Aileen Dela Pena

COX‐2 induction in mice with experimental nutritional steatohepatitis: Role as pro‐inflammatory mediator

The underlying mechanisms that perpetuate liver inflammation in nonalcoholic steatohepatitis are poorly understood. We explored the hypothesis that cyclooxygenase‐2 (COX‐2) can exert pro‐inflammatory effects in metabolic forms of fatty liver disease. Male wild‐type (WT) C57BL6/N or peroxisome proliferator–activated receptor α knockout (PPAR‐α−/−) mice were fed a lipogenic, methionine‐ and choline‐deficient (MCD) diet or the same diet with supplementary methionine and choline (control). COX‐2 was not expressed in livers of mice fed the control diet. In mice fed the MCD diet, hepatic expression of COX‐2 messenger RNA and protein occurred from day 5, continued to rise, and was 10‐fold higher than controls after 5 weeks, thereby paralleling the development of steatohepatitis. Upregulation of COX‐2 was even more pronounced in PPAR‐α−/− mice. Induction of COX‐2 was completely prevented by dietary supplementation with the potent PPAR‐α agonist Wy‐14,643 in WT but not PPAR‐α−/− mice. COX‐2 upregulation was preceded by activation of nuclear factor κB (NF‐κB) and coincided with increased levels of tumor necrosis factor α (TNF‐α), interleukin (IL)‐6, and intercellular adhesion molecule 1 (ICAM‐1). Selective COX‐2 inhibitors (celecoxib and NS‐398) protected against the development of steatohepatitis in WT but not PPAR‐α−/− mice. In conclusion, induction of COX‐2 occurs in association with NF‐κB activation and upregulation of TNF‐α, IL‐6, and ICAM‐1 in MCD diet–induced steatohepatitis. PPAR‐α suppresses both COX‐2 and development of steatohepatitis, while pharmacological inhibition of COX‐2 activity ameliorates the severity of experimental steatohepatitis. COX‐2 may therefore be a pro‐inflammatory mediator in metabolic forms of steatohepatitis. (HEPATOLOGY 2006;43:826–836.)

Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression

Background and Aims:  We examined extrinsic and intrinsic (endogenous) mitochondrial apoptosis pathways in experimental non‐alcoholic steatohepatitis (NASH).

Activation of peroxisome proliferator-activated receptor alpha by dietary fish oil attenuates steatosis, but does not prevent experimental steatohepatitis because of hepatic lipoperoxide accumulation

Background and Aim:  Non‐alcoholic fatty liver disease is the result of an imbalance in hepatic lipid partitioning that favors fatty acid synthesis and storage over fatty acid oxidation and triglyceride secretion. The progressive, inflammatory disorder of steatohepatitis can be prevented or reversed by correcting this lipid imbalance by activating peroxisome proliferator‐activated receptor (PPAR) α, a transcription factor which regulates fatty acid oxidation. n‐3 polyunsaturated fatty acids (PUFA), such as those found in fish oil (FO), are naturally occurring PPARα ligands which also suppress lipid synthesis.

CXCR4 mediates the homing of B cell progenitor acute lymphoblastic leukaemia cells to the bone marrow via activation of p38MAPK

The mechanisms regulating the migration of leukaemic cells between the blood and bone marrow compartments remain obscure, but are of fundamental importance for the dissemination of the disease. This study investigated the in vivo homing of human B cell progenitor acute lymphoblastic leukaemia (ALL) cells to the femoral bone marrow of non‐obese diabetic severe combined immunodeficient (NOD/SCID) mice. It was demonstrated that patient ALL cells use the chemokine axis, chemokine (CXC motif) receptor 4 (CXCR4)/ chemokine (CXC motif) ligand 12 (CXCL12), to home to the femoral marrow. CXCL12‐mediated signalling through p38 mitogen‐activated protein kinase (MAPK) was required for optimal homing. In contrast, the homing of normal peripheral blood CD34+ cells and the cytokine‐dependent CD34+ cell line Mo7e was independent of p38MAPK, consistent with the dependence of these cells, as well as normal CD34+ CD19+ B cell progenitors, on PI‐3K/AKT signalling. Altogether, our data provide clarification of the direct role of CXCL12 in the bone marrow homing of ALL cells and demonstrate unique signalling molecule usage that may have therapeutic implications for this disease.

Plerixafor (AMD3100) induces prolonged mobilization of acute lymphoblastic leukemia cells and increases the proportion of cycling cells in the blood in mice

The CXCR4 antagonist Plerixafor (AMD3100) induces the rapid mobilization of hematopoietic stem and progenitor cells into the blood in mice and humans. AMD3100 similarly induces the mobilization of human acute lymphoblastic leukemia (ALL) cells into the blood in mice. In this study, the temporal response of pre-B ALL cells to AMD3100 was compared with that of normal hematopoietic progenitor cells (HPC) using an NOD/SCID xenograft model of ALL and BALB/c mice, respectively. ALL cells remained in the circulation up to 6 hours after AMD3100 administration, by which time normal HPCs were no longer detectable. AMD3100 also increased the proportion of actively cycling ALL cells in the peripheral blood. Together, these data suggest that ALL cells are more sensitive to the effects of bone marrow disruption than normal progenitors. Using the NOD/SCID xenograft model, we demonstrated that AMD3100 increased the efficacy of the cell cycle specific drug vincristine, resulting in reduced disease levels in the blood and spleens of animals over 3 weeks and extended the survival of NOD/SCID mice with ALL. These data demonstrate that mobilizing agents can increase the therapeutic effect of cell cycle dependent chemotherapeutic agents.