Characterization of hepatic inflammatory changes in a C57BL/6J mouse model of alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a genetic disease caused by hepatic accumulation of mutant alpha-1 antitrypsin (ZAAT). Here, we sought to characterize the liver pathophysiology of a human transgenic mouse model for AATD with a manifestation of liver disease. Male and female transgenic mice for normal (Pi*M) and mutant variant (Pi*Z) human alpha-1 antitrypsin at 3 and 6 months of age were subjected to this study. The progression of hepatic ZAAT accumulation, hepatocyte injury, steatosis, liver inflammation and fibrotic features were monitored by performing an in vivo study. We also provide a comprehensive comparative transcriptomic analysis of gene regulation revealing dysregulated immune response to LPS in the liver of Pi*Z mice as compared to Pi*M. We show that hepatic ZAAT accumulation, followed by hepatocyte ballooning and liver steatosis, developed at 3 months in Pi*Z mice. Levels of hepatic inflammation were detected by the expression of macrophage markers in both 3- and 6-month-old Pi*Z mice as compared to Pi*M. Liver fibrosis was also determined by accumulation of collagen in the liver at 6 months of age in Pi*Z mice. This study aims to establish a mouse model of AATD with a strong manifestation of liver disease that will be a valuable in vivotool to study the pathophysiology of AATD-mediated liver disease. The human transgenic mouse model of AATD also provides new opportunities to test preventive and therapeutic reagents and drugs against AATD-mediated liver disease.