Therapeutic effect of combined protein C pathway factors on acutelung injury

背景：蛋白S（PS）和活化蛋白C（APC）具有抗凝和抗炎活性。PS可能通过促进APC的抗凝活性和/或直接抑制凝血酶原酶复合物来发挥抗凝活性。目的：探讨PS及APC + PS对小鼠急性肺损伤的保护作用。方法：采用C57/BL 6小鼠，腹腔内注射脂多糖（LPS）（5 mg/kg），建立急性肺损伤模型。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小时通过腹腔内注射单独的PS、PS和APC的组合或生理盐水处理动物。LPS注射后24小时处死这些动物，并进行支气管肺泡灌洗液和肺组织取样。结果：与对照组相比，LPS组小鼠肺泡上皮细胞总数、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水平均显著升高。与未治疗的动物相比，PS和PS + APC联合治疗的急性肺损伤小鼠的支气管肺泡灌洗液中的白细胞介素-6和单核细胞趋化蛋白-1的浓度显著降低。蛋白C通路因子治疗也可改善肺病理改变。PS单独显着减弱炎症细胞因子的表达从肺泡epithelial cells.Conclusions：这些结果表明，联合管理的蛋白C通路因子可能是一个潜在的治疗策略，用于治疗急性肺损伤。

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.