Role of thrombin-activatable fibrinolysis inhibitor in allergic bronchial asthma.
BACKGROUND
Bronchial asthma is an inflammatory disease of the airways. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase that besides inhibiting fibrinolysis, also regulates inflammatory processes. The only validated substrate known for TAFI is fibrin. In the present study we evaluated the role of TAFI in bronchial asthma by comparing the development of allergic bronchial asthma between wild-type (WT) and TAFI-deficient mice (KO).


METHODS
Asthmatic inflammation was induced by sensitization and challenge with ovalbumin in WT (WT/OVA) and TAFI KO (KO/OVA) mice. WT mice (WT/SAL) and TAFI KO (KO/SAL) were used as controls. Cytokines, markers of inflammation, and coagulation were measured in bronchoalveolar lavage fluid (BALF).


RESULTS
Airway hyperresponsiveness was worse in KO/OVA mice than in WT/OVA mice or control mice. Markers of lung injury were significantly increased in BALF from KO/OVA mice compared to WT/OVA mice. Airway hyperresponsiveness and the BALF concentrations of IL-5 and osteopontin were significantly increased in KO/OVA mice compared to WT/OVA mice. Treatment of WT/OVA and KO/OVA mice with a C5a receptor antagonist significantly decreased hyperresponsiveness along with the BALF concentrations of total protein and C5a compared to untreated asthmatic mice.


CONCLUSIONS
The results of this study suggest that TAFI plays a protective role in the pathogenesis of allergic inflammation probably by inhibiting the complement system.
Department of Pulmonary and Critical Care Medicine, Mie University School of Medicine, Edobashi 2-174, Tsu City, Mie Prefecture 514-8507, Japan.
Atsushi
A
Fujiwara
Osamu
O
Taguchi
Takehiro
T
Takagi
Corina N
CN
D'Alessandro-Gabazza
Daniel
D
Boveda-Ruiz
Masaaki
M
Toda
Atsushi
A
Yasukawa
Yuki
Y
Matsushima
Yasushi
Y
Miyake
Hiroyasu
H
Kobayashi
Tetsu
T
Kobayashi
Paloma
P
Gil-Bernabe
Masahiro
M
Naito
Masamichi
M
Yoshida
John
J
Morser
Yoshiyuki
Y
Takei
Esteban C
EC
Gabazza
D000403:Airway Resistance; D000818:Animals; D001249:Asthma / Q000201:enzymology / Q000276:immunology*; D015415:Biomarkers / Q000737:chemistry; D001777:Blood Coagulation; D016535:Bronchial Hyperreactivity / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D025901:Carboxypeptidase B2 / Q000172:deficiency / Q000378:metabolism*; D015936:Complement C5a / Q000276:immunology; D005342:Fibrinolysis; D015848:Interleukin-5 / Q000032:analysis / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000097:blood; D055370:Lung Injury / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053495:Osteopontin / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011951:Receptors, Complement / Q000037:antagonists & inhibitors
D015415:Biomarkers; D015848:Interleukin-5; D017395:Plasminogen Activator Inhibitor 1; D011951:Receptors, Complement; D053495:Osteopontin; D015936:Complement C5a; D010047:Ovalbumin; D007770:L-Lactate Dehydrogenase; D025901:Carboxypeptidase B2