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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1702-1709. Prepublished online as a Blood First Edition Paper on October 30, 2003; DOI 10.1182/blood-2002-05-1380. This Article Full Text (PDF) All Versions of this Article: 2002-05-1380v1 103/5/1702    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Rijneveld, A. W Articles by van der Poll, T. Search for Related Content PubMed PubMed Citation Articles by Rijneveld, A. W Articles by van der Poll, T. Social Bookmarking                   What's this? Submitted May 10, 2002 Accepted April 30, 2003 Thrombomodulin mutant mice with a strongly reduced capacity to generate Activated Protein C have an unaltered pulmonary immune response to respiratory pathogens and lipopolysaccharide Anita W Rijneveld*, Sebastiaan Weijer, Sandrine Florquin, Charles T Esmon, Joost C M Meijers, Peter Speelman, Pieter H Reitsma, Hugo Ten Cate, and Tom van der Poll Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Department of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands * Corresponding author; email: a.w.rijneveld{at}amc.uva.nl. The Thrombomodulin (TM)-Protein C (PC)-Protein S (PS) pathway exerts anti-coagulant and anti-inflammatory effects. We investigated the role of TM in the pulmonary immune response in vivo by the use of mice with a mutation in the TM gene (TMpro/pro) that was earlier found to result in a minimal capacity for activated PC (APC) generation in the circulation. We here demonstrate that TMpro/pro mice also display a strongly reduced capacity to produce APC in the alveolar compartment upon intrapulmonary delivery of PC and thrombin. We monitored procoagulant and inflammatory changes in the lung during Gram-positive (Streptococcus pneumoniae), and Gram-negative (Klebsiella pneumoniae) pneumonia, and after local administration of lipopolysaccharide (LPS). Bacterial pneumonia was associated with fibrin(ogen) depositions in the lung that colocalized with inflammatory infiltrates. LPS also induced a rise in thrombin-antithrombin complexes in bronchoalveolar lavage fluid. These pulmonary procoagulant responses were unaltered in TMpro/pro mice, except for enhanced fibrin(ogen) deposition during pneumococcal pneumonia. In addition, TMpro/pro mice displayed unchanged antibacterial defense, neutrophil recruitment and cytokine/chemokine levels. These data suggest that the capacity of TM to generate APC does not play a role of importance in the pulmonary response to respiratory pathogens or LPS. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. A. D. van Zoelen, S. Florquin, J. C. M. Meijers, R. de Beer, A. F. de Vos, O. J. de Boer, and T. van der Poll Platelet-Activating Factor Receptor Contributes to Host Defense against Pseudomonas aeruginosa Pneumonia but Is Not Essential for the Accompanying Inflammatory and Procoagulant Response J. Immunol., March 1, 2008; 180(5): 3357 - 3365. [Abstract] [Full Text] [PDF] R. Renckens, J. J. T. H. Roelofs, P. I. Bonta, S. Florquin, C. J. M. de Vries, M. Levi, P. Carmeliet, C. van't Veer, and T. van der Poll Plasminogen activator inhibitor type 1 is protective during severe Gram-negative pneumonia Blood, February 15, 2007; 109(4): 1593 - 1601. [Abstract] [Full Text] [PDF] T. T. Keller, K. F. van der Sluijs, M. D. de Kruif, V. E. A. Gerdes, J. C. M. Meijers, S. Florquin, T. van der Poll, E. C. M. van Gorp, D. P. M. Brandjes, H. R. Buller, et al. Effects on Coagulation and Fibrinolysis Induced by Influenza in Mice With a Reduced Capacity to Generate Activated Protein C and a Deficiency in Plasminogen Activator Inhibitor Type 1 Circ. Res., November 24, 2006; 99(11): 1261 - 1269. [Abstract] [Full Text] [PDF] P. Dahlem, A. P. Bos, J. J. Haitsma, M. J. Schultz, E. K. Wolthuis, J. C. M. Meijers, and B. Lachmann Mechanical ventilation affects alveolar fibrinolysis in LPS-induced lung injury Eur. Respir. J., November 1, 2006; 28(5): 992 - 998. [Abstract] [Full Text] [PDF] C.-H. Lin, H.-W. Cheng, M.-J. Hsu, M.-C. Chen, C.-C. Lin, and B.-C. Chen c-Src Mediates Thrombin-Induced NF-{kappa}B Activation and IL-8/CXCL8 Expression in Lung Epithelial Cells. J. Immunol., September 1, 2006; 177(5): 3427 - 3438. [Abstract] [Full Text] [PDF] R. Renckens, J. J. T. H. Roelofs, S. A. J. ter Horst, C. van 't Veer, S. R. Havik, S. Florquin, G. T. M. Wagenaar, J. C. M. Meijers, and T. van der Poll Absence of Thrombin-Activatable Fibrinolysis Inhibitor Protects against Sepsis-Induced Liver Injury in Mice J. Immunol., November 15, 2005; 175(10): 6764 - 6771. [Abstract] [Full Text] [PDF] S. Weijer, C. W. Wieland, S. Florquin, and T. van der Poll A thrombomodulin mutation that impairs activated protein C generation results in uncontrolled lung inflammation during murine tuberculosis Blood, October 15, 2005; 106(8): 2761 - 2768. [Abstract] [Full Text] [PDF] J. Branger, S. Florquin, S. Knapp, J. C. Leemans, J. M. Pater, P. Speelman, D. T. 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