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Visualization of Neutrophil Extracellular Traps in Mesenteric Venules After Mesenteric Ischemia-Reperfusion Injury via Intravital Microscopy
Published on: September 27, 2024
HepaticIschemia/Reperfusion Injuryinvolves functional tryptase/PAR-2 signaling in liver sinusoidal endothelial cell
Jian Song1, Zhigang He2, Muqing Yang3
1Geriatric Cancer Center, Huadong Hospital, Fudan University, West 221 Yan-an Road, Shanghai 200040, China; Department of General Surgery, Affiliated Wuxi No.2 People's Hospital of Nanjing Medical University, 68 Zhongshan Road, Wuxi 214002, Jiangsu, China.
Abstract:
Mast cells (MCs) are tissue-resident effector cells that could be the earliest responder to release a unique, stimulus-specific set of mediators in hepatic ischemia-reperfusion (IR) injury However, how MCs function in the hepatic IR has remained a formidable challenge due to the substantial redundancy and functional diverse of these mediators. Tryptase is the main protease for degranulation of MCs and its receptor-protease-activated receptor 2 (PAR-2) is widely expressed in endothelial cells. It is unclear whether and how tryptase/PAR-2 axis participates in hepatic IR. We employed an experimental warm 70% liver IR model in mice and found that tryptase was accumulated in the circulation during hepatic IR and positively correlated with liver injury. Tryptase inhibition by protamine can significantly down-regulate the expression of adhesion molecules and reduce neutrophil infiltration within the liver. The level of inflammatory factors and chemokines were also consistent with the pathological change of the liver. In addition, the treatment with exogeneous tryptase in MC-deficient mice can induce the damage observed in wild type mice in the context of liver IR. In vitro, neutrophil infiltration and inflammatory factor secretion were regulated by Tryptase/PAR-2, involving the adhesion molecule expression to regulate neutrophil adhesion dependent on NF-κB pathway. Conclusion: tryptase/PAR-2 participates in liver injury through the activation of LSECs in the early phase of liver IR.
Insights
Mast cells release tryptase during liver injury. Tryptase activates protease-activated receptor 2 (PAR-2) on liver cells, promoting inflammation and neutrophil infiltration in hepatic ischemia-reperfusion injury.
Area of Science:
- Immunology
- Hepatology
- Cell Biology
Background:
- Mast cells (MCs) are early responders in hepatic ischemia-reperfusion (IR) injury, releasing diverse mediators.
- The role of specific mediators like tryptase and its receptor protease-activated receptor 2 (PAR-2) in hepatic IR remains unclear.
- Tryptase is a key protease for MC degranulation, and PAR-2 is expressed on endothelial cells.
Purpose of the Study:
- To investigate the role of the tryptase/PAR-2 axis in hepatic IR injury.
- To determine if tryptase contributes to liver damage and inflammation during IR.
Main Methods:
- A warm 70% liver IR model in mice was utilized.
- Tryptase levels were measured and correlated with liver injury.
- Tryptase inhibition (protamine) and exogenous tryptase administration were employed.
- In vitro studies examined neutrophil infiltration and inflammatory factor secretion.
- NF-κB pathway activation was assessed.
Main Results:
- Tryptase accumulated in circulation during hepatic IR and correlated positively with liver injury.
- Tryptase inhibition reduced adhesion molecule expression and neutrophil infiltration.
- Inflammatory factors and chemokines mirrored liver pathology.
- Exogenous tryptase induced damage in MC-deficient mice.
- In vitro, Tryptase/PAR-2 regulated neutrophil adhesion and inflammation via NF-κB.
Conclusions:
- The tryptase/PAR-2 axis plays a significant role in early-phase liver injury during hepatic IR.
- Tryptase activation of liver sinusoidal endothelial cells (LSECs) contributes to IR-induced liver damage.
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