title: Thrombin-activatable fibrinolysis inhibitor protects against acute lung injury by inhibiting the complement system.
abstract: Acute lung injury (ALI) is a devastating disease with an overall mortality rate of 30 to 40%. The coagulation/fibrinolysis system is implicated in the pathogenesis of ALI. Thrombin-activatable fibronolysis inhibitor (TAFI) is an important component of the fibrinolysis system. Recent studies have shown that the active form of TAFI can also regulate inflammatory responses by its ability to inhibit complement C3a, C5a, and osteopontin. We hypothesized that TAFI might have a protective role in ALI. To demonstrate this hypothesis, the development of ALI was compared between wild-type (WT) and TAFI-deficient mice. ALI was induced by intratracheal instillation of LPS. Control mice were treated with saline. Animals were killed 24 hours after LPS. The number of inflammatory cells and the concentration of total protein and inflammatory cytokines were significantly increased in bronchoalveolar lavage fluid from LPS-treated, TAFI-deficient mice compared with their WT counterparts. Significantly higher concentrations of C5a were found in bronchoalveolar lavage fluid and plasma in LPS-treated TAFI knockout mice compared with WT mice. Pretreatment with inhaled C5a receptor antagonist blocked the detrimental effects of TAFI deficiency to levels found in WT mice. Our results show that TAFI protects against ALI, at least in part, by inhibiting the complement system.
authors.affiliation: 1 Department of Pulmonary and Critical Care Medicine.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Naito
authors.forename: Osamu
authors.initials: O
authors.lastname: Taguchi
authors.forename: Tetsu
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Takehiro
authors.initials: T
authors.lastname: Takagi
authors.forename: Corina N
authors.initials: CN
authors.lastname: D'Alessandro-Gabazza
authors.forename: Yuki
authors.initials: Y
authors.lastname: Matsushima
authors.forename: Daniel
authors.initials: D
authors.lastname: Boveda-Ruiz
authors.forename: Paloma
authors.initials: P
authors.lastname: Gil-Bernabe
authors.forename: Takahiro
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Ayshwarya-Lakshmi
authors.initials: AL
authors.lastname: Chelakkot-Govindalayathil
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yasukawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Hataji
authors.forename: John
authors.initials: J
authors.lastname: Morser
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takei
authors.forename: Esteban C
authors.initials: EC
authors.lastname: Gabazza
mesh_terms: D055371:Acute Lung Injury / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001777:Blood Coagulation / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D025901:Carboxypeptidase B2 / Q000172:deficiency / Q000378:metabolism*; D015936:Complement C5a / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005342:Fibrinolysis / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism; D013917:Thrombin / Q000276:immunology / Q000378:metabolism*
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D015936:Complement C5a; D025901:Carboxypeptidase B2; D013917:Thrombin