Therapeutic Recombinant Murine Activated Protein C Attenuates Pulmonary Coagulopathy and Improves Survival in Murine Pneumococcal Pneumonia

• Published in: The Journal of infectious diseases Vol. 202; no. 10; pp. 1600 - 1607
• Main Authors: Schouten, Marcel, van't Veer, Cornelis, van den Boogard, Florry E., Gerlitz, Bruce, Grinnell, Brian W., Roelofs, Joris J. T. H., Levi, Marcel, van der Poll, Tom
• Format: Journal Article
• Language: English
• Published: Oxford The University of Chicago Press 15-11-2010; University of Chicago Press; Oxford University Press
• Subjects: Animals; Anti-Bacterial Agents - therapeutic use; Antibiotics; BACTERIA; Bacteriology; Biological and medical sciences; Blood Coagulation Factors - antagonists & inhibitors; Ceftriaxone - administration & dosage; Ceftriaxone - therapeutic use; Coagulation; Coagulation Protein Disorders - drug therapy; Coagulation Protein Disorders - microbiology; Drug Evaluation, Preclinical; Drug Therapy, Combination; Fundamental and applied biological sciences. Psychology; Health care administration; Humans; Infections; Infectious diseases; Injections, Intraperitoneal; Lungs; Male; Medical sciences; Mice; Mice, Inbred C57BL; Microbiology; Miscellaneous; Pneumococcal pneumonia; Pneumonia; Pneumonia, Pneumococcal - complications; Pneumonia, Pneumococcal - drug therapy; Protein C - administration & dosage; Protein C - pharmacology; Protein C - therapeutic use; Recombinant Proteins - administration & dosage; Recombinant Proteins - pharmacology; Recombinant Proteins - therapeutic use; Sepsis; Streptococcus pneumoniae; Vehicles; Lung disease; Pneumonia; Serine endopeptidases; Enzyme; Respiratory disease; Rodentia; Hemopathy; Streptococcus pneumoniae; Infection; Peptidases; Streptococcaceae; Vertebrata; Mammalia; Mouse; Bacteria; Hydrolases; Micrococcales; Recombinant protein; Coagulopathy; Protein C (activated)
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/656787

Background. Recombinant human activated protein C (APC) improves survival of patients with severe sepsis; this beneficial effect is especially apparent in patients with pneumococcal pneumonia. The aim of this study was to determine the effect of APC treatment initiated after induction of pneumococcal pneumonia on pulmonary coagulation, inflammation, and survival, with or without concurrent antibiotic therapy. Methods. Mice were infected intranasally with viable Streptococcus pneumoniae and were treated intraperitoneally after 24 h of infection with vehicle, recombinant mouse (rm) APC (125 µg), ceftriaxone (500 µg), or rm-APC plus ceftriaxone. Treatment with rm-APC or vehicle was repeated every 8 h for a maximum of 96 h. Animals were either killed 48 h after infection or were monitored in a survival study (with an extra dose of ceftriaxone given after 72 h). Results. Rm-APC treatment inhibited pulmonary activation of coagulation, as reflected by lower levels of thrombin-antithrombin complexes and D-dimer. Rm-APC did not affect the pulmonary levels of 55 inflammatory mediators in the context of antibiotic therapy. Rm-APC added to ceftriaxone markedly improved survival, compared with ceftriaxone treatment alone. Conclusions. Rm-APC inhibits pulmonary activation of coagulation and, when added to antibiotic therapy, improves survival in murine pneumococcal pneumonia.