Evaluation of a transgenic mouse model for alpha-1-antitrypsin (AAT) related liver disease.

We have attempted to produce a transgenic mouse model of the neonatal liver disease associated with the human PIZ allele. Analysis of a number of transgenic mouse lines carrying either a normal human PIM gene construct or the mutant Z is reported. Using isoelectric focusing analysis of plasma from transgenic mice, we have shown that the human AAT proteins produced in mice are processed in a similar way to their counterparts in humans. By comparing the level of M and Z mRNA in liver with the levels of M and Z proteins in plasma we have inferred that, as in humans, the mutant protein tends to accumulate within the hepatocyte. Accumulation of Z protein has also been demonstrated by immunocytochemistry. Two of the M transgenic lines produce such high levels of the human protein that it, like the Z protein, accumulates as globules. Histological features of livers from 116 mice of different ages and genotypes were examined: 37 non-transgenic, 62 Z transgenic (23 low expressing and 39 high expressing) and 17 M transgenic mice, all high expressing. Cirrhosis or fibrosis was not seen in any animal and we were unable to find any evidence for neonatal liver disease. Some necrosis was seen in all genotypes and this increased significantly with age with one Z line showing significantly more frequent necrosis than any other group. This line, the highest expressing Z line, was back crossed onto 7 different genetic backgrounds but no major differences between the back crosses with respect to liver disease were observed. The mouse model we have developed is compared with other transgenic Z mouse models; none of these is representative of human neonatal liver disease. Our view is that the transgenic animals generated in these experiments may be most useful for investigating the liver manifestations that almost invariably occur in ZZ adults. Alteration of additional factors other than accumulation of Z protein, for example inactivation of the endogenous mouse genes or some environmental challenge, might produce a mouse model with more relevance to neonatal liver disease.