Therapeutic effect of combined protein C pathway factors on acutelung injury

背景：蛋白S （PS）和活化蛋白C （APC）具有抗凝血和抗炎活性。PS可能通过促进APC的抗凝血活性和/或直接抑制凝血酶原复合物来发挥抗凝血活性。目前尚不清楚PS及其与APC合用在急性肺损伤中的作用。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影响。方法：气管内灌注脂多糖（LPS） 5mg/kg诱导C57/BL6小鼠急性肺损伤。用生理盐水治疗的小鼠作为对照。为了评价PS和APC联合PS的治疗效果，在LPS注射前1小时分别给予PS、PS与APC联合或生理盐水腹腔注射。LPS注射24小时后处死，取支气管肺泡灌洗液和肺组织标本。我们还评估了PS对肺泡上皮细胞分泌炎性细胞因子的体外影响。结果：lps处理小鼠支气管肺泡灌洗液总蛋白、白细胞介素-6、单核细胞趋化蛋白-1水平显著高于对照组。急性肺损伤小鼠经PS和PS + APC联合治疗后，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的浓度明显低于未治疗小鼠。蛋白C通路因子治疗也可改善肺部病理改变。单独使用PS可显著降低肺泡上皮细胞炎症因子的表达。结论：这些结果提示联合给药蛋白C通路因子可能是治疗急性肺损伤的一种潜在的治疗策略。

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.