Bruton Tyrosine Kinase Inhibition Attenuates Liver Damage in a Mouse Warm Ischemia and Reperfusion Model

Abstract

Background Bruton’s tyrosine kinase (Btk) is a central player in multiple signaling pathways of lymphoid and myeloid cells. Myeloid cells are crucial early effectors in organ ischemia/reperfusion injury (IRI). BTKB66 is a selective, irreversible inhibitor of Btk. In this study, we hypothesized that Btk inhibition would reduce hepatocellular injury in a murine model of liver warm hepatic ischemia and reperfusion. Methods First, BTKB66 was tested in in vitro models of LPS-mediated neutrophil and macrophage activation. Then, to assess its efficacy in vivo, BTKB66 was administered orally to mice for seven days prior to subjecting them to 90 minutes of warm hepatic ischemia followed by reperfusion for 6 or 24 hours. Clinical and pathologic features in the livers, including AST, ALT, and a panel of cytokines and chemokines, were examined. Results BTKB66 potently inhibited LPS-mediated activation of bone-marrow derived neutrophils and macrophages in vitro. It also reduced the severity of IRI as determined by AST and ALT levels, as well as immune cell infiltrates. BTKB66 significantly decreased hepatic markers of sterile inflammation, such as CXCL1, CXCL2, and CXCL10, in parallel with depression of serum markers of the myeloid cell activation, such as CCL5, CCL11, and CXCL5. Conclusion BTKB66 treatment ameliorated hepatocellular injury in a well-established model of liver partial warm ischemia and in situ reperfusion. These findings confirm that neutrophil recruitment and activation play an essential role in IR-stress, and that targeting Btk activity may provide a useful approach for preventing hepatocellular damage and improving outcomes in liver transplantation.

Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion

“…In particular, acute kidney injury (AKI) after liver I/R is common (40–85% incidence) and greatly increases patient mortality and morbidity during the perioperative period [1-5]. Therefore, reducing the adverse effects of I/R injury (IRI) will increase the lifespan of patients after hepatic surgeries.…”

Assessment of liver ischemia reperfusion injury in mice using hepatic T2 mapping: Comparison with histopathology

“…The mouse model of partial liver IRI induced by transient clamping of the portal triad is well established and is frequently used to investigate the inflammatory response on a molecular level and possible treatment options to improve the outcome of IRI . In this study, increasing the ischemia time resulted in more severe liver injury and progressive infiltration by neutrophils accompanied by increasing liver enzyme levels.…”

“…Serum levels of liver enzymes ALT and AST, as well as histological markers, specifically the Suzuki score, are widely used to quantify liver injury in experimental studies. Although biochemical liver parameters are clinically relevant, they do not provide information about the regional distribution of liver damage.…”

“…evaluate new imaging-based parameters for early detection and quantification of IRI under well-defined conditions. Serum levels of liver enzymes ALT and AST, [27][28][29][30][31] as well as histological markers, 28,30,32,33 specifically the Suzuki score, 27,31 are widely used to quantify liver injury in experimental studies. Although biochemical liver parameters are clinically relevant, they do not provide information about the regional distribution of liver damage.…”

Exosomes from Human-Induced Pluripotent Stem Cell–Derived Mesenchymal Stromal Cells (hiPSC-MSCs) Protect Liver against Hepatic Ischemia/ Reperfusion Injury via Activating Sphingosine Kinase and Sphingosine-1-Phosphate Signaling Pathway

“…Hepatic I/R frequently leads to injury in remote organs, including kidney, lung, and heart. In particular, acute kidney injury (AKI) after major liver IR is very common (40-85% incidence) and greatly increases patient mortality and morbidity during perioperative period [1][2][3][4][5]. Therefore, reducing the adverse effects of I/R injury can significantly increase the patients' lifespan after liver transplantation.…”