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1 Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
2 Cardiovascular Research Institute, University of California, San Francisco, CA, USA
3 Cardiovascular Research Institute, University of California, San Francisco, CA, USA; Departments of Medicine and Anesthesia, University of California, San Francisco, CA, USA
* To whom correspondence should be addressed. E-mail: lorraine.ware{at}vanderbilt.edu.
Decreased circulating protein C and increased circulating thrombomodulin are markers of the prothrombotic, antifibrinolytic state associated with poor outcomes in sepsis, but have not been measured in patients with ALI/ARDS. We measured circulating and intra-alveolar protein C and thrombomodulin in 45 patients with ALI/ARDS from septic and non-septic causes and correlated the levels with clinical outcomes. Plasma protein C levels were lower in ALI/ARDS (37 ± 14%) compared to normals (n=10, 125 ± 24%, p < .001). Lower levels of protein C were associated with worse clinical outcomes including death, fewer ventilator-free days, and more non-pulmonary organ failures, even when only patients without sepsis (n = 25) were analyzed. Levels of thrombomodulin in pulmonary edema fluid from ALI/ARDS patients (704 ± 678 ng/ml) were over ten-fold higher than normal plasma (53 ± 28 ng/ml, p = .001) and two-fold higher than ALI/ARDS plasma (307 ± 244 ng/ml, p = .001). Higher edema fluid thrombomodulin levels were associated with worse clinical outcomes. The higher levels in edema fluid compared to plasma suggest local release of soluble thrombomodulin in the lung, possibly from a lung epithelial source. To determine whether lung epithelial cells can release thrombomodulin, A549 cells and primary isolates of human alveolar type II cells were exposed to H2O2 or inflammatory cytokines. Both epithelial cell types released thrombomodulin into the media. In summary, the protein C system is markedly disrupted in patients with ALI/ARDS from both septic and non-septic causes. The protein C system may be a potential therapeutic target in patients with ALI/ARDS.
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