Characterizing the Natural History of Liver Pathology in the Alpha 1 Antitrypsin Deficiency Mouse Model

Alpha 1 Antitrypsin Deficiency (A1ATD) is a rare, debilitating genetic disorder where the body cannot produce adequate amounts of A1AT protein. A1AT is predominately made in the liver and is responsible for inactivating neutrophil elastase (an anti-microbial protease) in the lungs after an immune response. Interestingly, A1AT deficiency is associated with liver dysfunction because the mutated, mis-folded z-form of the protein (zA1AT) accumulates in liver tissue, resulting in jaundice, neonatal hepatitis, cirrhosis, and hepatocellular carcinoma. A1ATD is one of the most common genetic cause of liver disease in the pediatric population, where 10% of newborns with this deficiency present with notable liver damage. To address this disorder, researchers have utilized genetically modified rodent models, including a transgenic mouse model of A1AT liver disease that expresses the human zA1AT. However, a well-defined natural history of this model measuring age-dependent expression of pathological biomarkers is currently incomplete and could provide additional insights on this model’s relevancy. Thus, the purpose of this dissertational work is to characterize the age-dependent development of liver pathology in the transgenic zA1AT mouse model. Our results indicate that insoluble zA1AT polymers accumulate as early as 4 weeks of age in these mice and increase by 5% bi- weekly until 36 weeks of age, when there is an abrupt drop in levels, most likely due to increasing liver stress. Sirius Red signal, indicative of liver fibrosis, is also elevated at 36 and 52 weeks of age. IBA-1, a marker of liver Kupffer cells, is only increased at 13 weeks of age. We also identified a soluble form of zA1AT, which likely precedes insoluble polymer formation. Together, these results begin to characterize, in detail, the liver disease progression of this mouse model and can help researchers strategize on treatment paradigms that focus on early prevention of polymer formation, or treatment later in life to model disease reversal paradigms