title: Dose-dependent differential effects of thrombin in allergic bronchial asthma.
abstract: BACKGROUND
  Apart from its role in the coagulation system, thrombin plays an important role in the inflammatory response through its protease-activated receptors (PARs). However, the role of thrombin in the immune response is not clear.
  
  
  OBJECTIVE
  To evaluate whether thrombin has a modulatory role in allergic bronchial asthma.
  
  
  METHODS
  Bronchial asthma was induced in mice by intraperitoneal sensitization and inhalation challenge with ovalbumin. Thrombin or its inhibitors were administered by inhalation before each allergen challenge.
  
  
  RESULTS
  Mice with low but sustained coagulation activation had reduced allergic inflammation, and allergic asthma was inhibited by low doses of thrombin but worsened by high doses. Allergic asthma was worsened by antithrombin, argatroban, hirudin, and anti-thrombomodulin antibody. Mice with a higher level of an inhibitor of both thrombin and activated protein C had worse disease. Heterozygous PAR-1 mice had less allergic inflammation, but PAR-1 agonist worsened it. Allergic bronchial inflammation was worsened in mice that received adoptive transfer of PAR-1 agonist-treated Th2 cells as compared with controls. Low levels of thrombin suppressed the maturation and secretion of cytokines in dendritic cells, but high levels enhanced this.
  
  
  CONCLUSIONS
  The effects of thrombin on allergic asthma are dose-dependent, with detrimental effects at high doses and protective effects at low doses. These data demonstrate that thrombin modulates the outcome in allergic bronchial asthma.
authors: Department of Immunology, Mie University Graduate School of Medicine, Tsu, Japan.
authors: Y
authors: Y
authors: Miyake
authors: C N
authors: CN
authors: D'Alessandro-Gabazza
authors: T
authors: T
authors: Takagi
authors: M
authors: M
authors: Naito
authors: O
authors: O
authors: Hataji
authors: H
authors: H
authors: Nakahara
authors: H
authors: H
authors: Yuda
authors: H
authors: H
authors: Fujimoto
authors: H
authors: H
authors: Kobayashi
authors: T
authors: T
authors: Yasuma
authors: M
authors: M
authors: Toda
authors: T
authors: T
authors: Kobayashi
authors: Y
authors: Y
authors: Yano
authors: J
authors: J
authors: Morser
authors: O
authors: O
authors: Taguchi
authors: E C
authors: EC
authors: Gabazza
mesh_terms: D000818:Animals; D001249:Asthma / Q000209:etiology* / Q000276:immunology / Q000517:prevention & control; D001992:Bronchoalveolar Lavage Fluid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006967:Hypersensitivity / Q000209:etiology* / Q000276:immunology / Q000517:prevention & control; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D044463:Receptor, PAR-1 / Q000819:agonists; D018418:Th2 Cells / Q000276:immunology; D013917:Thrombin / Q000494:pharmacology* / Q000502:physiology
chemical_list: D044463:Receptor, PAR-1; D013917:Thrombin
keywords: allergy; asthma; coagulation; fibrinolysis; inflammation; lung