Thrombin‐activatable fibrinolysis inhibitor influences disease severity in humans and mice with pneumococcal meningitis
| Autor: | M. Valls Seron, Stefan R. Havik, Mieke C. Brouwer, Barry B. Mook-Kanamori, Bryan Paul Morgan, D. van de Beek, A. van der Ende, Joost C. M. Meijers, Frank Baas, T. van der Poll, Madelijn Geldhoff |
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| Přispěvatelé: | Amsterdam institute for Infection and Immunity, Amsterdam Neuroscience, Neurology, Amsterdam Cardiovascular Sciences, Vascular Medicine, Medical Microbiology and Infection Prevention, Genome Analysis, Infectious diseases, Center of Experimental and Molecular Medicine, Experimental Vascular Medicine, Amsterdam Public Health |
| Rok vydání: | 2015 |
| Předmět: |
Adult
Male Carboxypeptidase B2 medicine.medical_treatment Inflammation Complement Membrane Attack Complex Meningitis Meningococcal Thrombomodulin Polymorphism Single Nucleotide Proinflammatory cytokine Mice Thrombin Fibrinolysis medicine Animals Humans Aged Cerebral Hemorrhage Meningitis Pneumococcal business.industry Hematology Middle Aged medicine.disease Shock Septic Community-Acquired Infections Mice Inbred C57BL Treatment Outcome Complement C3b Immunology Complement C3a Cytokines Brain Damage Chronic Female medicine.symptom Respiratory Insufficiency business Complement membrane attack complex Meningitis medicine.drug |
| Zdroj: | Journal of thrombosis and haemostasis, 13(11), 2076-2086. Wiley-Blackwell |
| ISSN: | 1538-7836 1538-7933 |
| Popis: | Background Mortality and morbidity in patients with bacterial meningitis result from the proinflammatory response and dysregulation of coagulation and fibrinolysis. Thrombin-activatable fibrinolysis inhibitor (TAFI) is activated by free thrombin or thrombin in complex with thrombomodulin, and plays an antifibrinolytic role during fibrin clot degradation, but also has an anti-inflammatory role by inactivating proinflammatory mediators, such as complement activation products. Objective To assess the role of TAFI in pneumococcal meningitis. Methods We performed a prospective nationwide genetic association study in patients with bacterial meningitis, determined TAFI and complement levels in cerebrospinal fluid (CSF), and assessed the function of TAFI in a pneumococcal meningitis mouse model by using Cpb2 (TAFI) knockout mice. Results Polymorphisms (reference sequences: rs1926447 and rs3742264) in the CPB2 gene, coding for TAFI, were related to the development of systemic complications in patients with pneumococcal meningitis. Higher protein levels of TAFI in CSF were significantly associated with CSF complement levels (C3a, iC3b, and C5b-9) and with more systemic complications in patients with bacterial meningitis. The risk allele of rs1926447 (TT) was associated with higher levels of TAFI in CSF. In the murine model, consistent with the human data, Cpb2-deficient mice had decreased disease severity, as reflected by lower mortality, and attenuated cytokine levels and bacterial outgrowth in the systemic compartment during disease, without differences in the brain compartment, as compared with wild-type mice. Conclusions These findings suggest that TAFI plays an important role during pneumococcal meningitis, which is likely to be mediated through inhibition of the complement system, and influences the occurrence of systemic complications and inflammation. |
| Databáze: | OpenAIRE |
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