Direct effects of protein S in ameliorating acute lung injury

Objective: Protein S may exert an anticoagulant activity by enhancing the anticoagulant activity of activated protein C and/or by directly inhibiting the prothrombinase complex. Protein S itself may also directly regulate inflammatory responses and apoptosis. The role of protein S in acute lung injury (ALI) was unknown. This study evaluated the effect of protein S on ALI in the mouse. Methods: Animal ALI was induced in C57/BL6 mice by intratracheal instillation of lipopolysaccharide (LPS). Mice were treated with protein S or saline by intraperitoneal injection 1 h before LPS instillation. Results: Activated protein or protein S alone and combined activated protein C + protein S therapy decreased inflammatory markers and cytokines in mice with acute lung injury. In LPS-treated mice compared with controls ALI was induced as shown by significantly increased levels of total protein, tumor necrosis factor-alpha, interleukin-6 and monocyte chemoattractant protein-1 in the bronchoalveolar lavage fluid. Mice with ALI treated with protein S had significantly decreased concentrations of tumor necrosis factor-alpha and interleukin-6 in the lung compared with untreated animals. Thrombin-antithrombin III, a marker of the activity of the coagulation cascade, was unchanged. Protein S inhibited the expression of cytokines in vitro and increased activation of the Axl tyrosine kinase pathway in A549 epithelial cells. Conclusion: Protein S protects against LPS-induced ALI, possibly by directly inhibiting the local expression of inflammatory cytokines without affecting coagulation.

目的：蛋白S可能通过增强活化蛋白C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。蛋白S自身也可能直接调节炎症反应和细胞凋亡。蛋白S在急性肺损伤（ALI）中的作用尚不清楚。本研究评估了蛋白S对小鼠ALI的影响。 方法：通过气管内滴注脂多糖（LPS）在C57/BL6小鼠中诱导动物ALI。在LPS滴注前1小时，通过腹腔注射用蛋白S或生理盐水对小鼠进行处理。 结果：活化蛋白或单独的蛋白S以及联合的活化蛋白C + 蛋白S治疗降低了急性肺损伤小鼠的炎症标志物和细胞因子。与对照组相比，LPS处理的小鼠出现ALI，表现为支气管肺泡灌洗液中总蛋白、肿瘤坏死因子 -α、白细胞介素 - 6和单核细胞趋化蛋白 - 1的水平显著升高。与未治疗的动物相比，用蛋白S治疗的ALI小鼠肺中肿瘤坏死因子 -α和白细胞介素 - 6的浓度显著降低。凝血酶 - 抗凝血酶III（凝血级联反应活性的标志物）未发生变化。蛋白S在体外抑制细胞因子的表达，并增加A549上皮细胞中Axl酪氨酸激酶途径的活化。 结论：蛋白S可预防LPS诱导的ALI，可能是通过直接抑制炎症细胞因子的局部表达而不影响凝血。