Autophagy A Potential Therapeutic Target in Lung Diseases

Am J Physiol Lung Cell Mol Physiol 305: L93L107, 2013.
First published May 24, 2013; doi:10.1152/ajplung.00072.2013.
Physiology in Medicine
Autophagy: a potential therapeutic target in lung diseases

Kiichi Nakahira and Augustine M. K. Choi
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Womens Hospital, Harvard
Medical School, Boston, Massachusetts
Submitted 18 March 2013; accepted in final form 17 May 2013
Nakahira K, Choi AM. Autophagy: a potential therapeutic target in lung diseases.

Am J Physiol Lung Cell Mol Physiol 305: L93L107, 2013. First published May 24,
2013; doi:10.1152/ajplung.00072.2013.Macroautophagy (hereafter referred to as
autophagy) is an evolutionally conserved intracellular process to maintain cellular
homeostasis by facilitating the turnover of protein aggregates, cellular debris, and
damaged organelles. During autophagy, cytosolic constituents are engulfed into
double-membrane-bound vesicles called autophagosomes, which are subsequently delivered to the lysosome for degradation. Accumulated evidence suggests
that autophagy is critically involved not only in the basal physiological states but
also in the pathogenesis of various human diseases. Interestingly, a diverse variety
of clinically approved drugs modulate autophagy to varying extents, although they
are not currently utilized for the therapeutic purpose of manipulating autophagy. In
this review, we highlight the functional roles of autophagy in lung diseases with
focus on the recent progress of the potential therapeutic use of autophagymodifying drugs in clinical medicine. The purpose of this review is to discuss the
merits, and the pitfalls, of modulating autophagy as a therapeutic strategy in lung
diseases.
autophagy
scarcity, cells survive by eating

and recycling part of themselves (73, 94). These cellular
processes are collectively named autophagy (in Greek, eating oneself). Autophagy is a cellular self-degradation process
in which cytosolic materials and organelles are sequestered and
delivered to lysosome for degradation and recycling (73, 94).
In addition to nutrient starvation, autophagy is induced by
various physiological and pathological conditions. Importantly, autophagy is regulated in various human diseases such
as cancer (120), metabolic diseases (e.g., obesity and Type 2
diabetes) (91), neurodegenerative diseases (e.g., Alzheimers
disease and Parkinson disease) (122), and infectious diseases
[e.g., human immunodeficiency virus (HIV) and tuberculosis]
(54, 60). These reports suggest that autophagy can serve as a
potential therapeutic target for human diseases. Here, we summarize the pathophysiological roles of autophagy in lung
disease, and we explore the possibility that modulating autophagy activity using a pharmacological approach can be a
useful therapeutic intervention.
IN TIMES OF NUTRIENT OR OXYGEN
MOLECULAR MECHANISM OF AUTOPHAGY
Autophagy encloses cytosolic materials by isolation membranes (phagophores) to form double membrane-bound vesicles
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Address for reprint requests and other correspondence: A. M. K. Choi,
Division of Pulmonary and Critical Care Medicine, Brigham and Womens
Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115 (e-mail:
amchoi@rics.bwh.harvard.edu).
http://www.ajplung.org
called autophagosomes (Fig. 1). The isolation membranes are

acquired from multiple sources including endoplasmic reticulum,
Golgi apparatus, mitochondrial outer membrane, and plasma
membrane (35, 76, 93, 116). Subsequently, the autophagosome
containing the cytosolic components and organelles fuses with the
lysosome to become autolysosome, with subsequent degradation
of cytosolic components (Fig. 1). More than 30 autophagy-related
gene (Atg) proteins have been identified to be involved in autophagosome formation (73, 94). The activation of autophagy is
mainly regulated by two signaling pathways including mammalian target of rapamycin (mTOR)-dependent and mTOR-independent pathways (94). In normal physiological condition, autophagy
activity is regulated at basal level by activation of mTOR, a
serine/threonine kinase that has diverse cellular functions. When
cells encounter nutritional starvation, mTOR is inactivated and
promotes the autophagosome formation (Fig. 2, left). In mTORindependent pathways, Ca2 calpainGs and cyclic AMP
(cAMP)phospholipase C (PLC)inositol-(1,4,5)-trisphosphate
(IP3) pathways are involved in autophagy activation (Fig. 2,
right).
FUNCTION OF AUTOPHAGY
Whereas autophagy nonselectively engulfs and degrades

intracellular proteins for recycling under nutritional starvation,
autophagy can selectively target and remove specific subcellular components (selective autophagy) (18). This selective
degradation pathway includes eliminating invading pathogens
(xenophagy) (60), dysfunctional cellular organelles such as
mitochondria (mitophagy) (126), and polyubiquitinated protein
aggregates (aggrephagy) (56). Autophagy is also involved in
lipid metabolism (lipophagy) (108). Selective autophagy
1040-0605/13 Copyright 2013 the American Physiological Society
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AUTOPHAGY MODULATION IN LUNG DISEASES
Lysosome
ULK1 complex
Phagophore
3-MA
Autolysosome
Autophagosome
Class III
PI3K
Beclin 1
BCL-2
Initiation,
isolation membrane
BH3 mimetics
LC3II
Elongation
Completion
Autophagosome and
Lysosome fusion
Degradation
Spautin 1
Atg5-Atg12-Atg16L
Acid hydrolase
Class III PI3K complex
Cargos
Chloroquine
Cystatin B
Bafilomycin A
Pepstatin A
Azithromycin
Autophagy activator
Autophagy inhibitor
Fig. 1. Autophagy process and potential targets for modulating autophagy. Activation of UNC51-like kinase (ULK) complex in response to certain signals
initiates isolation membrane and the formation of phagophore. (Upstream pathway of ULK1 complex is depicted in Fig. 2.) Class III phosphoinositide 3-kinase
(PI3K) complex composed of Beclin 1, class III PI3K, PIK3R4, and activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1) is also required
for the phagophore formation. The Atg-Atg12-Atg16L complex and LC3-II phosphatidylethanolamine (PE) conjugate promote the elongation and enwrap the
cytosolic cargos including mitochondria, leading to the formation of autophagosome. Subsequently, lysosome fuses with the autophagosome (the formation of
autolysosome) and releases acid hydrases into the interiors to degrade the cytosolic cargos. Autophagy can be activated by drugs such as BCL-2 homology 3
(BH3) mimetics that prevent the formation of autophagy inhibitory complex of Beclin 1 and BCL-2. In contrast, ubiquitin-mediated decrease of Beclin 1 protein
by Spautin-1 and inhibition of class III PI3K by 3-methyladenine (3-MA) can inhibit autophagy. In addition, there are drugs to inhibit the late phase of autophagy
process. Lysosomotropic agents that enhance lysosomal pH such as chloroquine inhibit lysosomal enzymes and also prevent the fusion of autophagosome and
lysosome, resulting in inhibition of autophagy. Bafilomycin A1 inhibits the fusion of autophagosome and lysosome by inhibiting vacuolar ATPase (V-ATPase)
located in the lysosomal membrane. Compounds such as pepstatin A and cystatin B are inhibitors for lysosomal protease. (Please also see Table 4.)
plays important roles in maintaining cellular homeostasis in

basal physiological states and in response to various cellular
stresses.
Cytoprotective roles of autophagy under stress conditions
such as starvation have been well documented (73). However,
when cells receive lethal signals, the cellular stresses cause
autophagy and also cell death including apoptosis. Although
interactions of autophagy- and apoptosis-related molecules
such as Beclin 1 and B cell lymphoma 2 (BCL-2), or LC3B and
Fas have been reported in various models (16, 87), it is still
unclear whether autophagy induced by lethal signals promotes
cell death or is an independent process from cell death (94).
The functional role of autophagy on cell death is likely to be
dependent on stress models.
Against invading microbes, autophagy actively participates
in innate immune responses (54, 60). For example, autophagy
exerts its host defense role by degrading various pathogens by
lysosomal system (xenophagy) (60). The target pathogens
include bacteria, such as group A Streptococcus pyrogen (60),
Mycobacterium tuberculosis (Mtb) (23), Salmonella enterica
(54), and Pseudomonas aeruginosa (127); viruses such as
herpes simplex virus 1 (54, 60); and parasites such as Toxoplasma gondii (54). In contrast, recent studies also suggest that
autophagy machinery contributes to the replication and survival of microbes in the host cells. The list of pathogens
exploiting autophagy machinery includes clinically important
microbes, e.g., bacterial agents such as Brucella abortus (99)
and Coxiella burnetii (99) and viruses such as HIV (99),
hepatitis B virus (HBV) (54, 99), and avian influenza A H5N1
(H5N1) (109). Of note, autophagy exerts both killing and
prosurvival properties for HIV (60, 99). Autophagy has diverse
effects on both innate and adaptive immune systems (54, 60).
Atg5 is involved with the production of type I interferons in
response to single-stranded RNA viruses (54, 60). Autophagy
proteins are also involved in the regulation of inflammasome,
cytosolic multiprotein complexes responsible for activation of
caspase-1 and its downstream signaling including secretion of
IL-1 and IL-18 (20, 79). Beclin 1 and LC3B negatively
regulate inflammasome activation by preserving mitochondrial
homeostasis (79). The roles of autophagy in adaptive immunity
include antigen presentation and antibody production. Autophagy is required for presenting antigen on both major
histocompatibility complex class I and II molecules and activating CD8 and CD4 T lymphocytes, respectively (60).
Autophagy is also required for B cell differentiation (19) and
for sustainable antibody production in plasma cells (88). Thus
AJP-Lung Cell Mol Physiol doi:10.1152/ajplung.00072.2013 www.ajplung.org
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Cell membrane
Cytoplasm
L type Ca2+ channel blockers

(verapamil, amidarone)
Clonidine
EGFR antagonists (ertinib)
Ca2+ channel
I1R
Receptor
tyrosine kinase
AC
Class I
PI3K
Gs
Insulin and IGF

receptor
Ca2+
25ddA
cAMP
ATP
Akt
Epac
Metformin
Calpastatin,
calpeptin
Calpain
PI103
Rap2B
TSC1/2
AMPK
Xestospongin B
PLC-
IP3 receptor
PIP2
IP3
Rheb
ER
IP2
Ca2+
Rapamycin and
analogues, Torin 1
Ins
IMPase
mTOR
Lithium, L-960,330
Autophagy activator
Autophagy activator
IP1
Valproic acid,
Carbamazepine
ULK1 complex
via cleavage of Atg5
Autophagy inhibitor
Autophagy
Fig. 2. Overview of the regulation of autophagy pathways and targets for modulating autophagy by drugs/compounds. Two major signaling pathways to regulate
autophagy are depicted in this figure: mammalian target of rapamycin (mTOR) signaling pathways and mTOR-independent signaling pathways. Autophagy is
modulated by mTOR in response to certain nutritional stimulations. Insulin or growth factors activate class I PI3K pathway, leading to activation of mTOR and
inhibition of autophagy. Glucose starvation activates AMPK and inhibits mTOR, followed by activating of ULK1 complex and activating autophagy. mTOR can
be pharmacologically inhibited by activating AMPK (e.g., metformin) or inhibiting class I PI3K (e.g., EGFR antagonist). Recent new drugs such as PI-103 can
activate autophagy by inhibiting both class I PI3K and mTOR. In the mTOR-independent pathway, increase of intracellular cAMP level and Ca2 inhibits
autophagy. Intracellular level of cAMP is upregulated by adenylyl cyclase (AC) and the calpain-Gs pathway, which is activated by intracellular Ca2 level.
The inhibitory effect of cAMP on autophagy is mediated by increase of synthesis of inositol-(1,4,5)-trisphosphate (IP3) and inositol. Increased level of IP3
activates IP3 receptor in endoplasmic reticulum (ER) and release Ca2 into cytosol, leading to inhibition of autophagy. Activation of L-type Ca2 channel triggers
Ca2 influx and elevates intracellular Ca2 level, which activates cysteine protease called calpain. In addition to elevating cAMP by the calpain-Gs pathway,
calpain inhibits autophagy by cleavage of Atg5. However, the concise mechanism by which cytosolic cAMP, Ca2, inositol, and IP3 regulate autophagy is still
unclear. In this cyclical mTOR-independent pathway, autophagy can be modulated by mainly targeting intracellular levels of cAMP or Ca2. L-type Ca2
receptor blockers such as verapamil inhibit Ca2 influx, which leads inhibition of calpain activity and cAMP synthesis. Activation of autophagy by drugs such
as lithium or carbamazepine is mediated by at least reduction of Ca2 release by IP3 receptor (IP3R). EGFR, epidermal growth factor receptor; IGF, insulin-like
growth; TSC, tuberous sclerosis 2; AMPK, AMP-activated protein kinase; V-ATPase, vacuolar ATPase; I1R, imidazoline-1 receptor; PLC, phospholipase C
epsilon; 2=5=ddA, 2=,5=-dideoxyadenosine; PIP2, phosphatidylinositol-4,5-bisphosphate; cAMP, cyclic AMP; Ins, inositol; IP2, inositol-(1,4)-bisphosphate; IP3,
Inositol-(1,4,5)-trisphosphate; IMPase, inositol monophosphatase.
autophagy plays crucial diverse roles in immune systems

including pathogen degradation and immune signaling, suggesting that the involvement of autophagy in infectious and
inflammatory diseases.
Autophagy is critically involved in various metabolic pathways for maintaining cellular homeostasis (91). For example,
autophagy is an important energy generator in the liver. Mice
with specific deletion of atg7 gene in liver display decreased
level of blood glucose and amino acids after starvation (25).
Autophagy is also involved in lipid metabolism by breaking
down lipid droplets to generate energy (lipophagy) (108).

Metabolome analysis also suggests autophagy is required for
maintenance of tricarboxylic acid cycle-related metabolites
(33), suggesting that autophagy is involved in the quality
control of mitochondria. Damaged mitochondria are selectively targeted and removed by autophagy to maintain normal
mitochondrial function (mitophagy) (126). Although the concise molecular mechanism of mitophagy is still unclear, the
importance of preserving mitochondrial homeostasis by autophagy is now further linked to the pathogenesis of human
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diseases such as Parkinson disease (68, 80, 81, 118). Thus the
autophagy process is critically involved in not only physiological but also pathological metabolic responses.
AUTOPHAGY PATHWAY: POTENTIAL THERAPEUTIC TARGET

FOR LUNG DISEASES
MEASUREMENT OF AUTOPHAGY
The functional roles of autophagy on various lung diseases

have been studied both in vitro and in vivo. Tables 2 and 3
represent the functions of autophagy or autophagic proteins in
lung diseases on the basis of studies using genetic or biochemical perturbation of autophagy. Although autophagy has been
initially thought as a cytoprotective response in pathophysiological states, accumulating data reveal diverse functions of
autophagy in lung diseases (Tables 2 and 3). For example,
chronic obstructive pulmonary disease (COPD) is one lung
disease that has been shown to be associated with autophagy
(15). Increased number of autophagosomes is observed by
electron microscopy analysis, and expression of autophagic
protein LC3B-II is increased in lung tissues from patients with
COPD (15). Several molecules involved in autophagy-mediated COPD include FAS (16), Toll-like receptor 4 (5), and
cystic fibrosis transmembrane conductance regulator (CFTR)
(11). In addition, alveolar macrophages isolated from smokers
show increased of LC3 expression with defect of autophagy
flux (77). In vivo, genetic deletion of LC3B displays resistance
to cigarette smoke-induced airway space enlargement compared with the control mice (16). Similar adverse effects of
As the research of autophagy continues to evolve, methods

for monitoring autophagy have been evaluated and discussed in
detail. Klionsky et al. (51) have recently reported the guideline
for monitoring autophagy in higher eukaryotes and described
useful methods and how to interpret the data. A key tenet to
emphasize is that investigators need to recognize whether they
are evaluating the steady-state levels of autophagosomes or
dynamic state of autophagy generated by their models (51,
101). If they are seeking to assess the change of autophagy flux
or activity (e.g., the rate of delivery of autophagosomes substrate to lysosomes) in certain points, it is likely that monitoring steady state of autophagosome (e.g., measuring LC3-II
expression without examining turnover by Western blot, counting autophagosomes by using electron microscopy, or counting
puncta formation of LC3 by immunofluorescence microscopy)
is not sufficient. Table 1 demonstrates the various methods to
monitor autophagy both in vitro and in vivo. Generally, it is
recommended to use multiple different assays (ideally for both
steady and dynamic states), rather than relying on the results
from a single method (51, 101).
Autophagy in Models of Human Lung Diseases
Table 1. Methods for monitoring autophagy in vitro and in vivo

Monitoring static state autophagy
Quantifying autophagosomes
Methods
Key Points
Electron microscopy
Positive correlation of elevated number of

autophagosomes and increased autophagy flux has not
been proved reliably in all models.
Increased level of LC3-II (ratio of LC3-II/LC3-I) does not
always correlate with autophagy flux.
This method can be applied to in vivo using GFP-LC3
transgenic mice.
Increased puncta formation of LC3 does not reliably
correlate with autophagic flux.
LC3-II level (ratio of LC3-II/LC3-I)
Western blot
Puncta formation of LC3
Immunofluorescence
microscopy
Monitoring dynamic state autophagy

Turnover of LC3-II
Western blot
Turnover of p62/SQSTMI
Western blot
Cytosolic protein sequestration assays
Western blot
LC3-II on the autophagosome membrane is normally

continuously degraded during autophagy process. LC3-II
can be accumulated by adding lysosomal proteolysis
inhibitors such as leupeptin, chloroquine or bafilomycin.
Cells or animals can be treated with lysosomal protease
inhibitors.
Autophagic flux can be expressed as the difference in
LC3B-II signal on Western blot obtained in the presence
or absence of lysosome protein inhibitors.
P62/SQSTMI is a cytosolic protein that has an LC3
binding domain (REF). It binds to ubiquitinated protein
and carry them to autophagosome. Subsequently, both
p62/SQSTMI and the cargo proteins are degraded by
autophagy.
Similar with LC3-II, p62/SQSTMI turnover can be
measured by adding lysosome protease inhibitors in vitro
or in vivo.
Cells are incubated (or animals are intraperitoneally
administered) with leupeptin to inhibit lysosomal
proteolysis. Autophagosomes are purified via mechanical
disruption (34) followed by density centrifugation.
Autophagy flux is expressed by the amount of cytosolic
protein, such as LDH recovered in the autophagosome
fraction (Western blot).
LDH, lactate dehydrogenase.

References
110
75
72, 74
38, 41
10, 38
38, 52, 106
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Table 2. The functional role of autophagic proteins in experimental models of lung diseases
Lung Diseases
COPD
IPF
PH (PAH)
CF
Lung cancer
LAM
HALI
Sepsis
Nanoparticle-induced ALI
Function of Autophagic Proteins
References
LC3B and Beclin 1 deficiency inhibits CSE-induced cell death in pulmonary epithelial cells.
LC3B-deficient mice display inhibition of airspace enlargement and apoptosis in lungs after cigarette smoke
exposure.
LC3 deficiency promotes CSE-induced IL-8 secretion in HBEC.
Autophagy inhibition by bafilomycin A enhances CSE-induced IL-8 secretion in HBEC.
Autophagy activation by rapamycin inhibits IL-17A-induced collagen production in lung epithelial cells.
Autophagy inhibition by 3-MA suppresses degradation of collagen in epithelial cells.
3-MA reverses the therapeutic effect of IL-17 antagonism on bleomycin-induced lung fibrosis and mortality
of mice.
LC3B and Beclin 1 deficiency promotes TGF--induced activation of lung fibroblast in vitro.
Autophagy activation by rapamycin inhibits TGF--induced fibronectin and -SMA expression in lung
fibroblast.
Rapamycin inhibits bleomycin-induced lung fibrosis in mice.
Rapamycin inhibits anti-TLR4 antibody-induced lung fibrosis in mice.
Atg5 and LC3 deficiency promotes TGF--induced fibroblast activation in vitro.
Inhibition of mTOR by Torin1 inhibits tunicamycin (ER stress inducer)-induced senescence in HBEC.
Atg5 and LC3 deficiency promotes tunicamycin-induced senescence in HBEC.
LC3B deficiency promotes hypoxia-induced pulmonary hypertension in mice.
LC3B deficiency promotes cell proliferation in pulmonary artery endothelial cells and vascular smooth
muscle cells.
Autophagy inhibition by 3-MA and chloroquine increase angiogenesis in PAEC from fetal lambs with
persistent pulmonary hypertension (PPHN-PAEC).
Beclin-1 knockdown promotes angiogenesis in PPHN-PAEC.
Beclin 1 deficiency promotes aggresome accumulation in CF epithelia.
Beclin 1 deficiency promotes macrophage infiltration and MPO activity in nasal mucosa of CF.
Autophagy inhibition by 3-MA abrogates CF phenotype in nasal mucosa.
LC3 deficiency promotes growth of B. cepacia and IL-1 secretion in macrophages.
Autophagy activation by rapamycin inhibits growth of B. cepacia and IL-1 secretion in macrophages.
Autophagy activation reduces bacterial burden of lung and inflammation in lung of CF mice after B.
cepacia infection.
Overexpression of SQSTM1/p62 inhibits intracellular survival of B. cepacia in macrophages.
Deficiency of SQSTM1/p62 promotes intracellular survival of B. cepacia in macrophages.
Blocking chaperone-mediated autophagy by LAMP-2A depletion suppresses cell proliferation and
increases cell death in lung cancer cells.
Injection of lung cancer cells with LAMP-2A deficiency reduces tumor formation in xenograft mouse
model.
Autophagy inhibition by chloroquine enhances cytotoxicity of gefinitib and erlotinib in lung cancer cells.
Atg5 and Atg7 deficiency enhances cytotoxicity of gefinitib and erlotinib in lung cancer cells.
Atg7 deficiency reduces cancer cell proliferation in NSCLC cell lines.
Atg7 deficiency sensitizes the cancer cells to cisplatin-induced apoptosis in NSCLC cell lines.
Atg3 deficiency reverses erlotinib resistance in erlotinib-resistant lung cancer cells.
TSC2 knockdown increases autophagy-dependent cell survival in mouse embryonic fibroblasts.
Atg5 deficiency inhibits TSC2-null xenograft tumor cell survival.
Autophagy inhibition by chloroquine inhibits xenograft tumor size in mice of TSC2-null xenograft tumor.
LC3B knockdown promotes hyperoxia-induced cell death in lung epithelial cells.
Depletion of LC3B and Beclin 1 leads mitochondrial dysfunction and enhances NLRP3 inflammasomemediated IL-1 and IL-18 secretion in macrophages.
LC3B knockdown increases serum level of IL-1 and IL-18 production in CLP-induced polymicrobial
sepsis and sensitizes mice to endotoxic shock.
Autophagy activation by rapamycin restores CLP-induced myocardial dysfunction in mice.
LC3 overexpression ameliorates acute lung injury and survival in CLP-induced polymicrobial model of
sepsis.
Knockdown of VPS34 increases cell death and liver injury in CLP-induced polymicrobial models of
sepsis.
Autophagy inhibition suppresses releases of neutrophil extracellular trap (NET) induced by E. coli in
human neutrophils.
Knockdown of Atg6 improves nanoparticle-induced cell death in lung epithelial cells.
Autophagy inhibition by 3-MA ameliorates nanoparticle-induced ALI in mice.
15, 16, 47
28
71
85
124
7
59
114
65
2
53
36
46
57
84
112
79
40
64
14
45
61, 62
COPD, chronic obstructive pulmonary disease; CSE, cigarette smoke extract; HBEC, human bronchial epithelial cells; IPF, idiopathic pulmonary fibrosis;
TGF-, transforming growth factor-; -SMA, -smooth muscle actin; 3-MA, 3-methyladenine; TLR4, Toll-like receptor 4; ER, endoplasmic reticulum; P(A)H,
pulmonary (artery) hypertension; PAEC, pulmonary artery endothelial cells; CF, cystic fibrosis; MPO, myeloperoxidase; B. cepacia, Burkholderia cenocepacia;
NSCLC, nonsmall cell lung cancer; LAMP2, lysosome-associated membrane protein 2; LAM, Lymphangioleiomyomatosis; TSC, tuberous sclerosis; HALI,
hyperoxia-induced acute lung injury; NLRP3, NOD-like receptor family, pyrin domain containing 3; CLP, cecal ligation and puncture; E. coli, Escherichia coli;
ALI, acute lung injury.
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Table 3. The functional role of autophagic proteins on pathogen(s) causing respiratory tract infection
Pathogens
Role of Autophagy or Autophagic Proteins
References
Tuberculosis (M. tuberculosis)
Autophagy induction by rapamycin or starvation inhibits M. tuberculosis survival in

infected macrophages.
IL-4 and IL-13 inhibit autophagy activation and autophagy-mediated killing of
intracellular M. tuberculosis in macrophages.
Autophagy activation by rapamycin enhances presentation of mycobacterial antigen
in macrophages.
Subcutaneous injection of mycobacteria-infected dendritic cells pretreated with
rapamycin enhances Th1 response and increases vaccine efficacy in mice.
Autophagy induction by Vitamin D3 promotes killing of M. tuberculosis.
Isoniazid-induced autophagy is associated with antimicrobial activity in M.
tuberculosis-infected macrophages.
Knockdown of Atg5 and TSC2 inhibits H5N1-induced cell death in lung epithelial
cells.
Autophagy inhibition by 3-MA ameliorates acute lung injury and mice survival rate in
mice infected with H5N1
Knockdown of Atg5 ameliorates acute lung injury and mice survival rate in mice
infected with H5N1.
Autophagy induction by rapamycin promotes P. aeruginosa clearance and
autophagy inhibition by 3-MA inhibits the bacterial clearances in macrophages.
Knockdown of Beclin 1 inhibits P. aeruginosa clearance in macrophages.
Autophagy inhibition by Azithromycin inhibits intracellular killing of M. abscessus
in macrophages.
Autophagy inhibition by Azithromycin promotes M. abscessus infection in mice.
Autophagy activation by rapamycin increases replication of human rhinovirus 2
(HRV-2).
Autophagy inhibition by 3-MA suppresses replication of HRV-2.
Knockdown of Atg5 inhibits human adenovirus-mediated cell lysis.
Knockdown of Atg5 inhibits replication of S. aureus and S. aureus-mediated cell
death.
Knockdown of Beclin 1 or LC3 attenuates respiratory syncytial virus-induced
proinflammatory cytokines production.
34
Avian influenza A H5N1
P. aeruginosa
M. abscessus
Human rhinovirus 2
Human adenovirus type 5

S. aureus
Respiratory syncytial virus
37
42
128
49
109
127
96
50
44
105
78
M. tuberculosis, Mycobacterium tuberculosis; P. aeruginosa, Pseudomonas aeruginosa; M. abscessus, Mycobacterium abscessus; S. aureus, Staphylococcus
aureus.
autophagy are observed in other lung diseases including lung

cancer (36, 46, 53) and acute lung injury induced by H5N1
infection (109). In contrast, the beneficial roles of autophagy
are also observed in the diseases such as cystic fibrosis (CF) (1,
2, 65), tuberculosis (23, 34, 42), and sepsis (14, 40, 45, 64, 79).
Thus autophagy is an important cellular process to regulate or
contribute to the pathogenesis of lung diseases. Importantly,
Fig. 3 demonstrates specificity of the pathophysiological functions of autophagy in each lung disease, resulting in either
favorable or deleterious phenotype depending in the disease
process.
Autophagy in Clinical Trials
Although drugs modulating autophagy such as rapamycin or
chloroquine have been clinically used for years without the
intent to modulate autophagy activity, these drugs are now
studied as autophagy modulators in clinical trials for lung
diseases (17, 99, 120, 125). For example, chloroquine, which
inhibits autophagy-mediated cell survival in tumor cells, is
used as an intervention for patients with small cell lung cancer
in a clinical trial (phase 1). In addition, the interventions using
hydrochloroquine and other anticancer drugs such as erlotinib
are used for non-small cell lung cancer in two clinical trials
(phase 1/2 and 2) (125). Although autophagy has been initially
shown to be associated with anti-tumorigenesis in rodent ani-
mal studies (90, 111), the current strategy for cancer therapy is
more likely to be based on inhibition of autophagy (17, 120,
125).
This paradox may be due to the differential roles of autophagy in different stages of tumorigenesis (99, 120). Although initiation of tumorigenesis in normal cells is associated
with defect of autophagy, autophagy subsequently may exert
prosurvival effect in tumor cells (99, 120). Lymphangioleiomyomatosis (LAM), a progressive lung disease caused by
mutation in the tuberous sclerosis genes (tsc), is associated
with inappropriate activation of mTOR signaling, which regulates cellular growth and lymphangiogenesis (39). The pathogenesis of LAM is in part similar with those of tumorigenesis
including inappropriate cell growth and survival (39). Chloroquine is also used with rapamycin for patients with LAM
(phase 1). This clinical trial is based on the rationale that
rapamycin blocks mTOR of downstream kinases and restores
homeostasis in cells with defective tsc function (39, 69, 84).
The use of chloroquine aims to inhibit autophagy-mediated
survival of LAM cells induced by rapamycin (39, 84). A recent
clinical study concludes chloroquine does not prevent infection
with influenza including H1N1 strain (86). Interestingly, autophagy is involved in infection with H5N1, rather than H1N1
(109). Therefore, it is possible that chloroquine has a differential effect on infection with H5N1 vs. H1N1, with genetic and
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Cystic fibrosis
Clearance of protein aggregate
and regulating oxidative stress
LAM
Promoting survival and
proliferation of LAM cells
Lung infection
Promoting or inhibiting
replication of microbes in host
cells
Lung cancer
Xenophagy
Aggrephagy
Promoting survival and

proliferation of cancer cells
Sepsis
Tumor suppression
Mitophagy
Regulating inflammatory
response (i.e. inflammasome)
Lipophagy
COPD
Promoting apoptosis
PAH
IPF
Fig. 3. Diverse effects of autophagy in lung

diseases. The functional modes of autophagy
at cellular levels include eliminating intracellular microbes (xenophagy), dysfunctional
mitochondria (mitophagy), and protein aggregate (aggrephagy). Autophagy also regulates lipid metabolism (lipophagy). Autophagy is involved in pathogenesis of various lung diseases. The roles of autophagy in
each disease are shown. In lung cancer, autophagy may prevent tumorigenesis, whereas
autophagy can promote survival and proliferation of tumor cells. In infectious diseases,
the roles of autophagy are dependent on microbes. Autophagy may promote bacterial
killing and inhibit intracellular survival of
microbes such as Mycobacterium tuberculosis. On the other hand, autophagy may promote replication and survival of microbes
such as H5N1.
Regulating vascular cell

proliferation
Regulating fibroblast
activation and proliferation
biochemical inhibition of autophagy rescue in mice infected

with H5N1 (109). Since chloroquine also has autophagyindependent pharmacological effects such as anti-inflammatory property, the effect of chloroquine on diseases including
tumor may not be entirely explained by modulating autophagy
(120). Although further studies are needed to evaluate the
off-target effects of chloroquine on diseases, these reports
suggest that autophagy modulation by clinically used drugs
may be more accessible to study in clinical trials because of
their favorable safety profiles. The details of ongoing clinical
trial targeting modulating autophagy are listed (http://www.
clinicaltrials.gov/ct2/results?termautophagy&SearchSearch).
Autophagy Modulators
Given the important association between autophagy and
human lung diseases, it is worthwhile to review whether
modulating autophagy can serve as potent therapeutic targets
for various lung diseases. Table 4 demonstrates a list of
autophagy modulating drugs that are clinically used or being
studied in clinical trials. Table 5 shows conventional and newly
developed compounds or molecules modulating autophagy
activity. There are several target signaling pathways wherein
autophagy activity is modulated by drugs.
mTOR signaling pathways. The mTOR is one of the main
targets for modulating autophagy by drugs and forms two
distinct complexes to regulate autophagy: mTOR complex 1
(mTORC1) and mTOR complex 2 (mTORC2) (94) (Fig. 2,
left). Rapamycin and its analogs inhibit mTORC1, a main
complex responsible for autophagy regulation, and promote
autophagy induction (92, 95, 121). A recently identified com-
pound Torin1 directly inhibits both mTORC1 and mTORC2

and induces greater autophagy than does rapamycin (115). Of
note, another new class of drugs has dual targets in autophagy
pathways. PI-103 hydrochloride inhibits both mTOR and class
I phosphoinositide 3-kinase (class I PI3K), suggesting an
effective autophagy inducer (22).
mTOR-independent pathways. Figure 2, right, shows mTORindependent pathways.
PHOSPHOINOSITOL SIGNALING PATHWAY. Intracellular inositol
and IP3 levels negatively regulate autophagy (94). Drugs such
as lithium (103) or carbamazepine (103, 121) increase autophagy activity by decreasing intracellular level of inositol.
CA2-CAMP-PLC-IP3 PATHWAY. Intracellular Ca2 and cAMP
negatively regulate autophagy by increasing intracellular inositol level (94). In addition, calpain activated by elevated level
of intracellular Ca2 inhibits autophagy by cleavage of Atg5
(94, 99). Antihypertensive drugs including Ca2 receptor
blockers (9, 121, 129) or imidazolin receptor agonists (98, 121)
induce autophagy by decreasing cAMP.
Degradation steps of autophagy. Inhibiting formation of
autolysosome and lysosomal protease are also important targets to inhibit autophagy (Fig. 1). Chloroquine is a lysosomotropic and inhibits the fusion of autophagosome and lysosome
(4, 12). Cystatin B is a potent inhibitor of cystatin protease
(cathepsin B) in lysosome (99).
Other pathways. BCL-2 homology 3 (BH3) mimics inhibit
the interaction of BCL-2 and BCL-x with Beclin 1, an inhibitory complex for autophagy (66) (Fig. 1). Resveratrol induces
autophagy by activating sirtuin 1 and inhibits P70 S6 kinase (8,
43, 82). There are several compounds or drugs such as L-
L100
Table 4. Drugs that modulate autophagy activity

Drugs
Autophagy inducers
Rapamycin and analogs
Clinical Application or Pharmacological Class
Amidarone
Immunosuppressant for preventing rejection

in organ transplant and coronary stent
coating for anti-proliferation
Class III antiarrhytmic
Nicosamide
Antiparasitic
EGFR antagonists (erltinib

hydrochlorine)
Resveratrol (Stilbenoids)
Anticancer
Suberoylanilide hydroxamic acid

Dexamethasone (glucocorticoide)
Supplementary diet. Secondary products of

heartwood formation in trees that act as
phytoalexins
Anticutaneous T cell lymphoma
Anti-inflammatory or immunosuppressant
Metformin
Antidiabetic
Verapamil, nicardipine, nimodipine

(L-type Ca2 channel blockers)
Sodium valproate
Vasodilator
Clonidine
Rilmenidine
Antihypertensive, treatment for ADHD and

anxiety/panic disorder
Antihypertensive
Lithium, L-690 330
Mood-stabilizing drug
Carbamazepine
Tamoxifen (estrogen receptor
antagonist)
Statin (HMG-CoA reductase
inhibitor)
Vitamin D3
Antiepileptics
Anti-breast cancer and anti-bipolar disorder
BH3 mimetics (ABT-737)

Carbon monoxide (at 250 ppm)
Minoxidil (potassium channel

opener)
Salbutamol (2 adrenergic receptor
agonist)
Isoniazid, pyrazinamide
Autophagy inhibitors
Azithromycin
Chloroquine/hydroxychloroquine
Vinblastine
IL-4
IL-13
Anticonvulsant
Lower cholesterol
Supplementary diet to reduce the risk of
fractures and falls
Undergoing clinical trial for ovarian cancer
Vasodilator, anti-inflammation and
antiproliferation Undergoing clinical
trials for idiopathic pulmonary fibrosis
and sepsis
Vasodilator
Mechanism of Action in Autophagy Pathway
References
Inhibit mTORC1
92, 95, 121
Inhibits mTORC1 or upstream in

mTOR pathway
Inhibits mTORC1 or upstream in
mTOR pathway
Inhibit PI3K-Akt-mTOR pathway
Activates sirtuin 1 (histone deacetylase)

and inhibits S6 kinase
8, 43, 82
Inhibits mTOR
Upregulates PML and Akt
dephosphorylation
Upregulates AMPK (and ULK1
phosphorylation)
Reduce intracellular Ca2 levels
13
31, 55
Inhibits histone deacetylase and reduces

intracellular Ca2 levels
Reduces cAMP levels (Imidazoline-1
receptor agonist)
Reduces cAMP levels (imidazoline-1
receptor agonist)
Inhibit IMPase and reduce inositol and
IP3 levels
Reduces inositol and IP3 levels
Accumulation of sterol, Increases
Beclin 1
Depletes geranylgeranyl diphosphate
9
30, 36
48, 70
9, 121, 129
103, 121
121
98, 121
103
103, 121
21, 99
83
Increases Beclin 1 expression by

upregulating cathelicidin
Disrupts interaction between the BH3
domain of Beclin 1 and the
antiapoptotic proteins BCL-2
Increases mitochondrial reactive oxygen
species
128
Unknown
121
66
58
Treatment for asthma by smooth muscle

relaxant
Antibiotics for tuberculosis
Unknown
AMPK and intracellular Ca
dependent
49
Macrolide antibiotic
Inhibits fusion of autophagosome and

lysosome
Inhibits fusion of autophagosome and
lysosome
96
Inhibits microtubule formation

Activates Akt and STAT6
89
37
Activates Akt and STAT6
37
Treatment for RA, SLE, and malaria

Undergoing clinical trials for various
cancers
Anticancer
Undergoing clinical trial for tuberculosis by
blocking IL-4
Undergoing clinical trial for advanced
cancers
6
2
4, 12
mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; PI3K, phosphoinositide 3-kinase; NF-B, nuclear factor-B, AMPK, AMP-activated
protein kinase: ULK1, UNC51-like kinase; cAMP, cyclic AMP; IP3, inositol-(1,4,5)-trisphosphate; IMPase, inositol monophosphatase; BH3, BCL-2 homology
3; BCL-2, B cell lymphoma 2; EGFR, epidermal growth factor receptor; HMG-CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; STAT6, signal transduction and
transcription 6; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; PML, promyelocytic leukemia protein; ADHD, attention deficit hyperactivity
disorder; IL-4, interleukin 4; IL-13, interleukin 13. For details of clinical trials, please see the website http://www.clinicaltrials.gov/.
L101
Table 5. Molecules or compounds that modulate autophagy activity

Molecules or Compounds
Autophagy activators
Torin1
PP242
PI103 hydrochloride
2=,5=- Dideoxyadenosine
Xestospongin B
Spermidine
Tat-beclin1
Calpastatin, calpeptin
Trehalose (an -linked disaccharide
L-NAME (inhibition of NOS and decrease of NO
production)
GGTi-298 (inhibition of geranylgeranyl transferase 1)
Autophagy inhibitors
Spautin-1
3-MA
Pepstatin A
Cystatin B
Leupeptin
Bafilomycin A1
Nocodazole
Mechanism of Action in Autophagy Pathway
References
Directly inhibits both mTORC1 and mTORC2

Inhibits mTORC1
Highly selective class I PI3K inhibitor and ATP-competitive mTOR inhibitor
Reduces cAMP levels (Adenynyl cyclase inhibitor)
IP3R antagonist
Postulated to affect expression of Atg genes
A cell permeable peptide derived from a region (267284) of Beclin 1
Inhibit calpain
mTOR independent
Unknown
115
26
22
121
117
24
107
121
102
104
P53 dependent
29
Lowers Beclin 1 levels by promoting its ubiquitination

Inhibits class III PI3K
Inhibits aspartyl protease (cathepsin D)
Inhibits cystatine protease (cathepsin B)
Inhibits serine and cysteine proteases
Inhibits V-ATPase; Inhibits fusion of autophagosome and lysosome
Inhibits microtubule formation
63
100
113
99
38
92, 123
97, 119
IP3R, inositol-(1,4,5)-trisphosphate receptor; L-NAME, N-L-arginine methyl ester; 3-MA, 3-methyladenine; NO, nitric oxide; NOS, nitric oxide synthase; Atg,
autophagy-related; V-ATPase, vacuolar ATPase.
NAME (104), trehalose (102), or 2-adrenergic receptor agonist (6) whose mechanisms to modulate autophagy are still
unclear (Table 4). Further studies will be needed to identify
concise pathways by which those drugs or compounds modulate autophagy.
Since there are several pathways regulating autophagy, it
is possible that some drugs can stimulate both proautophagy
and antiautophagy pathways. For example, although lithium
has been shown to activate autophagy via an mTOR-independent pathway, lithium also inhibits GSK-3, which can
activate mTOR and lead to inhibition of autophagy (27)
(Fig. 2). In addition, some drugs may inhibit Ca2 channel
(activating autophagy by mTOR-independent pathways) and
also inhibit EGFR receptor (inhibiting autophagy by activating mTOR), which offset both the cellular signaling
pathways against each other and result in no autophagy
activation being observed. Thus it is also important to
analyze the effect of drugs on the individual pathways to
regulate autophagy. These profiles may lead to developing
the combined use of different types of autophagy modulators such as lithium and rapamycin, which can gain the
greater activation of autophagy (27) (Fig. 2).
Autophagy Modulation as a Potential Therapeutic
Intervention for Lung Diseases
Although various classes of clinically used drug modulate
autophagy pathways (Table 4), it is still unclear in many cases
whether the therapeutic effects of those drugs arise from
autophagy or autophagy-independent pathways. Even if autophagy is involved, there is still an important question remaining whether modulating autophagy by drugs contributes to
their beneficial pharmacological effects. For example, metformin, one of the most commonly used drugs for treatment of
Type 2 diabetes, induces autophagy (48, 70). The role of
autophagy on the pathogenesis of diabetes is still controversial
(94). Antidiabetic effects of metformin may be mediated by
metformin-induced autophagy activation or conversely may be

compromised by the autophagy activation. Recent clinical
studies show new possible interventions using drugs for lung
diseases including COPD (3) and tuberculosis (67). Azithromycin, a macrolide antibiotic, inhibits the frequency of exacerbation of COPD (3). High-dose supplement of vitamin D3
(VitD3) reduces time of sputum culture conversion of Mycobacterium tuberculosis (Mbt) in patients with polymorphism of
VitD3 receptor (67). Although the concise mechanisms by
which these drugs exert the beneficial effects are still unclear,
they commonly modulate autophagy activity. The pharmacological effect of azithromycin is similar with bafilomycin A1,
a family of macrolide antibiotic and also a well-known autophagy inhibitor (96) (Fig. 1). The beneficial roles of azithromycin on COPD may be associated with the inhibitory effect of
azithromycin on autophagy, since autophagy gene deficiency
displays protective effects in a mouse model of COPD. In
contrast, VitD3 inhibits replication of Mbt by increasing autophagy activity (128). Interestingly, drugs can also increase
autophagy activity in specific pathological condition. Isoniazid, an antibiotic for Mbt, induces autophagy in macrophages
infected with Mbt, rather than in uninfected cells (49). Although further studies are needed to clarify how autophagy is
involved in the beneficial effects of those drugs, these reports
suggest that pharmacological manipulation on autophagy activity can serve as a potential therapeutic strategy in lung
diseases. In addition, investigating the effect of drugs on
autophagy activity can reveal the new mechanism of disease
pathogenesis and previously unknown pharmacological actions
of the drugs.
It is also important to explore the possibility to use autophagy modulators as an intervention for treatment of lung
diseases. For example, an intervention to enhance autophagy
activity may have beneficial effects in lung diseases such as
tuberculosis or CF, since the effective drugs reported for those
diseases activate autophagy (32, 67). However, the caution
L102
should be taken for this strategy. Autophagy has diverse effects

depending on diseases or pathological conditions. Although
activation of autophagy is beneficial for Mbt infection, the
activated autophagy may also exert protective roles for microbes such as HIV or HBV (99). If patients with tuberculosis
have latent infections with HIV or HBV, it is possible that
autophagy activation promotes replication and survival of
those microbes in the patients (99). On the other hand, autophagy inducers may have the additive beneficial effects in
patients enrolled in clinical trials for treatment of tuberculosis,
such as patients with Parkinson disease, where autophagy plays
protective roles (99). Finally, therapeutic interventions by
modulating autophagy can add to the current therapeutic strategies, rather than be used solely. For example, a recent clinical
trial for lung cancer utilizes the combined interventions of
erlotinib, a tyrosine kinase inhibitor, and chloroquine (125).
The anticancer mechanism of erlotinib is likely to be autophagy independent (36, 57). Inhibiting autophagy by chloroquine enhances anticancer effect of erlotinib by minimizing
prosurvival effect of erlotinib-mediated autophagy in tumor
cells (36, 57, 120, 125). Modulating autophagy activity may
enhance the beneficial roles of autophagy or minimize the
adverse effect of autophagy on each disease. Furthermore,
adding autophagy modulators may improve the current pharmacological effect of drugs used for the treatment.
Although clinical trials for investigating the therapeutic
effects of autophagy modulators are most desirable to observe the usefulness of drugs, cohort studies to examine the
effect of autophagy modulator on patients prognosis would
be more accessible. For example, there are a number of
patients with COPD who use autophagy modulators such as
Ca2 blockers, statin, or metformin for their medication;
these drugs may influence patients quality of life, lung
function, and frequency of acute exacerbation. In addition,
these studies may help to identify drugs which are suitable
for the clinical trials.
CONCLUSION
Until now more than 20 different classes of drug used for

treatment have been identified as autophagy modulators (9,
129) (Table 4). Moreover, the new-class autophagy modulators
with improved specificity and effectiveness have been developed for human disease indications as potential therapeutics
(Table 5). Given the important roles of autophagy in various
lung diseases (Fig. 3 and Tables 2 and 3), utilizing autophagy
modulators may improve the therapeutic effects of the current
interventions in various lung diseases. However, there are also
several important points to keep in mind. Although similar
situations are observed in other medical interventions, effective
and less-invasive methods to monitor autophagy activity for
patients (e.g., biomarkers) are not currently available. Secondly, since autophagy is such a fundamental cellular process
that affects various pathophysiological conditions, it is plausible that modulating autophagy causes other untoward effects
that may be clinically deleterious. Finally, the autophagy modulators listed in Tables 4 and 5 may have off-target effects in
addition to modulating autophagy. Nonetheless, recent clinical
studies using autophagy modulators (3, 32, 67) and ongoing
clinical trials (more than 15 active trials targeting autophagy)
still suggest that autophagy modulators unravel new avenues in
therapeutic interventions of various human diseases including

lung diseases. Although further development of assays for
autophagy activity and drugs with improved selectivity are
needed, the day when we use autophagy-modifying drugs to
treat lung disease may come sooner than later.
ACKNOWLEDGMENTS
The authors thank Jeffrey Adam Haspel for critical review of this manuscript.
GRANTS
This study is supported by NIH T32HL007633-27 (K. Nakahira) and NIH
PO1 HL105339 (A. M. K. Choi) and R01 HL05530 (A. M. K. Choi).
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
K.N. and A.M.K.C. conception and design of research; K.N. drafted
manuscript; K.N. and A.M.K.C. edited and revised manuscript; K.N. and
A.M.K.C. approved final version of manuscript.
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Autophagy A Potential Therapeutic Target in Lung Diseases

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Am J Physiol Lung Cell Mol Physiol 305: L93L107, 2013.

First published May 24, 2013; doi:10.1152/ajplung.00072.2013.

Autophagy: a potential therapeutic target in lung diseases

Nakahira K, Choi AM. Autophagy: a potential therapeutic target in lung diseases.

scarcity, cells survive by eating

IN TIMES OF NUTRIENT OR OXYGEN

MOLECULAR MECHANISM OF AUTOPHAGY

called autophagosomes (Fig. 1). The isolation membranes are

Whereas autophagy nonselectively engulfs and degrades

1040-0605/13 Copyright 2013 the American Physiological Society

AUTOPHAGY MODULATION IN LUNG DISEASES

Class III PI3K complex

plays important roles in maintaining cellular homeostasis in

AJP-Lung Cell Mol Physiol doi:10.1152/ajplung.00072.2013 www.ajplung.org

AUTOPHAGY MODULATION IN LUNG DISEASES

L type Ca2+ channel blockers

EGFR antagonists (ertinib)

Insulin and IGF

autophagy plays crucial diverse roles in immune systems

down lipid droplets to generate energy (lipophagy) (108).

AJP-Lung Cell Mol Physiol doi:10.1152/ajplung.00072.2013 www.ajplung.org

AUTOPHAGY MODULATION IN LUNG DISEASES

AUTOPHAGY PATHWAY: POTENTIAL THERAPEUTIC TARGET

The functional roles of autophagy on various lung diseases

As the research of autophagy continues to evolve, methods

Autophagy in Models of Human Lung Diseases

Table 1. Methods for monitoring autophagy in vitro and in vivo

Positive correlation of elevated number of

LC3-II level (ratio of LC3-II/LC3-I)

Puncta formation of LC3

Monitoring dynamic state autophagy

Cytosolic protein sequestration assays

LC3-II on the autophagosome membrane is normally

LDH, lactate dehydrogenase.

38, 52, 106

AUTOPHAGY MODULATION IN LUNG DISEASES

Function of Autophagic Proteins

AUTOPHAGY MODULATION IN LUNG DISEASES

Role of Autophagy or Autophagic Proteins

Tuberculosis (M. tuberculosis)

Autophagy induction by rapamycin or starvation inhibits M. tuberculosis survival in

Avian influenza A H5N1

Human adenovirus type 5

autophagy are observed in other lung diseases including lung

AJP-Lung Cell Mol Physiol doi:10.1152/ajplung.00072.2013 www.ajplung.org

AUTOPHAGY MODULATION IN LUNG DISEASES

Promoting survival and

Fig. 3. Diverse effects of autophagy in lung

Regulating vascular cell

biochemical inhibition of autophagy rescue in mice infected

pound Torin1 directly inhibits both mTORC1 and mTORC2

AJP-Lung Cell Mol Physiol doi:10.1152/ajplung.00072.2013 www.ajplung.org

AUTOPHAGY MODULATION IN LUNG DISEASES

Table 4. Drugs that modulate autophagy activity

Clinical Application or Pharmacological Class

Immunosuppressant for preventing rejection

EGFR antagonists (erltinib

Suberoylanilide hydroxamic acid

Supplementary diet. Secondary products of

Verapamil, nicardipine, nimodipine

Antihypertensive, treatment for ADHD and

Lithium, L-690 330

BH3 mimetics (ABT-737)