title: Indomethacin increases liver damage in a murine model of liver injury from alpha-1-antitrypsin deficiency.
abstract: Homozygous (PIZZ) alpha-1-antitrypsin (alpha(1)-AT) deficiency is associated with the development of liver damage in children as well as chronic liver injury and hepatocellular carcinoma in adults. The alpha(1)-AT mutant Z gene encodes a mutant protein that accumulates in the endoplasmic reticulum of hepatocytes rather than being secreted appropriately into serum. Liver injury is caused by the accumulation of alpha(1)-AT mutant Z protein in hepatocytes, which triggers downstream intracellular injury pathways. However, development of clinical liver disease among PIZZ homozygotes is highly variable, suggesting other genetic or environmental factors contribute to liver injury. In this study, we tested whether nonsteroidal anti-inflammatory drugs (NSAIDs) could be a comorbid factor in the development of liver injury in alpha(1)-AT deficiency using the PiZ mouse. This mouse model is transgenic for the mutant Z allele of the human alpha(1)-AT gene, in which alpha(1)-ATZ expression is regulated by the human promoter regulatory sequences. Our results showed that administration of indomethacin to PiZ mice resulted in increased hepatic injury, indicated by increased hepatocellular proliferation and increased activation of caspase 9. This indomethacin-induced injury was associated with activation of IL-6-STAT3 signaling, increased expression of alpha(1)-AT mRNA, and greater accumulation of mutant polymerized alpha(1)-ATZ protein in livers of indomethacin-treated PiZ mice compared to vehicle-treated PiZ animals. In conclusion, environmental factors, such as exogenous medication administration, can significantly potentiate the liver injury associated with alpha(1)-ATZ hepatic accumulation; NSAIDs may be especially injurious to patients with alpha(1)-AT deficiency, possibly by increasing the expression and accumulation of the hepatotoxic mutant protein.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, St. Louis, MO 63110, USA. rudnick_d@kids.wustl.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Rudnick
authors.forename: Olga
authors.initials: O
authors.lastname: Shikapwashya
authors.forename: Keith
authors.initials: K
authors.lastname: Blomenkamp
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Teckman
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000187:drug effects; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D007213:Indomethacin / Q000009:adverse effects* / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000378:metabolism*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000515:alpha 1-Antitrypsin; C068169:alpha 1-antitrypsin binding protein 1; C506433:CASP9 protein, human; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases; D007213:Indomethacin