C5a and TNF-α up-regulate the expression of tissue factor in intra-alveolar neutrophils of patients with the acute respiratory distress syndrome
C5a and TNF-α up-regulate the expression of tissue factor in intra-alveolar neutrophils of patients with the acute respiratory distress syndrome
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DOI：
10.4049/jimmunol.180.11.7368
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发表时间：
2008-06-01
影响因子：
4.4
通讯作者：
Ritis, Konstantinos D.
中科院分区：
文献类型：
--
作者：
Kambas, Konstantinos;Markiewski, Maciej M.;Ritis, Konstantinos D.
急性呼吸窘迫综合征（ARDS）的特征是肺泡内存在富含纤维蛋白的炎性渗出物，中性粒细胞广泛迁移到肺泡内。从ARDS患者获得的支气管肺泡灌洗液（BALF）的组织因子（TF）依赖性促凝特性有利于纤维蛋白沉积，并且可能是炎症介质和止血机制之间相互作用的结果。然而，这些相互作用的调节仍然难以捉摸。先前的研究结果表明，中性粒细胞，在某些炎症条件下，可以表达功能性TF，我们调查了肺泡内中性粒细胞的贡献，从ARDS患者的BALF的促凝特性。我们的研究结果证实，从ARDS患者的BALF的促凝特性是TF诱导的结果，并进一步表明，BALF中性粒细胞是一个主要来源的TF在肺泡内的液体。我们还发现，这些患者的BALF中性粒细胞比外周血中性粒细胞表达更高水平的TF。这些结果表明，肺泡微环境有助于TF诱导在ARDS。另外的实验表明，BALF诱导健康供体中性粒细胞中TF表达的能力可以通过抑制C5 a或TNF-α信号传导来消除，这表明这些炎症介质在ARDS中肺泡中性粒细胞中TF上调中的主要作用。炎症介质和肺泡内中性粒细胞TF表达的诱导之间的这种相互作用可能是限制ARDS相关凝血障碍的新治疗策略的潜在靶点。
Acute respiratory distress syndrome (ARDS) is characterized by the presence of fibrin-rich inflammatory exudates in the intra-alveolar spaces and the extensive migration of neutrophils into alveoli of the lungs. Tissue factor (TF)-dependent procoagulant properties of bronchoalveaolar lavage fluid (BALF) obtained from ARDS patients favor fibrin deposition, and are likely the result of cross-talk between inflammatory mediators and hemostatic mechanisms. However, the regulation of these interactions remains elusive. Prompted by previous findings suggesting that neutrophils, under certain inflammatory conditions, can express functional TF, we investigated the contribution of intra-alveolar neutrophils to the procoagulant properties of BALF from patients with ARDS. Our results confirm that the procoagulant properties of BALF from ARDS patients are the result of TF induction, and further indicate that BALF neutrophils are a main source of TF in intra-alveolar fluid. We also found that BALF neutrophils in these patients express significantly higher levels of TF than peripheral blood neutrophils. These results suggest that the alveolar microenvironment contributes to TF induction in ARDS. Additional experiments indicated that the ability of BALF to induce TF expression in neutrophils from healthy donors can be abolished by inhibiting C5a or TNF-alpha signaling, suggesting a primary role for these inflammatory mediators in the up-regulation of TF in alveolar neutrophils in ARDS. This cross-talk between inflammatory mediators and the induction of TF expression in intra-alveolar neutrophils may be a potential target for novel therapeutic strategies to limit ARDS-associated disturbances of coagulation.