Excessive Plasmin Compromises Hepatic Sinusoidal Vascular Integrity After Acetaminophen Overdose

Gao, Siqi; Silasi‐Mansat, Robert; Behar, Amanda R.; Lupu, Florea; Griffin, Courtney T.

doi:10.1002/hep.30070

Cited by 14 publications

(16 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is important to note that these phenotypes -sinusoidal congestion and hemorrhage -are common features of acetaminophen induced liver injury. Previous studies have revealed that APAP treatment results in excess generation of the fibrinolytic enzyme plasmin, which in turn leads to matrix degradation that detaches sinusoidal endothelial cells from the underlying basement membrane (56). This process, which most likely results from plasmin-dependent activation of matrix metalloproteinases, disrupts sinusoidal blood flow leading to congestion and hemorrhage.…”

Section: Discussionmentioning

confidence: 99%

Differential TAM receptor regulation of hepatic physiology and injury

Загорска

Través

Jiménez-García

et al. 2020

Preprint

View full text Add to dashboard Cite

The TAM receptor tyrosine kinases (RTK) Mer and Axl have been implicated in liver disease, yet our understanding of their roles in liver homeostasis and injury is limited. We therefore examined the performance of Mer and Axl mutant mice during aging, and in four models of liver injury. We find that Mer and Axl are most prominently expressed in Kupffer and hepatic endothelial cells, and that as Axl -/-Mertk -/mice normally age, they develop profound liver disease. We further find that Mer signaling is critical to the phagocytosis of apoptotic hepatocytes that are generated during acute hepatic injury, and that Mer and Axl act in concert to inhibit injury-triggered cytokine production. TAM expression in Kupffer cells is crucial for these effects. In contrast, we show that Axl is uniquely important in mitigating liver damage during acute acetaminophen intoxication. Finally, we demonstrate that Axl exacerbates the fibrosis that develops in a model of chronic hepatic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that target these RTKs in the liver.

show abstract

Section: Discussionmentioning

confidence: 99%

Differential TAM receptor regulation of hepatic physiology and injury

Загорска

Través

Jiménez-García

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Beyond the fibrinolytic properties, recent studies revealed its versatility to mediate the processes of both inflammation and regeneration in various liver dieases. [14][15][16][17] In the context of hepatectomy, early activity of Plg activators was reported in humans following hepatectomy. 18,19 An in vivo chemotaxis assay using a mice cremaster model from our group suggested the inhibition of SPs or plasmin suppressed intravascular accumulation and transmigration of neutrophils.…”

Section: Backg Rou N Dmentioning

confidence: 99%

“…After activation, plasmin cleaves insoluble fibrin clots into a soluble fibrin degradation product. Beyond the fibrinolytic properties, recent studies revealed its versatility to mediate the processes of both inflammation and regeneration in various liver dieases 14–17 . In the context of hepatectomy, early activity of Plg activators was reported in humans following hepatectomy 18,19 .…”

Section: Introductionmentioning

confidence: 99%

Serine proteases mediate leukocyte recruitment and hepatic microvascular injury in the acute phase following extended hepatectomy

et al. 2023

View full text Add to dashboard Cite

Objective: Post-hepatectomy liver failure (PHLF) is the main limitation of extended liver resection. The molecular mechanism and the role of leukocytes in the development of PHLF remain to be unveiled. We aimed to address the impact of serine proteases (SPs) on the acute phase after liver resection by intravitally analyzing leukocyte recruitment and changes in hemodynamics and microcirculation of the liver.Methods: C57BL/6 mice undergoing 60% partial hepatectomy were treated with aprotinin (broad-spectrum SP inhibitor), tranexamic acid (plasmin inhibitor), or vehicle.Sham-operated animals served as controls. In vivo fluorescence microscopy was used to quantify leukocyte-endothelial interactions immediately after, as well as 120 min after partial hepatectomy in postsinusoidal venules, along with measurement of sinusoidal perfusion rate and postsinusoidal shear rate. Recruitment of leukocytes, neutrophils, T cells, and parameters of liver injury were assessed in tissue/blood samples.Results: Leukocyte recruitment, sinusoidal perfusion failure rate, and shear rate were significantly increased in mice after 60% partial hepatectomy compared to shamoperated animals. The inhibition of SPs or plasmin significantly attenuated leukocyte recruitment and improved the perfusion rate in the remnant liver. ICAM-1 expression and neutrophil recruitment significantly increased after 60% partial hepatectomy and were strongly reduced by plasmin inhibition.Conclusions: Endothelial activation and leukocyte recruitment in the liver in response to the increment of sinusoidal shear rate were hallmarks in the acute phase after liver resection. SPs mediated leukocyte recruitment and contributed to the impairment of sinusoidal perfusion in an ICAM-1-dependent manner in the acute phase after liver resection.

show abstract

“…15 Recently, it was reported that animals deficient in plasminogen are less susceptible to APAP-induced liver toxicity, 12 and mechanisms are currently being investigated. 16 Interestingly, it has been shown that plasminogen activators may contribute to APAP-induced liver injury independently of fibrin(ogen). 12 In addition to being the main effector enzyme of the fibrinolytic system, plasmin has been shown to have other functions, including cleavage of high-molecular-weight kininogen (HK).…”

Section: Introductionmentioning

confidence: 99%

Plasmin-mediated Cleavage of High Molecular Weight Kininogen Contributes to Acetaminophen-Induced Acute Liver Failure

Sparkenbaugh

Wang

Ilich

et al. 2021

Blood

View full text Add to dashboard Cite

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 (FXII and PK) 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, ELISA, and mass spectrometry analysis demonstrated 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.

show abstract

Excessive Plasmin Compromises Hepatic Sinusoidal Vascular Integrity After Acetaminophen Overdose

Cited by 14 publications

References 19 publications

Differential TAM receptor regulation of hepatic physiology and injury

Differential TAM receptor regulation of hepatic physiology and injury

Serine proteases mediate leukocyte recruitment and hepatic microvascular injury in the acute phase following extended hepatectomy

Plasmin-mediated Cleavage of High Molecular Weight Kininogen Contributes to Acetaminophen-Induced Acute Liver Failure

Contact Info

Product

Resources

About