Inhibition of the extrinsic or intrinsic coagulation pathway during pneumonia-derived sepsis

Author:

Stroo Ingrid12,Ding Chao13,Novak Andreja1,Yang Jack1,Roelofs Joris J. T. H.4,Meijers Joost C. M.56,Revenko Alexey S.7,van ’t Veer Cornelis1,Zeerleder Sacha28,Crosby Jeff R.7,van der Poll Tom19

Affiliation:

1. Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

2. Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands

3. Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China

4. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

5. Department of Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

6. Department of Plasma Proteins, Sanquin Research, Amsterdam, The Netherlands

7. Drug Discovery and Corporate Development, Ionis Pharmaceuticals, Incorporated, Carlsbad, California

8. Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

9. Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Abstract

Pneumonia is the most frequent cause of sepsis, and Klebsiella pneumoniae is a common pathogen in pneumonia and sepsis. Infection is associated with activation of the coagulation system. Coagulation can be activated by the extrinsic and intrinsic routes, mediated by factor VII (FVII) and factor XII (FXII), respectively. To determine the role of FVII and FXII in the host response during pneumonia-derived sepsis, mice were treated with specific antisense oligonucleotide (ASO) directed at FVII or FXII for 3 wk before infection with K. pneumoniae via the airways. FVII ASO treatment strongly inhibited hepatic FVII mRNA expression, reduced plasma FVII to ~25% of control, and selectively prolonged the prothrombin time. FXII ASO treatment strongly suppressed hepatic FXII mRNA expression, reduced plasma FXII to ~20% of control, and selectively prolonged the activated partial thromboplastin time. Lungs also expressed FVII mRNA, which was not altered by FVII ASO administration. Very low FXII mRNA levels were detected in lungs, which were not modified by FXII ASO treatment. FVII ASO attenuated systemic activation of coagulation but did not influence fibrin deposition in lung tissue. FVII ASO enhanced bacterial loads in lungs and mitigated sepsis-induced distant organ injury. FXII inhibition did not affect any of the host response parameters measured. These results suggest that partial inhibition of FVII, but not of FXII, modifies the host response to gram-negative pneumonia-derived sepsis.

Funder

State Scholarship Fund from Chinese Scholarship Council

Publisher

American Physiological Society

Subject

Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology

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