2013-06-25 1 Autophagy: Friend or foe in asthma and COPD? Augustine M.K. Choi, MD Parker B. Francis Professor of Medicine Harvard Medical School Pulmonary and Critical Care Medicine Brigham and Women’s Hospital Airway Vista 2013 Asan Medical Center Seoul, Korea March 30, 2013 Disclosures • Proterris
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2013-06-25
1
Autophagy: Friend or foe in asthma and COPD?
Augustine M.K. Choi, MD
Parker B. Francis Professor of Medicine
Harvard Medical School
Pulmonary and Critical Care Medicine
Brigham and Women’s Hospital
Airway Vista 2013
Asan Medical Center
Seoul, Korea
March 30, 2013
Disclosures
• Proterris
2013-06-25
2
Outline
• Introduction
• Autophagy: Regulation and function in experimental
and human lung disease (e.g. COPD)
• Selective Autophagy: Mitophagy and “ciliophagy” in
experimental and human lung disease (e.g. COPD)
• Translational/Clinical Implications
J. Cell Biol, 1962 J. Cell Biol, 1967
2013-06-25
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NEJM, 2013
Autophagy
NEJM, 2013
Autophagy
2013-06-25
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NEJM, 2013
Selective Autophagy
Nature 2008
Autophagy and Human Diseases
Cancer
Infection and immunity
Heart disease
Liver disease
Aging
Myopathies
Neurodegeneration
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Mizushima N et al., Cell, 2011
Physiologic or Pathologic Roles of Autophagy
NEJM, 2013
2013-06-25
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Ryter and Choi, Annual Review of Physiology, 2012
Functional Role of Autophagy in Lung Disease
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Autophagy in Smoke Induced COPD
Chen et al., PLoS ONE 2008
Chen, et al. PNAS 2010
Kim et al., Autophagy 2008
Ryter et al., Autophagy 2009
Kim et al., Methods Enzymol 2009
LC3B
Histone acetylation
Egr-1 E2F4
LC3B-II
Atg4
Autophagy
HDAC Activity
COPD
Lung cell apoptosis
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Chen* & Lam* et al. PNAS, 2010 (Track II)
Emphysema Apoptosis
Autophagy
Autophagy
Less lung injury Less apoptosis
LC3 LC3
LC3
Atg5
Atg12
LC3 Cav-1
Cav-1
Cav-1
Chen* & Lam* et al. PNAS, 2010 (Track II)
Autophagy in Smoke Induced Emphysema
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Bax
Caspase-8
LC3B Cav-1 Cav-1 LC3B FAS
FADD
Autophagosome
Cigarette Smoke COPD Autophagy
Mitochondrial ROS
t-Bid
Apoptosis
Caspase-3
Caspase-9
Bid
Cyto-c
LC3B
Cardiolipin Ox-cardiolipin
ROS
LC3B
LC3B
LC3B secretion
CS CS
Autophagy
Autophagic Flux
Blood biomarker
Chen* & Lam* et al. PNAS, 2010 (Track II)
Nat Med 2010
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a. Control CSE
0 10 2 10 3 10 4 10 5 0
20
40
60
80
100
0
0.5
1
1.5
2
2.5
Control CSE2h CSE4h
c.
Even
ts (
% o
f m
ax)
MitoSOX
Unstained
Control
CSE 2h
CSE 4h R
elat
ive
MF
I
*
*
Unstained Control
CSE 2h
CSE 4h
MitoTracker Deep Red MitoTracker Green
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Control CSE 2h CSE 4h Control CSE 2h CSE4h
Mitotracker Deep Red Mitotracker Green
Rel
ativ
e M
FI
*
*
0 10 2 10 3 10 4 10 5 0
20
40
60
80
100
0 10 2 10 3 10 4 10 5 0
20
40
60
80
100
Even
ts (
% o
f m
ax) d.
Cigarette smoke causes mitochondrial dysfunction
Never
Smokers
COPD
e.
PINK1
β-Actin
d. Never smokers Patients with COPD (GOLD2)
LC3B
0 0.5 1 2 4 8 12 24 (h)
CSE
PINK1
a.
β-Actin
full length
processed
0 0.5 1 2 4 8 12 24 (h)
CSE
β-Actin
PINK1
b.
PINK1, a mitochondrial membrane protein is regulated in CSE treated cells and in