Enhancing Autophagy with Drugs or Lung-directed Gene Therapy Reverses the Pathological Effects of Respiratory Epithelial Cell Proteinopathy.
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.
From the Departments of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
Tunda
T
Hidvegi
Cell Biology, and.
Donna B
DB
Stolz
From the Departments of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
John F
JF
Alcorn
Pathology University of Pittsburgh School of Medicine and.
Samuel A
SA
Yousem
From the Departments of Pediatrics.
Jieru
J
Wang
Medicine.
Adriana S
AS
Leme
Medicine.
A McGarry
AM
Houghton
From the Departments of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
Pamela
P
Hale
From the Departments of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
Michael
M
Ewing
From the Departments of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
Houming
H
Cai
From the Departments of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
Evelyn Akpadock
EA
Garchar
Department of Translational Medicine, Federico II University, Naples, Italy, 80138.
Nunzia
N
Pastore
Department of Translational Medicine, Federico II University, Naples, Italy, 80138.
Patrizia
P
Annunziata
Medicine.
Naftali
N
Kaminski
Medicine.
Joseph
J
Pilewski
Medicine.
Steven D
SD
Shapiro
From the Departments of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224.
Stephen C
SC
Pak
From the Departments of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, Cell Biology, and.
Gary A
GA
Silverman
Department of Translational Medicine, Federico II University, Naples, Italy, 80138 Telethon Institute of Genetics and Medicine, Pozzuoli, Naples, Italy, 80131, and.
Nicola
N
Brunetti-Pierri
From the Departments of Pediatrics, Children's Hospital of Pittsburgh of UPMC, Pittsburgh, Pennsylvania 15224, Cell Biology, and david.perlmutter@chp.edu.
David H
DH
Perlmutter
D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology; D015316:Genetic Therapy; D008168:Lung / Q000473:pathology; D051379:Mice; D019896:alpha 1-Antitrypsin Deficiency / Q000188:drug therapy / Q000473:pathology / Q000628:therapy*
autophagy; chronic obstructive pulmonary disease (COPD); misfolded α1antitrypsin; protein misfolding; proteostasis; pulmonary fibrosis; α1antitrypsin deficiency