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J Biol Chem. 2015 Dec 11;290(50):29742-57. doi: 10.1074/jbc.M115.691253. Epub 2015 Oct 22.

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

Author information

1
From the Departments of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
2
Cell Biology, and.
3
Pathology University of Pittsburgh School of Medicine and.
4
From the Departments of Pediatrics.
5
Medicine.
6
Department of Translational Medicine, Federico II University, Naples, Italy, 80138.
7
From the Departments of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, Cell Biology, and.
8
Department of Translational Medicine, Federico II University, Naples, Italy, 80138 Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy, 80131, and.
9
From the Departments of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, Cell Biology, and david.perlmutter@chp.edu.

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.

KEYWORDS:

autophagy; chronic obstructive pulmonary disease (COPD); misfolded α1antitrypsin; protein misfolding; proteostasis; pulmonary fibrosis; α1antitrypsin deficiency

PMID:
26494620
PMCID:
PMC4705969
DOI:
10.1074/jbc.M115.691253
[Indexed for MEDLINE]
Free PMC Article

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