Marti Ortega Ribera, PhD

American Liver Foundation Postdoctoral Research Fellowship Award
$25,000 over one year

BIDMC & Harvard Medical School

Mechanisms of neutrophil extracellular traps in hepatocyte damage in ACLF

Mentor: Gyongyi Szabo, MD, PhD

Acute-on-chronic liver failure, also known as ACLF, is a recently defined syndrome characterized by poor survival (around 50% survival after 1 month of hospitalization) and multi-organ dysfunction and/or failure. ACLF arises in patients with cirrhosis after an acute precipitating event, being alcohol misuse the most frequent one. Current treatment options for ACLF patients are limited to close monitoring after admission into the hospital and organ support or transplantation, making ACLF a dreadful clinical condition affecting patients and their families. In order to increase the therapeutic options for these patients, we developed and studied the factors that promote this disease in a novel mouse model of ACLF induced by alcohol. Taking advantage of this model, which mimics the disease condition in humans, we identified neutrophil activation and their production of NETs (web-like structures that neutrophils produce to capture and entrap microbes) as a key contributing mechanism in the development and progression of ACLF. We hypothesize that these NETs might directly damage hepatocytes (main cells in the liver), overall worsening and impairing liver function. In the current proposal, we aim at first, understanding how neutrophil activation and more specifically the formation of NETs are influencing liver damage in ACLF and second, block these pathways by using a NET-specific inhibitor with the aim of preventing or ameliorating ACLF development. Results derived from this study will propose new treatment candidates for ACLF patients, overall contributing to improving their health and quality of life.