Thrombomodulin mutant mice with a strongly reduced capacity to generate activated protein C have an unaltered pulmonary immune response to respiratory pathogens and lipopolysaccharide.
The thrombomodulin-protein C-protein S (TM-PC-PS) pathway exerts anticoagulant 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 (TM(pro/pro)) that was earlier found to result in a minimal capacity for activated PC (APC) generation in the circulation. We here demonstrate that TM(pro/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 TM(pro/pro) mice, except for enhanced fibrin(ogen) deposition during pneumococcal pneumonia. In addition, TM(pro/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.
Academic Medical Center, University of Amsterdam, The Netherlands. a.w.rijneveld@amc.uva.nl
Anita W
AW
Rijneveld
Sebastiaan
S
Weijer
Sandrine
S
Florquin
Charles T
CT
Esmon
Joost C M
JC
Meijers
Peter
P
Speelman
Pieter H
PH
Reitsma
Hugo
H
Ten Cate
Tom
T
van der Poll
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D016207:Cytokines / Q000096:biosynthesis; D007249:Inflammation; D007711:Klebsiella pneumoniae / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009504:Neutrophils / Q000378:metabolism; D011486:Protein C / Q000378:metabolism*; D017293:Protein S / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism; D018180:Thrombomodulin / Q000235:genetics*; D013997:Time Factors
D016207:Cytokines; D008070:Lipopolysaccharides; D011486:Protein C; D017293:Protein S; D018180:Thrombomodulin; D013917:Thrombin