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Protein C concentrate controls leukocyte recruitment during inflammation and improves survival during endotoxemia after efficient in vivo activation.
- Source :
-
The American journal of pathology [Am J Pathol] 2011 Nov; Vol. 179 (5), pp. 2637-50. Date of Electronic Publication: 2011 Sep 09. - Publication Year :
- 2011
-
Abstract
- Anti-inflammatory properties of protein C (PC) concentrate are poorly studied compared to activated protein C, although PC is suggested to be safer in clinical use. We investigated how PC interferes with the leukocyte recruitment cascade during acute inflammation and its efficacy during murine endotoxemia. We found that similar to activated protein infusion, intravenous PC application reduced leukocyte recruitment in inflamed tissues in a dose- and time-dependent manner. During both tumor necrosis factor-α induced and trauma-induced inflammation of the cremaster muscle, intravital microscopy revealed that leukocyte adhesion and transmigration, but not rolling, were profoundly inhibited by 100 U/kg PC. Moreover, PC blocked leukocyte emigration into the bronchoalveolar space during lipopolysaccharide (LPS) induced acute lung injury. PC was efficiently activated in a murine endotoxemia model, which reduced leukocyte infiltration of organs and strongly improved survival (75% versus 25% of control mice). Dependent on the inflammatory model, PC provoked a significant inhibition of leukocyte recruitment as early as 1 hour after administration. PC-induced inhibition of leukocyte recruitment during acute inflammation critically involves thrombomodulin-mediated PC activation, subsequent endothelial PC receptor and protease-activated receptor-1-dependent signaling, and down-regulation of intercellular adhesion molecule 1 leading to reduced endothelial inflammatory response. We conclude that during acute inflammation and sepsis, PC is a fast acting and effective therapeutic approach to block leukocyte recruitment and improve survival.<br /> (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Animals
Anti-Bacterial Agents pharmacology
Antigens, CD metabolism
Cell Adhesion immunology
Cell Movement immunology
Chemotaxis, Leukocyte drug effects
Chemotaxis, Leukocyte immunology
Cytokines metabolism
Dose-Response Relationship, Drug
Endothelial Protein C Receptor
Endotoxemia drug therapy
Escherichia coli Infections drug therapy
Escherichia coli Infections immunology
Intercellular Adhesion Molecule-1 physiology
Lipopolysaccharides toxicity
Lymphocyte Function-Associated Antigen-1 physiology
Mice
Mice, Inbred C57BL
Muscle, Smooth, Vascular immunology
Muscle, Smooth, Vascular injuries
Myositis immunology
Receptors, Cell Surface metabolism
Signal Transduction
Survival Analysis
Thrombomodulin metabolism
Tumor Necrosis Factor-alpha toxicity
Acute Lung Injury immunology
Anti-Inflammatory Agents pharmacology
Endotoxemia immunology
Leukocytes drug effects
Pneumonia immunology
Protein C pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1525-2191
- Volume :
- 179
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The American journal of pathology
- Publication Type :
- Academic Journal
- Accession number :
- 21907691
- Full Text :
- https://doi.org/10.1016/j.ajpath.2011.07.023