Anna Palmiotti, PhD

Travel Award
$1,500

Yale University

Development of portal vascular endothelial dysfunction in a mouse model of cystic fibrosis related liver disease

Mentor: Romina Fiorotto, PhD

Cystic fibrosis (CF) can lead to liver complications in up to 30% of affected individuals, with 10-15% developing severe outcomes like cirrhosis and portal hypertension. Cystic fibrosis–related liver disease (CFLD) has classically been attributed to impaired bile secretion caused by the genetic mutation of CFTR. However, recent studies have highlighted the critical involvement of innate immune responses of the biliary epithelium and the gut-liver axis. In addition, it has recently described that liver explants from CF patients with portal hypertension show sign of a vascular disease in the absence of cirrhosis. We hypothesize that liver vascular dysfunction in CFLD is driven by endothelial injury, resulting from an exaggerated inflammatory response to gut-derived pathogen-associated molecular patterns (PAMPs). We have used genetically modified mice that lack the CFTR gene (CFTR-KO, KO) to develop a model to study the liver vascular disease in CF. Analysis of the livers from KO mice showed progressive inflammatory and structural changes in liver portal veins, including immune cell infiltration, fibrosis, and vascular remodeling not seen in normal mice. Transcriptomic analyses revealed activation of inflammatory pathways in response to microbial signals. 3D imaging of the venous system using micro-CT scan showed fewer terminal portal vein branches. We are now developing a human in vitro model using induced pluripotent stem cells (iPSCs) from CF patients to study vascular responses under inflammatory conditions. In conclusion, CFTR-KO mice display characteristic of the vascular disease as seen in CF patients. Both in vivo and in vitro models of CF could be useful for studying the mechanisms of non-cirrhotic portal hypertension.