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Up-Regulate the Expression of Tissue Factor in Intra-Alveolar Neutrophils of Patients with the Acute Respiratory Distress Syndrome1
,
* First Division of Internal Medicine and
Intensive Care Unit, Medical School, Democritus University of Thrace, Alexandroupolis, Greece; and
Department of Pathology and
Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
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-
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Governing Board of Academic Hospital of Alexandroupolis and the Greek General Secretariat of Research and Technology (to K.D.R.), and partially supported by National Institutes of Health Grant GM-62134 and AI068730 (to J.D.L.).
2 K.K., M.M.M., and I.A.P. contributed equally to this work.
3 J.D.L. and K.D.R. cosupervised this work.
4 Address correspondence and reprint requests to Dr. Konstantinos Ritis, PO Box 205, 68100 Alexandroupolis, Greece. E-mail address: ritis2{at}otenet.gr or Dr. John D. Lambris, Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, 422 Curie Boulevard, Philadelphia, PA 19104. E-mail address: lambris{at}mail.med.upenn.edu
5 Abbreviations used in this paper: ARDS, acute respiratory distress syndrome; BALF, bronchoalveolar lavage fluid; TF, tissue factor; PMN, polymorphonuclear cell; ALI, acute lung injury; APAAP, alkaline-phosphatase anti-alkaline-phosphatase; mPT, modified prothrombin time; asTF, alternative spliced TF; GRO, growth related gene product.
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