title: Pulmonary hypertension is ameliorated in mice deficient in thrombin-activatable fibrinolysis inhibitor.
abstract: BACKGROUND
  The fibrinolytic system has been implicated in the pathogenesis of pulmonary hypertension (PH). Thrombin-activatable fibrinolysis inhibitor (TAFI) inhibits fibrinolysis and therefore its absence would be expected to increase fibrinolysis and ameliorate PH.
  
  
  OBJECTIVE
  The objective of the present study was to evaluate the effect of TAFI deficiency on pulmonary hypertension in the mouse.
  
  
  RESULTS
  PH was induced in C57/Bl6 wild-type (WT) or TAFI-deficient (KO) mice by weekly subcutaneous treatment with 600 mg kg(-1) monocrotaline (MCT) for 8 weeks. PH was inferred from right heart hypertrophy measured using the ratio of right ventricle-to-left ventricle-plus-septum weight [RV/(LV+S)]. Pulmonary vascular remodeling was analyzed by morphometry. TAFI-deficient MCT-treated and wild-type MCT-treated mice suffered similar weight loss. TAFI-deficient MCT-treated mice had reduced levels of total protein and tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), transforming growth factor-beta (TGF-beta) and monocyte chemoattractant protein-1 (MCP-1) in bronchial alveolar lavage compared with wild-type MCT-treated mice. The ratio of RV to (LV+S) weight was significantly higher in WT/MCT than in KO/MCT mice. The pulmonary artery wall area and vascular stenosis were both greater in MCT-treated WT mice compared with MCT-treated TAFI-deficient mice.
  
  
  CONCLUSIONS
  TAFI-deficient MCT-treated mice had less pulmonary hypertension, vascular remodeling and reduced levels of cytokines compared with MCT-treated WT animals, possibly as a result of reduced coagulation activation.
authors.affiliation: Department of Immunology, Mie University School of Medicine, Edobashi 2-174, Tsu city, Mie 514-8507, Japan.
authors.forename: L
authors.initials: L
authors.lastname: Qin
authors.forename: C N
authors.initials: CN
authors.lastname: D'Alessandro-Gabazza
authors.forename: S
authors.initials: S
authors.lastname: Aoki
authors.forename: P
authors.initials: P
authors.lastname: Gil-Bernabe
authors.forename: Y
authors.initials: Y
authors.lastname: Yano
authors.forename: T
authors.initials: T
authors.lastname: Takagi
authors.forename: D
authors.initials: D
authors.lastname: Boveda-Ruiz
authors.forename: A Y
authors.initials: AY
authors.lastname: Ramirez Marmol
authors.forename: V T
authors.initials: VT
authors.lastname: San Martin Montenegro
authors.forename: M
authors.initials: M
authors.lastname: Toda
authors.forename: Y
authors.initials: Y
authors.lastname: Miyake
authors.forename: O
authors.initials: O
authors.lastname: Taguchi
authors.forename: Y
authors.initials: Y
authors.lastname: Takei
authors.forename: J
authors.initials: J
authors.lastname: Morser
authors.forename: E C
authors.initials: EC
authors.lastname: Gabazza
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002199:Capillary Permeability; D025901:Carboxypeptidase B2 / Q000172:deficiency* / Q000235:genetics; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005342:Fibrinolysis / Q000235:genetics; D006976:Hypertension, Pulmonary / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000097:blood / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016686:Monocrotaline; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015431:Weight Loss
chemical_list: D015415:Biomarkers; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018836:Inflammation Mediators; D015850:Interleukin-6; D010982:Platelet-Derived Growth Factor; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D016686:Monocrotaline; D025901:Carboxypeptidase B2