Plasmin-mediated Cleavage of High Molecular Weight Kininogen Contributes to Acetaminophen-Induced Acute Liver Failure
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Plasmin-mediated Cleavage of High Molecular Weight Kininogen Contributes to Acetaminophen-Induced Acute Liver Failure. / Henderson, Michael W; Sparkenbaugh, Erica M; Wang, Shaobin; Ilich, Anton; Noubouossie, Denis F; Mailer, Reiner K; Renné, Thomas; Flick, Matthew J; Luyendyk, James P; Chen, Zu-Lin; Strickland, Sidney; Stravitz, R Todd; McCrae, Keith R; Key, Nigel S; Pawlinski, Rafal.
in: BLOOD, Jahrgang 138, Nr. 3, 22.07.2021, S. 259-272.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Plasmin-mediated Cleavage of High Molecular Weight Kininogen Contributes to Acetaminophen-Induced Acute Liver Failure
AU - Henderson, Michael W
AU - Sparkenbaugh, Erica M
AU - Wang, Shaobin
AU - Ilich, Anton
AU - Noubouossie, Denis F
AU - Mailer, Reiner K
AU - Renné, Thomas
AU - Flick, Matthew J
AU - Luyendyk, James P
AU - Chen, Zu-Lin
AU - Strickland, Sidney
AU - Stravitz, R Todd
AU - McCrae, Keith R
AU - Key, Nigel S
AU - Pawlinski, Rafal
N1 - Copyright © 2021 American Society of Hematology.
PY - 2021/7/22
Y1 - 2021/7/22
N2 - Acetaminophen (APAP)-induced liver injury is associated with activation of coagulation and fibrinolysis. In mice, both tissue factor-dependent thrombin generation and plasmin activity have been shown to promote liver injury after APAP overdose. However, the contribution of the contact and intrinsic coagulation pathways has not been investigated in this model. Mice deficient in individual factors of the contact (factor XII [FXII] and prekallikrein) or intrinsic coagulation (FXI) pathway were administered a hepatotoxic dose of 400 mg/kg of APAP. Neither FXII, FXI, nor prekallikrein deficiency mitigated coagulation activation or hepatocellular injury. Interestingly, despite the lack of significant changes to APAP-induced coagulation activation, markers of liver injury and inflammation were significantly reduced in APAP-challenged high-molecular-weight kininogen-deficient (HK-/-) mice. Protective effects of HK deficiency were not reproduced by inhibition of bradykinin-mediated signaling, whereas reconstitution of circulating levels of HK in HK-/- mice restored hepatotoxicity. Fibrinolysis activation was observed in mice after APAP administration. Western blotting, enzyme-linked immunosorbent assay, and mass spectrometry analysis showed that plasmin efficiently cleaves HK into multiple fragments in buffer or plasma. Importantly, plasminogen deficiency attenuated APAP-induced liver injury and prevented HK cleavage in the injured liver. Finally, enhanced plasmin generation and HK cleavage, in the absence of contact pathway activation, were observed in plasma of patients with acute liver failure due to APAP overdose. In summary, extrinsic but not intrinsic pathway activation drives the thromboinflammatory pathology associated with APAP-induced liver injury in mice. Furthermore, plasmin-mediated cleavage of HK contributes to hepatotoxicity in APAP-challenged mice independently of thrombin generation or bradykinin signaling.
AB - Acetaminophen (APAP)-induced liver injury is associated with activation of coagulation and fibrinolysis. In mice, both tissue factor-dependent thrombin generation and plasmin activity have been shown to promote liver injury after APAP overdose. However, the contribution of the contact and intrinsic coagulation pathways has not been investigated in this model. Mice deficient in individual factors of the contact (factor XII [FXII] and prekallikrein) or intrinsic coagulation (FXI) pathway were administered a hepatotoxic dose of 400 mg/kg of APAP. Neither FXII, FXI, nor prekallikrein deficiency mitigated coagulation activation or hepatocellular injury. Interestingly, despite the lack of significant changes to APAP-induced coagulation activation, markers of liver injury and inflammation were significantly reduced in APAP-challenged high-molecular-weight kininogen-deficient (HK-/-) mice. Protective effects of HK deficiency were not reproduced by inhibition of bradykinin-mediated signaling, whereas reconstitution of circulating levels of HK in HK-/- mice restored hepatotoxicity. Fibrinolysis activation was observed in mice after APAP administration. Western blotting, enzyme-linked immunosorbent assay, and mass spectrometry analysis showed that plasmin efficiently cleaves HK into multiple fragments in buffer or plasma. Importantly, plasminogen deficiency attenuated APAP-induced liver injury and prevented HK cleavage in the injured liver. Finally, enhanced plasmin generation and HK cleavage, in the absence of contact pathway activation, were observed in plasma of patients with acute liver failure due to APAP overdose. In summary, extrinsic but not intrinsic pathway activation drives the thromboinflammatory pathology associated with APAP-induced liver injury in mice. Furthermore, plasmin-mediated cleavage of HK contributes to hepatotoxicity in APAP-challenged mice independently of thrombin generation or bradykinin signaling.
U2 - 10.1182/blood.2020006198
DO - 10.1182/blood.2020006198
M3 - SCORING: Journal article
C2 - 33827130
VL - 138
SP - 259
EP - 272
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 3
ER -