The Role of Secretory Phospholipase A2 (sPLA2) in Mediating the Progression of Injury in Acetaminophen-induced Acute Liver Failure
Date of Award
Master of Science in Biomedical Sciences
Vishakha Bhave, BS, PhD
Shashidharamurthy Taval, PhD
Harish Parihar, PhD
Francis Jenney, PhD
Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF) in the United States with limited treatment options. APAP induced hepatotoxicity continues to progress even after the initial toxicant APAP has been eliminated from the body. Following APAP overdose, toxicity is initiated by conversion of APAP to its reactive metabolite N-acetyl-p-benzoquinone (NAPQI), which binds irreversibly to form NAPQI-protein adducts. This irreversible binding of NAPQI-protein adducts leads to hepatocellular necrosis. There are two possible mechanisms through which the progression of injury continues even after the elimination of the initial APAP toxicant: 1) leakage of cytosolic enzymes, 2) inflammation due to the recruitment of pro-inflammatory cytokines to the injured hepatocytes. Following initial necrosis caused by APAP metabolism, the progression of injury in the liver continues due to the leakage of cytosolic enzymes such as secretory phospholipase A2 (sPLA2) from necrosed hepatocytes. The high extracellular content of calcium ions activates the sPLA2 enzymes. SPLA2 binds to the phospholipids of neighboring healthy hepatocytes, and hydrolyzes fatty acid at the sn2 position of phospholipids, which disrupts the membrane integrity of the hepatocytes. In this way, the progression of injury continues even in the absence of APAP that initiated the injury. The focus of this study is to investigate the role of secretory phospholipase A2 (sPLA2) in mediating progression of APAP induced acute liver failure through recruitment of pro-inflammatory cytokines to the site of injury and compromising hepatocyte membrane integrity. At present, the mechanisms of APAP overdose induced acute liver failure (ALF) mediated by sPLA2 are not fully understood. The aim of this study is to investigate the mechanisms of progression of ALF injury mediated by sPLA2 using in vitro HEPG2 cell lines. We hypothesize that sPLA2 mediates the progression of APAP induced acute liver failure through the modulation of pro-inflammatory cytokines and compromising the membrane integrity of neighboring cells. Preliminary data indicate that following injury there are higher levels of sPLA2 released in the extracellular environment. This extracellular sPLA2 gets activated in the high calcium environment and can act on membrane phospholipids in hepatocellular membranes, thus compromising their integrity. We hope that by investigating the role of sPLA2 and its recombinant isoforms type IIA and type V, we can find novel therapeutic approach to prevent the progression of injury following APAP overdose.
Noor, Najiullah, "The Role of Secretory Phospholipase A2 (sPLA2) in Mediating the Progression of Injury in Acetaminophen-induced Acute Liver Failure" (2020). PCOM Biomedical Studies Student Scholarship. 189.