A mouse model of alpha-1 antitrypsin deficiency (AATD) is being used to characterize the hepatic inflammatory changes observed in those with AATD, according to a recent in vivo study published in the American Journal of Physiology-Gastrointestinal and Liver Physiology.

Recognizing that AATD-mediated liver disease and inflammation appear to be closely connected, the researchers of the current analysis sought to describe the liver pathophysiology of a human transgenic mouse model for AATD with an appearance of liver disease compared with a normal transgenic mouse model.

In the current analysis, male and female transgenic mice for normal (Pi*M) and mutant variant (Pi*Z) human AAT at
3 and 6 months of age were part of the study. An in vivo analysis was performed to monitor the hepatic ZAAT accumulation, hepatocyte injury, liver inflammation, steatosis, and fibrotic features.


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A Next-Gene transcriptomic analysis of liver tissue from the transgenic mice was performed 16 hours following lipopolysaccharide administration to delineate hepatic inflammatory response in Pi*Z mice compared with
Pi*M mice.

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Results of the study demonstrated that hepatic ZAAT accumulation, followed by ballooning and liver steatosis, developed at 3 months in Pi*Z mice compared with the mice carrying the normal variant of human AAT.

In 3- and 6-month-old Pi*Z mice, higher levels of hepatic immune cell infiltrations were observed compared with Pi*M mice, which was indicative of liver inflammation. Liver fibrosis was seen as a build up of collagen in 6-month-old Pi*Z mice liver tissues compared with Pi*M control mice.

Per transcriptomic analysis, a dysregulated hepatic immune response to lipopolysaccharide was observed in Pi*Z mice, compared with Pi*M mice.

The authors concluded that, “Our data suggest that the human transgenic mouse model of AATD could provide [a] suitable model for the evaluation of therapeutic approaches and preventive reagents against AATD-mediated liver disease.”

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The genetic disorder AATD is defined as the misfolding and accumulation of mutant variant alpha-1 antitrypsin
(Z variant of AAT, or ZAAT)—the most abundant circulating serine protease inhibitor—within the endoplasmic reticulum of hepatocytes.

Individuals with AATD are prone to the development of chronic liver disease that remains undiagnosed until later stages of the disorder. Resulting low levels of AAT are associated with chronic obstructive pulmonary disease because of profound activity of proteases in the lung.

Reference

Khodayari N, Oshins R, Aranyos AM, et al. Characterization of hepatic inflammatory changes in a C57BL/6J mouse model of alpha-1 antitrypsin deficiency. Am J Physiol Gastrointest Liver Physiol. Published online October 18, 2022. doi:10.1152/ajpgi.00207.2022