Kambas Konstantinos, Markiewski Maciej M, Pneumatikos Ioannis A, Rafail Stavros S, Theodorou Vassiliki, Konstantonis Dimitrios, Kourtzelis Ioannis, Doumas Michael N, Magotti Paola, Deangelis Robert A, Lambris John D, Ritis Konstantinos D
First Division of Internal Medicine, Democritus uNiversity of Thrace, Alexandoupolis, Greece.
J Immunol. 2008 Jun 1;180(11):7368-75. doi: 10.4049/jimmunol.180.11.7368.
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.
急性呼吸窘迫综合征（ARDS）的特征是肺泡腔内存在富含纤维蛋白的炎性渗出物，以及大量中性粒细胞迁移至肺的肺泡内。从ARDS患者获得的支气管肺泡灌洗液（BALF）中依赖组织因子（TF）的促凝特性有利于纤维蛋白沉积，这可能是炎性介质与止血机制之间相互作用的结果。然而，这些相互作用的调节机制仍不清楚。基于先前的研究结果提示中性粒细胞在某些炎症条件下可表达功能性TF，我们研究了肺泡内中性粒细胞对ARDS患者BALF促凝特性的作用。我们的结果证实，ARDS患者BALF的促凝特性是TF诱导的结果，并且进一步表明BALF中性粒细胞是肺泡内液中TF的主要来源。我们还发现，这些患者的BALF中性粒细胞表达的TF水平明显高于外周血中性粒细胞。这些结果表明，肺泡微环境促成了ARDS中TF的诱导。额外的实验表明，通过抑制C5a或TNF-α信号传导可消除BALF诱导健康供体中性粒细胞中TF表达的能力，这表明这些炎性介质在ARDS肺泡中性粒细胞TF上调中起主要作用。炎性介质与肺泡内中性粒细胞TF表达诱导之间的这种相互作用可能是限制ARDS相关凝血紊乱的新型治疗策略的潜在靶点。
