Enhancing Autophagy with Drugs or Lung-directed Gene Therapy Reverses the Pathological Effects of Respiratory Epithelial Cell Proteinopathy.

Abstract

Recent studies have shown that autophagy mitigates the pathological effects of proteinopathies in the liver, heart, and skeletal muscle but this has not been investigated for proteinopathies that affect the lung. This may be due at least in part to the lack of an animal model robust enough for spontaneous pathological effects from proteinopathies even though several rare proteinopathies, surfactant protein A and C deficiencies, cause severe pulmonary fibrosis. In this report we show that the PiZ mouse, transgenic for the common misfolded variant α1-antitrypsin Z, is a model of respiratory epithelial cell proteinopathy with spontaneous pulmonary fibrosis. Intracellular accumulation of misfolded α1-antitrypsin Z in respiratory epithelial cells of the PiZ model resulted in activation of autophagy, leukocyte infiltration, and spontaneous pulmonary fibrosis severe enough to elicit functional restrictive deficits. Treatment with autophagy enhancer drugs or lung-directed gene transfer of TFEB, a master transcriptional activator of the autophagolysosomal system, reversed these proteotoxic consequences. We conclude that this mouse is an excellent model of respiratory epithelial proteinopathy with spontaneous pulmonary fibrosis and that autophagy is an important endogenous proteostasis mechanism and an attractive target for therapy.

• Authors: Tunda Hidvegi, Donna B Stolz, John F Alcorn, Samuel A Yousem, Jieru Wang, Adriana S Leme, A McGarry Houghton, Pamela Hale, Michael Ewing, Houming Cai, Evelyn Akpadock Garchar, Nunzia Pastore, Patrizia Annunziata, Naftali Kaminski, Joseph Pilewski, Steven D Shapiro, Stephen C Pak, Gary A Silverman, Nicola Brunetti-Pierri, David H Perlmutter
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 50 Pg. 29742-57 (Dec 11 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 26494620 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Topics

• Animals
• Autophagy (drug effects, genetics)
• Disease Models, Animal
• Epithelial Cells (pathology)
• Genetic Therapy
• Lung (pathology)
• Mice
• alpha 1-Antitrypsin Deficiency (drug therapy, pathology, therapy)