: 2006-11-01
• 期刊: JOURNAL OF THROMBOSIS AND HAEMOSTASIS
• 影响因子: 10.4
• 作者: Nishii, Y.;Gabazza, E. C.;Taguchi, O.
• 通讯作者: Taguchi, O.