A thrombomodulin mutation that impairs activated protein C generation results in uncontrolled lung inflammation during murine tuberculosis.
Thrombomodulin (TM) plays an essential role in the generation of activated protein C (APC), a mediator with both anticoagulant and anti-inflammatory properties, and is preferentially expressed in lungs. To investigate the role of TM in the coagulant and inflammatory response in the lung during tuberculosis, mice with a mutation in the TM gene (Thbd), which results in a minimal capacity for APC generation (TMpro/pro mice), were intranasally infected with live virulent Mycobacterium tuberculosis. Whereas pulmonary tuberculosis was not associated with activation of coagulation in either wild-type or TMpro/pro mice, 5 weeks after infection TMpro/pro mice displayed an uncontrolled inflammatory response in their lungs, as reflected by higher lung weights, a diminished ability to form well-shaped granulomas, elevated levels of proinflammatory cytokines, and concurrently reduced concentrations of anti-inflammatory cytokines. During a 36-week follow-up after infection with a lower dose of M tuberculosis, 35% of TMpro/pro mice died from week 28 onward versus none of the wild-type mice, and the surviving TMpro/pro mice displayed increased lung inflammation accompanied by higher mycobacterial loads in liver and spleen. These data suggest that a TM mutation that impairs APC generation results in uncontrolled lung inflammation during tuberculosis.
Weijer
Sebastiaan
S
Academic Medical Center Amsterdam, Laboratory of Experimental Internal Medicine, Room G2-130, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
Wieland
Catharina W
CW
Florquin
Sandrine
S
van der Poll
Tom
T
D000818:Animals; D002465:Cell Movement; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D007958:Leukocyte Count; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009504:Neutrophils / Q000166:cytology; D011014:Pneumonia / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D011486:Protein C / Q000378:metabolism*; D015996:Survival Rate; D018180:Thrombomodulin / Q000235:genetics* / Q000378:metabolism*; D014397:Tuberculosis, Pulmonary / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology
D018925:Chemokines; D016207:Cytokines; D011486:Protein C; D018180:Thrombomodulin