Autophagy and Cellular Senescence in Lung Diseases
Kazuyoshi
Kuwano, Jun Araya, Hiromichi Hara, Shunsuke Minagawa, Naoki Takasaka, Saburo
Ito,
Katsutoshi
Nakayama
Kazuyoshi
Kuwano, Jun Araya, Hiromichi Hara, Shunsuke Minagawa, Naoki Takasaka, Saburo
Ito, Katsutoshi Nakayama, Division
of Respiratory Diseases, Department of Internal Medicine, The Jikei University
School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan
Correspondence to: Kazuyoshi Kuwano, MD, PhD, Division of Respiratory
Diseases, Department of Internal Medicine, The Jikei University School of
Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.
Email: kkuwano@jikei.ac.jp
Telephone: +81-3-3433-1111 Ext.3271 Fax: +81-3-3433-1020
Received: March 29,
2015
Revised: May 26, 2015
Accepted: May 30, 2015
Published online: June 6, 2015
ABSTRACT
Autophagy is a
process of lysosomal self-degradation that helps maintain homeostatic balance
between the synthesis, degradation and recycling of cellular proteins and
organelles. In addition to nutrient starvation, a wide array of cellular
stresses are also known to be strong inducers of autophagy, indicating that
autophagy is not only simple amino acid supply machinery in response to energy
demand but also a central component of the integrated stress response for
cytoprotection. Since autophagy is an adaptive pathway of cytoprotection from
cellular stresses, involving starvation, reactive oxygen species, endoplasmic
reticulum stress, and microbe infection, it is reasonable to suggest that
autophagy is closely related with aging. Indeed, autophagy diminishes with
aging and accelerated aging can be attributed to reduced autophagy. Cellular
senescence is also one of the cellular stress responses as well as autophagy,
and considered to be one of the processes of aging. Cellular senescence has
been widely implicated in disease pathogenesis in terms of not only impaired
cell repopulation but also aberrant cytokine secretions of senescence associated
secretory phenotype, which may exert deleterious effects on the tissue
microenvironment of neighboring cells. The detailed molecular mechanism for
regulation of autophagy and cellular senescence is complex and the role of
autophagy and cellular senescence is overlap significantly. We review molecular
mechanisms of autophagy and cellular senescence, and summarize the role of
autophagy and cellular senescence in pulmonary disease pathogeneses.
© 2015 ACT. All
rights reserved.
Key words: Autophagy; Senescence; Aging; Infection; Lung cancer;
Bronchial asthma; Chronic obstructive lung disease (COPD); Idiopathic pulmonary
fibrosis (IPF)
Kuwano K, Araya J,
Hara H, Minagawa S, Takasaka N, Ito S, Nakayama K. Autophagy and
Cellular Senescence in Lung Diseases. Journal of
Biochemistry and Molecular Biology Research 2015; 1(2): 54-66 Available from: URL:
http://www.ghrnet.org/index.php/jbmbr/article/view/1075
Autophagy
Autophagy is a process of lysosomal self-degradation that helps
maintain homeostatic balance between the synthesis, degradation and recycling
of cellular proteins and organelles[1]. At the cellular level,
auto-digestion takes place within lysosomes and proteasomes. Proteasomes are
involved in the clearance of ubiquitin-conjugated soluble proteins, whereas
autophagy delivers diverse cytoplasmic components to the lysosome, including
soluble proteins, aggregate-prone proteins, and organelles[2].
Autophagy is not simply machinery for amino acid supply in response to energy
demand, it is an adaptive pathway of cytoprotection from cellular stresses,
involving starvation, reactive oxygen species (ROS), endoplasmic reticulum (ER)
stress, and microbe infection[2].
Three forms of distinct autophagy
have been demonstrated: chaperon (Hsc70)-mediated autophagy (CMA),
microautophagy, and macroautophagy. CMA degrades soluble proteins only, via
direct translocation to the lysosome through Lamp2A, a lysosomal transmembrane
protein. During microautophagy, small components of the cytoplasm are engulfed
by direct invagination into lysosomes. Engulfment of cytoplasmic components by
the isolation membrane (phagophore) is the initial step in autophagy, and is
followed by elongation and fusion, resulting in formation of double-membranous
vesicles (autophagosome). Subsequent fusion of the autophagosome with the
lysosome to form the autolysosome is absolutely required for proper degradation[3].
Recent advances in the molecular mechanisms of autophagy have mainly focused on
macroautophagy, specifically on the detection of a series of autophagy-related
(ATG) genes. Among 35 autophagy-related, (Atg), proteins identified in yeast,
there are core Atg proteins required for autophagosome formation, which are
well conserved in mammals[4]. Hence, in general in the literature,
macroautophagy is designated as autophagy[3].
Initially,
autophagy was proposed to be a non-selective bulk degradation system, but
recent advances demonstrate that a variety of ubiquitinated cargos, including
protein aggregates, mitochondria, and microbes, are selective targets for
autophagic degradation[3]. Accordingly, ubiquitination is an
important tag for not only proteasomal degradation but also for selective autophagy.
The p62 protein / sequestosome 1 (SQSTM1) has been shown to be an adaptor
protein for selective autophagy based on its ability to bind both ubiquitin and
microtubule-associated protein 1A/1B-light chain 3 (LC3), a crucial component
for autophagosome formation[4]. Because of the dynamic nature of
autophagy, in which autophagosome can be formed within several minutes, it is
difficult to distinguish between increased autophagy flux and impaired
subsequent clearance when using electron microscopic detection of
autophagosomes or when examining ATG expression levels. Therefore, to detect
the conversion of LC3-I to LC3-II, (which is conjugated to
phosphatidylethanolamine (PE) to ensure stable association to the
autophagosomal membrane), the use of protease inhibitors is generally accepted
to be standard methodology for evaluation of autophagy flux. In addition, based
on the findings of selective autophagic degradation, concomitant accumulation
of p62 and ubiqitinated protein is also recognized to at least partly reflect
autophagy activity[5].
Due to the
large number of physiological and aberrant intracellular components that are
potential targets for autophagic degradation, autophagy status is linked to a
diverse array of cellular processes and cell fates, including energy supply,
homeostatic turnover of organelles, cell fate, cellular senescence and immune
responses[1]. In terms of the pathogenic role of autophagy,
excessive activation may be associated with disease progression in
extraphysiologic conditions[6], whereas impairment of autophagy
activity has been widely implicated in the pathogenic sequence of a variety of
human disorders[7]. Indeed, recent in vitro and in vivo gene
knockout studies revealed that insufficient autophagy is involved in the
development of lung diseases[8-11].
Continuous
ventilation of large amounts of air with high oxygen concentration, which may
contain noxious particles and harmful microbes, is a fundamental function of
the lungs, and is required for sufficient gas exchange. Subsequently,
indicating lung cells are serially exposed to a diverse array of cellular
stresses, and it is reasonable to speculate that autophagy-mediated alleviation
of cellular stress plays a key regulatory role in lung pathophysiology.
Cellular senescence
Aging is associated with the impaired function of maintaining
homeostasis in organs and bodies. The phenotypes of aging include genomic
instability, telomere erosion, epigenetic changes, loss of proteostasis,
deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence,
stem cell exhaustion, and altered cellular communication[12].
Hayflick et al firstly used the term “replicative senescence” to
describe phenomenon of irreversible growth arrest of normal human fibroblasts
after extensive serial passaging in culture[13]. Replicative
senescence was caused by telomere shortening. Senescent cells in tissues have
usually been identified using histological staining for DNA damage markers such
as p21, p16, or senescent-associated -galactosidase (SA-gal) activity. In
the liver, skin, lung, and spleen, total of ~8% and ~17% senescent cells in
young and old mice were identified respectively, although there was no change
in heart, skeletal muscle, and kidney[14]. Therefore, cellular
senescence is not a generalized property of aged tissues, and aging and
senescence is not equal. As the first identification of cellular senescence in
lung diseases, Wang et al demonstrated positive staining for senescence
associated heterochromatin foci marker H2AX in the alveolar epithelial
cells of old mice[14]. In human lung tissue, Holz et al. found that
human lung fibroblasts obtained from lung tissues from patients with COPD
showed reduced proliferation rate compared with those from healthy lung[15].
Cellular senescence is induced by not only telomere shortening but various
cellular stresses such as oxidative stress, oncogene activation, DNA damage,
and chromatin abnormality[16]. In addition, it is noteworthy that
cellular senescence also plays instructive roles in organ and tissue
development[17].
The
characteristics of senescent cells include irreversible growth arrest, enlarged
morphology, expression of cyclin-dependent kinase inhibitor (CDKI), the
formation of senescence-associated heterochromatin foci, and senescence
associated secretory phenotype (SASP)[18]. CDKIs, such as p21 and
p16, control cell cycling. The increased expression of CDKIs results in cell
cycle arrest in senescent cells[19,20]. Senescent cells affect microenvironment
through gene expression of growth factors, cytokines and proteases, so called
SASP. SASP presents biological activities and plays a key role in diverse
effects on carcinogenesis and the pathogenesis of degenerative diseases[21].
Senescent cells increase in size in vitro but not in vivo, enlarging sometimes
as double as non-senescent cells. The markers of senescent cells include
positive staining for SA-gal which reflects the increase of lysosome contents,
senescence-associated CDKIs p21, p16, p15, and p27 expression, and
senescence-associated heterochromatin foci which inhibit gene expression of
cell proliferation. These markers are not entirely specific to cellular
senescence, therefore, cellular senescence has been defined by a collection of
these markers. The phenotype of cellular senescence is various depending on the
type of cell, senescent stimuli, and SASP[22] (Figure 1).
Cellular
senescence plays roles in tissue repair and regeneration[23]. SASP
secreted from senescent cells stimulates the migration of phagocytic immune
cells which play important roles in the clearance of senescent cells and the
repair or resolution of damaged tissues. The tissue damage is prolonged when
damaged tissue is not normally repaired or resolved. The prolongation of
damaged tissues can lead to the accumulation of senescent cells. Therefore,
senescent cells accumulate and secreted proteins and other factors induce
remodeling of damaged tissues or proliferation of tumor cells in the old[23].
Recently, senescence has been reported to play important roles in the
development processes and to compensate the role of apoptosis to remove
unnecessary cells[17].
The relationship between autophagy and cellular senescence
Cellular senescence has been widely implicated in disease pathogenesis
in terms of not only impaired cell repopulation but also aberrant cytokine
secretions of SASP[24]. SASP may exert deleterious effects on the
tissue microenvironment of neighboring cell[24,25]. Increased
cellular senescence is one of major features of aging and hence cellular
senescence has been widely implicated in age-associated disorders. The detailed
molecular mechanism for regulation of cellular senescence is complex and
incompletely understood, but one of the typical manifestations is accumulation
of damaged proteins and organelles, occasionally associated with ubiquitinated
aggregations[26]. Therefore, it has been proposed that functional
insufficiencies in the cellular cleaning and housekeeping mechanisms of
autophagy play a pivotal role in the accumulation of deleterious cellular
components and therefore in the regulation of cellular senescence[26].
Indeed,
autophagy diminishes with aging and accelerated aging can be attributed to
reduced autophagy. Thus, autophagy activation appears to be associated with
longevity[27]. Pathologic premature aging due to autophagy
malfunction has been intensively examined using animal models of autophagy
inhibition by tissue specific knockout of ATG genes. Those animal models with
insufficient autophagy demonstrated a cellular phenotype of progressive
accumulation of ubiquitinated aggregates and disorganized mitochondria,
suggesting the causal relationship between loss of autophagy and aging-associated
disease phenotypes[28]. However, those phenotypic alterations were
mainly evaluated in the central nervous system and liver, not in other organs.
Among the variety of targets for autophagic degradation, selective autophagy of
mitochondria (mitophagy) has been widely implicated in cellular senescence in
terms of regulation of reactive oxygen species (ROS) of oxidative stress.
Mitochondria are the main organelle responsible for intrinsic ROS release
through respiratory chain reactions and insufficient mitophagy results in
accumulation of damaged mitochondria accompanied by increased ROS production[29].
The role of
stress-induced autophagy activation in longevity has been mainly demonstrated
in the case of caloric restriction (CR)[30]. CR induces autophagy
through the inhibition of mammalian target of rapamycin (mTOR), an essential
negative regulator of autophagy, and also through activation of adenosine
monophosphate-activated protein kinase (AMPK) and Sirtuin1 (SIRT1)[31].
In response to the rising AMP/ATP ratio during CR, AMPK induces autophagy via
phosphorylation of ULK1, a mammalian orthologue of the yeast protein kinase
Atg1[32]. SIRT1 deacetylation of Atg proteins and transcription
factors, including the FOXO family, is involved in autophagy induction[33,34].
The involvement of CR-induced autophagy in longevity was confirmed by
inhibition of autophagy, and SIRT1-mediated longevity by CR is at least partly
conferred by autophagy activation[34]. Intriguingly, recent paper
demonstrated that SIRT1 protects against emphysema by a FOXO3-mediated
reduction of premature senescence in mice, but the involvement of autophagy was
not examined[35].
Gamerdinger et
al showed that autophagy are getting more importance during the aging
process, because proteasome pathway could not degrade protein aggregates in the
presence of an enhanced pro-oxidant and aggregation-prone milieu characteristic
of aging[36]. Patshan et al investigated whether the
autophagy is involved in development of premature senescence of endothelial
cells[37]. They found that pharmacological inhibition of autophagy
prevented development of premature senescence but did lead to the enhanced rate
of apoptosis in human umbilical vein endothelial cells[38]. Young et
al. showed that a subset of autophagy-related genes are up-regulated during
senescence: Overexpression of one of those genes, ULK3, induces autophagy and
senescence. Furthermore, inhibition of autophagy delays the senescence phenotype,
including senescence-associated secretion[39]. Goehe at al showed
that autophagy and senescence tend to occur in parallel, and furthermore that
autophagy accelerates the development of the senescent phenotype[40].
Collectively, autophagy and cellular senescence is associated with each other
in some situations, but these two important cellular processes may be
interdependently involved in the pathophysiology of lung diseases.
Infection and immunity
Autophagy
Autophagy has been implicated in regulation of inflammation and
immunity[41]. In the setting of bacterial and viral infections,
selective autophagic degradation of intracellular pathogens for host defense is
designated as xenophagy. Consistent with other selective autophagy, involvement
of ubiquitination and p62 has been proposed for xenophagic recognition of
intracellular microbes[1].
In the innate
immune response, there is a wide variety of close interactions between
autophagy and the pattern recognition receptors (PRRs), including Toll-like
receptors (TLRs), Nod-like receptors (NLRs), and RIG-I-like receptors (RLRs).
Autophagy can be triggered by TLRs during innate immune signaling[42].
TRAF6-mediated Lys[63] (K63)-linked ubiquitination of Beclin1 is the
mechanism of autophagy activation used by TLR4, and disrupting the association
between Beclin1 and Bcl2 is a proposed mechanism of autophagy activation
mediated by the TLR adaptors, MyD88 and TRIF[43]. NLRs are
components of the inflammasome, an integral part of the innate immune system’s
response to infections and cellular stress. Inflammasome activation results in
the maturation of interleukin 1 (IL-1) and IL-18[44].
Autophagy has been shown to negatively regulate inflammasome activation through
the elimination of dysfunctional mitochondria[45].
In adaptive
immunity, autophagy is also responsible for MHC class II antigen presentation
in thymic epithelial cells (TECs), which is involved in the generation of a
functional and self-tolerant CD4 T-cell repertoire[46]. Furthermore,
autophagy may have a significant role in T-cell function, including survival
and proliferation, via maintaining mitochondrial clearance and ER and calcium
homeostasis[47,48].
Mycobacterium
tuberculosis (Mtb) primarily targets macrophages. Stimulation of autophagy in
infected macrophages significantly reduces the number and viability of
intracellular Mtb[49,50]. Vitamin D3 is a known anti-mycobacterial
immunomodulator, and the active form of vitamin D induces autophagy in human
monocytes via transactivation of Beclin-1 and Atg5[51]. TLRs
activation by Mtb infection induces a variety of inflammatory reactions and
also induces autophagy[52,53]. Intriguingly, TLR-induced signaling
and vitamin D receptor (VDR) signaling synergistically enhance antibacterial
autophagy[54]. ROS-induced autophagy has been proposed to be a
mechanism for killing of intracellular pathogens in macrophages[53]
and the "enhanced intracellular survival" gene of Mtb enhances
intracellular survival of Mtb by modulating ROS-dependent autophagy[55].
Therefore, autophagy plays a key regulatory role in clearance of pathogens and
autophagy induction by appropriate stimuli can be an ambitious therapeutic
option.
Cellular
senescence
The change of immune system with aging is called “immunosenescence”,
which represents deterioration of innate and adaptive immunity resulting in
impaired ability to fight against infection and to respond to vaccination, and
in increase of cancer and autoimmune diseases with aging[56,57].
In innate
immunity, there are two main changes which consist of the presence of chronic
inflammation shown by the increase of IL-6 and TNF- expression, and the decreased
function of specific immune effector cells[57,58]. Chronic
inflammation without obvious infection in the old is called “inflamm-ageing”[58].
Although the number of circulating neutrophils does not change with aging, the
capacity to eliminate phagocytized pathogens and chemotaxis are decreased, and
ROS production was increased in neutrophils in the old[59]. The
number of circulating monocytes does not decrease, but the sterilizing
capacity, the expression of toll-like receptor, and cytokine production, such
as IL-1, IFN, MCP-1, MIP-1, of macrophages
are decreased in the old, which is one of the reasons that infection tends to
be serious[60]. The capacity to antigen presentation of dendritic
cells to translate innate and adaptive immunity is also decreased with aging[61].
The number of natural killer cells is increased with aging, but their capacity
to cytotoxic capacity is decreased[62]. These disabilities of
killing pathogens make the old susceptible to infection and contribute to
morbidity and mortality[60].
In adaptive
immunity, the number of T cells and their function are deteriorated with aging[63].
Although the number of naive T cells is decreased in peripheral blood and
tissues with aging, those of differentiated CD8, CD4 and regulatory T cells are
increased[64]. However, these T cells respond to new antigens less
efficiently[56,57]. CD8 cells accumulate in aged tissues, but do not
proliferate efficiently. CD4 cells show reduced T cell receptor signaling and
cytokine production after antigen binding[65]. The lymphopoiesis of
B cell is decreased, and antibodies produced by B cells have less affinity to
antigens. The ability to undergo class switch recombination is impaired in the
old compared with the young[66].
Kreiling et
al demonstrated that senescent cells accumulated within lungs and other
tissues in the old and enhanced susceptibility to bacterial infection[67].
Although it is clear that cellular senescence with aging impairs the regulation
of immune and inflammatory reactions, the effect of senescence on each kind of
cells remains to be understood. In a mouse model of pneumococcus pneumonia,
rapamycin prevents epithelial cell senescence and regulates the cytokine and
receptor expression required for pneumococcus adherence, and prolongs the
survival of mice by attenuation of lung injury caused by infection[68].
Caloric restriction (CR) has been reported to stimulate lymphopoiesis and
inhibit accumulation of senescent T cells[69]. As shown in these
results including rapamycin and CR, there are a lot of overlap in the role of
autophagy and senescence in infection and immunity. Therefore, the association
of autophagy and senescence is an intriguing issue in this field.
Lung cancer
Autophagy
Both tumor-suppressive and promoting roles have been proposed for
autophagy, which may be dependent on the stage in cancer development[70].
Autophagy suppresses generation of ROS that could damage DNA, which could
contribute to cellular transformation[71,72]. Genetic defects of
autophagy gene ATG7 or heterozygous disruption of the beclin 1 with reduced
autophagic activity increased the frequency of spontaneous malignancies,
indicating that autophagy is a suppressive mechanism of tumorigenesis[73].
Accumulation of p62, reflecting insufficient autophagic degradation, has been
shown to be an independent prognostic factor for non-small cell lung cancer
(NSCLC)[74]. The expression of p62 promotes tumorigenesis through
altered NF-B regulation and
gene expression[75]. Additionally, p62-mediated stabilization of
Nrf2, an important transcription factor for antioxidant protein expression, may
be involved in the survival of tumor cells[76,77].
In contrast,
autophagy can maintain tumor cell survival by protecting cells from oxidative
stress thorugh eliminating damaged organelles and proteins[78,79].
Amino acids supplied by autophagy can be fundamental to survival and
proliferation for established cancer cells[2]. In vitro
experiments demonstrated that autophagy inhibition may be a potential strategy
to overcome the mechanisms of drug resistance to cancer chemotherapy and
radiation in human NSCLC[80,81]. Several clinical trials using
autophagy-inhibiting agents in combination with conventional cytotoxic agents
are active and recruiting as novel modalities of lung cancer treatment[82].
Autophagy is also reported to be a fundamental requirement for maintenance of
tumor stem cells[83]. Whether autophagy has the tumor suppressive or
promoting effects depends on tissues or cells. Systemic influence of autophagy
induction or inhibition should be verified before clinical applications[70].
Cellular
senescence
Various stimuli also induce DNA damage which results in telomere
shortening and cellular senescence, which are barrier to cell transformation
and proliferation[16,84]. When DNA damage is not repaired, damaged
cells are induced to apoptosis or senescence. Therefore, apoptosis and cellular
senescence are important regulatory mechanisms of carcinogenesis. Cellular
senescence is dependent on two major pathways, that is, p53-p21 and p16-pRB
pathways[16,85,86]. Some deficiencies in these pathways may
compromise appropriate cellular senescence and increase the susceptibility to
carcinogenesis[87]. Oncogene-induced senescence (OIS) is induced by
activation of anti-oncogene such as p53, p21, and p16, which are stimulated by
cell proliferation due to oncogene activation[88]. Persistent
activation of Ras oncogene induces OIS associated with mitogen-activated
protein kinase activation, and retinoblastoma protein (pRB) / p53. OIS against
excessive cell proliferation is one of physiological regulatory mechanisms to
inhibit carcinogenesis[89]. Machineries responsible for autophagy
and senescence can coexist in the cell treated with DNA damage agents[90].
As well as
autophagy, senescent cells do not always inhibit carcinogenesis. Rather,
cellular senescence facilitates tumorigenesis[70]. Cancer is an
age-associated disease, and age is the highest risk factor for cancer. Whether
cellular senescence is beneficial or deleterious may depend on the age[18].
Deleterious effects of senescent cells is not senescent cells themselves but
the accumulation of senescent cells, stem cells exhaustion, increasing damage,
and the consequence of the SASP in the microenvironment. When senescent cells
present for long time, SASP affects neighboring cells and induces proliferation
of cancer and cancer-associated cells[91]. In fact, many SASP
factors, such as IL-6, IL-8, and VEGF, are known to promote phenotypes
associated with cancer cells. It is now well known that cancer-associated
senescent fibroblasts secret factors as SASP to promote tumor development[92,93].
Bronchial asthma
Autophagy
Bronchial Asthma is considered a chronic allergic inflammatory disease
with Th2-type cytokine dominance, characterized by reversible airflow obstruction,
airway hyper-responsiveness, and airway wall remodeling[94]. Th1and
Th2-type immune response in viral infection is involved in the development and
exacerbation of bronchial asthma[95]. Autophagy is implicated in the
pathogenic sequence in bronchial asthma in terms of regulation of immunity and
viral clearance[96]. A recent study demonstrates that single
nucleotide polymorphisms (SNP) in ATG5, including a functional promoter
variant, are associated with childhood asthma[97]. Furthermore, a
SNP located in intron 3 of ATG5 is associated with forced expiratory volume in
1 second (FEV1) in asthmatic patients[98]. Although ATG5 is a
crucial component of the autophagy machinery used for viral elimination, the
Atg12-Atg5 conjugate has also been shown to negatively regulate the anti-viral
properties of type I IFN[97,99]. Autophagy is also modulated by both
Th1 and Th2-type cytokines[99,100]. IFN-, a Th1 cytokine, has been
demonstrated to induce, but the Th2 cytokines, IL-4 and IL-13, inhibit
starvation-induced autophagy in macrophages[99]. Airway
hyper-responsiveness is achieved by conditional Atg7 knockout in airway
epithelial cells[101]. Autophagy is also involved in regulation of
ROS production and in elimination of oxidized proteins in order to minimize
tissue damage[98]. Oxidative stress is associated with airway
inflammation in bronchial asthma and exhaled hydrogen peroxide (H2O2)
and nitric oxide (NO) are associated with asthma severity[102].
Oxidative stress is also closely associated with cellular senescence.
Senescence
Bronchial asthma is common in the old. Four to 13% of adults older than
65 years old are estimated to have bronchial asthma[103]. Aged
patients with bronchial asthma tend to be unstable and resistant to treatment,
and about 90% of patients who died of bronchial asthma are the old[104].
The number of neutrophils in bronchial walls is increased in aged patients, and
inflammatory mediators such as MMP-9, elastase, and IL-8 are increased in
sputum from aged patients[105,106]. Eosinophils in bronchial walls
from mouse model of bronchial asthma are increased along with aging, in which
airway wall is intensively remodeled[107]. The serum levels of IL-17
are increased along with aging[108]. IL-17 induces neutrophil
inflammation and Th2 type eosinophilic inflammation in the airways, results in
the acceleration of airway hyper-reactivity+. Chronic inflammation is a major
characteristic of bronchial asthma, and is likely to induce cellular senescence
in epithelial cells in patients with asthma.
In fact, the
expression of senescence marker p21 and p16 are increased in bronchial
epithelial cells, and the expression of type I collagen and -SMA are
increased in the airway walls from patients with bronchial asthma[110].
Thioredoxin reduces gene expression of p21 and prevent airway remodeling in an
asthma mouse model[111]. These results suggest that cellular
senescence in bronchial epithelial cells is increased along with airway
remodeling[112]. Thymic stromal lymphopoietin (TSLP) production from
bronchial epithelial cells is increased in patients with bronchial asthma[113].
TSLP plays a critical role in the inflammatory responses in asthma, through
activating multiple signaling pathways, such as stat3/5, IL-1, and MAP kinases[114].
Wu et al demonstrated that cellular senescence as shown by the
expression of p21 and p16 in bronchial epithelial cells is required for
TSLP-induced airway remodeling in mice, and also showed that epithelial cell
senescence and airway remodeling are abrogated by stat3 inhibition[110].
Telomere
length of neutrophils in the peripheral blood is shorter in patients with
asthma than that of controls[115]. Belsky et al. demonstrated that
asthma seemed to relate to shorter telomere length in cases with childhood
onset and persistent course[112]. They also suggested that the link
between the phenotype of life-course-persistent asthma and telomere length is
related to elevated systemic eosinophilic inflammation. Although the mechanisms
linking the asthma and shortened telomere length are not characterized, the
expression of telomerase reverse transcriptase in the airway wall is reported
to be correlated with telomere shortening in circulating leukocytes from
patients with bronchial asthma[115].
It is reported
that cellular senescence due to shortened telomere length is associated with
the severity of bronchial asthma[112,115,116]. Since the
susceptibility to viral infection is increased along with cellular senescence
of NK cells in the old[117], the deterioration of bronchial asthma
induced by infection may be easy to occur in aged patients. Cellular senescence
may be involved in the effect of aging on the pathophysiology of bronchial
asthma, of which mechanisms is poorly understood. Telomere shortening could be
induced by oxidative stress[118] and asthma is associated with
systemic and bronchial wall inflammation and oxidative stress. Oxidative stress
is associated with senescence and at least in part regulated by autophagy.
Further examination is warranted to clarify the mechanisms of cellular
senescence and autophagy involvement in the pathophysiology of asthma.
Chronic obstructive pulmonary disease (COPD)
Autophagy
Chronic obstructive pulmonary disease (COPD) is one of the leading
causes of death worldwide and is characterized by partially irreversible and
progressive airflow limitation. Cigarette smoke, the major cause of COPD, is
rich in toxic components including ROS, and a variety of biological responses
to cigarette smoke exposure have been demonstrated[2,3,7,8].
Although detailed molecular mechanisms for COPD development remain unclear, the
possible participation of autophagy in the pathogenic sequence of COPD has been
intensively explored. It has been reported that autophagy in lung tissue from
COPD patients is augmented by means of an increase in the LC3B-II/LC3B-I ratio
and Egr-1-induced LC3B expression is essential for autophagy activation[119].
LC3B-/- mouse experiments confirmed the pivotal role of LC3B in epithelial cell
apoptosis induction by cigarette smoke exposure. The proposed mechanism of
LC3B-induced apoptosis is attributed to the balance in a trimolecular
interaction between LC3B with Fas and caveolin-1(Cav-1), a lipid raft protein.
LC3B knockdown inhibits apoptosis by increasing Cav-1-dependent Fas
sequestration and dissociation of Fas and LC3B from Cav-1 in response to CSE
exposure initiates apoptosis in epithelial cells[120]. LC3B is a key
component for autophagy machinery and association between LC3B and Fas is an
interesting observation, however it is still unclear whether autophagy
activation by LC3B expression is crucial for apoptosis induction in this COPD
models. Furthermore, in cases of hyperoxia-induced apoptosis in epithelial
cells, LC3B interacts with Fas, resulting in prevention of apoptosis[121],
suggesting that the role of association between LC3B and Fas in apoptosis
regulation is dependent on the stimuli or experimental conditions.
Intriguingly, decreased autophagy activity in alveolar macrophages derived from
smokers has been reported in terms of impaired xenophagy. In spite of increased
LC3B-II and autophagosomes in macrophages from smokers, impairment of autophagy
flux was shown using protease inhibitors and also by detecting accumulation of
p62 aggregates[122], indicating that autophagy activity in COPD lung
may be regulated via cell type specific mechanisms.
Senescence
COPD has been assumed to be a disease of accelerated lung aging and
cellular senescence has been widely implicated in the pathogenesis of COPD,
presumably by impairing cell repopulation and by the aberrant cytokine
secretion seen in SASP[123-125]. Telomere length of neutrophils of
COPD is shorter than that of healthy controls. Cellular senescence is found in
lung epithelial cells, endothelial cells, and fibroblasts in patients with COPD[124,126].
Autophagy plays a pivotal regulatory role for cellular senescence, hence we
have attempted to elucidate the involvement of autophagy in the regulation of
cigarette smoke extract (CSE)-induced human bronchial epithelial cell (HBEC)
senescence[8]. CSE transiently induces autophagy activation followed
by accumulations of p62 and ubiquitinated proteins accompanied by an increase
in HBEC senescence. Autophagy inhibition by 3MA, a specific inhibitor of
autophagic sequestration, or by LC3B and ATG5 knockdown further enhanced HBEC
senescence with concomitant accumulation of p62 and ubiquitinated proteins[8].
In contrast, autophagy activation by Torin1, a mammalian target of rapamycin
(mTOR) inhibitor, suppressed p62 and ubiquitinated protein accumulations, and
also inhibited HBEC senescence. In line with previous finding of increased
autophagy activation in COPD epithelial cells, we observed an increase in
baseline autophagy, but also found significantly decreased autophagy induction
in response to CSE exposure in HBEC isolated from COPD patients compared to
those from non-smokers[8]. We speculated that the mechanism for
enhanced baseline autophagy flux was attributed to increased oxidative stress,
which was demonstrated by the accumulation of carbonylated proteins in HBEC
from COPD patients[125]. Therefore, it is probable that the
attenuation of autophagy flux in response to CSE exposure may reflect an
insufficient reserve of autophagy activation in HBEC from COPD patients.
Concomitant accumulation of p62 and ubiquitinated protein is also recognized to
at least partly reflect autophagy activity. Increased accumulations of p62 and
ubiquitinated proteins detected in lung homogenates supports the notion that
insufficient autophagic clearance is involved in accelerated cellular
senescence in COPD[8].
Sirtuin family
belongs to Class III histone deacetylases (HDAC), and one of sirtuin family
SIRT1 has extensively studied and well known as an anti-aging molecule because
of SIRT1-mediated longevity by calorie restriction[127]. SIRT1
expression is decreased in the lung tissues from patients with COPD by
oxidative stress and smoking[128]. Decreased SIRT1 expression
results in the increased expression of proinflammatory cytokines due to NF-B activation, and
also results in the acceleration of cellular senescence mediated by the
decrease of anti-senescent activity through FOXO3[129]. Cellular
senescence and emphysema were suppressed in SIRT1 transgenic mice by a
FOXO3-mediated reduction of premature senescence in mice, while those are
deteriorated in SITR1 knockout mice[130]. SIRT1 activator SRT1720
suppressed emphysematous change in mice lung induced by elastase instillation
and smoking inhalation[131].
SIRT6 has been
demonstrated to regulate longevity by modulating insulin-like growth factor
(IGF)-I signaling[132]. IGF-I-signaling activates mTOR and a recent
paper demonstrated that IGF-1 exposure was sufficient to induce cellular
senescence through inhibition of baseline autophagy[133].
Intriguingly, we demonstrated that CSE decreased the SIRT6 expression in HBEC,
and that CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, and
that histone deacetylase (HDAC) activity of SIRT6 was indispensable for
inhibition of CSE-induced HBEC senescence through autophagy activation, which
was mainly attributed to attenuation of IGF-Akt-mTOR signaling[134].
Decreased expression levels of SIRT6 found in lung homogenates from COPD
patients supports the hypothesis that reduced SIRT6 expression with
accompanying autophagy insufficiency may be associated with COPD development
through the enhancement of cellular senescence, especially in the setting of
increased IGF signaling. Furthermore, Decreased SIRT6 expression was
significantly correlated with the decrease of FEV1%[134]. As IGF-1
shares receptors and signaling pathways with insulin, and type 2 diabetes
mellitus with hyperinsulinemia is a common comorbidity in COPD, it may be
associated with COPD development via increased IGF/ insulin signaling and
autophagy inhibition, especially in cases of decreased SIRT6 expression.
Mitochondria
are the main organelle producing ATP as well as reactive oxygen species (ROS),
and play central roles in cell fate regulation. Mitochondria also release
mitochondrial DNA as one of damage associated molecular pattern. Therefore,
maintenance of mitochondria homeostasis is prerequisite for cellular
homeostasis[135]. Mitochondria are dynamic organelles, which
continuously change their shape through fission and fusion. Damaged and
fragmented mitochondria are removed through mitochondria specific autophagic
degradation (mitophagy). Disruption of mitochondrial dynamics is involved in
disease pathology through excessive reactive oxygen species (ROS) production[136].
In electron microscopic examination of lung tissues, we demonstrated that
mitochondria in bronchial epithelial cells tended to be fragmented in COPD,
suggesting the fission process dominancy of mitochondrial dynamics in COPD
pathogenesis[137]. In vitro studies further confirmed that
CSE-induced excessive fragmentation of mitochondria is associated with
mitochondrial ROS production, resulting in HBEC senescence. Autophagy inducer
Torin1 accelerate degradation of damaged mitochondria in autophagosome,
resulted in the increase of healthy mitochondria[137].
The phosphatase and
tensin homolog (PTEN)-induced putative protein kinase 1 (PINK1)-PARK2 pathway
has been largely implicated in the removal of damaged mitochondria with
depolarized membranes. Stress-induced membrane depolarization stabilizes PINK1,
resulting in recruitment of PARK2, an E3-ubiquitin ligase, to mitochondria[138,139].
We found that PARK2-mediated ubiquitination is crucial for mitophagic
degradation in damaged mitochondria in HBEC. Knockdown of PINK1 or PARK2
decreased autophagy activation, the accumulation of damaged mitochondria
accompanied by increased ROS production and cellular senescence in HBEC[140].
PARK2 expression in lung tissue from patients with COPD was significantly
decreased compared with that from smokers without COPD. The decreased PARK2
expression was significantly correlated with the decrease of FEV1%.
Immunohistochemistry results showed the expression of PARK2 in bronchial
epithelial cells from patients with COPD was significantly decreased compared
with that from nonsmokers or smokers without COPD. Therefore, the decrease of
PARK2 expression may be associated with the deficiency of mitophagy and
cellular senescence in COPD pathogenesis[140].
Idiopathic pulmonary fibrosis (IPF)
Autophagy
Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial
pneumonia of unknown cause, but is influenced by a combination of genetic,
epigenetic, and environmental factors[141]. IPF is usually a lethal
disease with poor prognosis, with a 3-year median survival time from the time
of diagnosis and no current conventional medical intervention available to
extend life span[141]. IPF is characterized pathologically by
irregular scars composed of dense collagen fibrosis alternating with areas of
fibroblastic proliferation, as well as cystic remodeled airspaces lined by
metaplastic epithelium, corresponding to the usual interstitial pneumonia (UIP)
pattern[142]. Advanced age is one of the most important risk factors
for development of IPF, of which the prevalence is increased with aging[141].
Autophagy has
been implicated in the pathogenesis of bleomycin-induced pulmonary fibrosis in
mouse, and neutralization of IL-17A attenuated bleomycin-induced pulmonary
fibrosis and increased survival in epithelial cells via autophagy[143].
A recent paper demonstrated decreased autophagy flux as measured by p62
accumulation, as well as reduced LC3-II expression levels in lung tissue
homogenate from IPF patients[144]. The authors also proposed that
TGF--mediated
autophagy inhibition in fibroblasts is responsible for myofibroblast
differentiation[144]. Additionally, increased endoplasmic reticulum
(ER) stress responses have been demonstrated in metaplastic epithelial cells in
IPF lung and ER stress response is known to induce autophagy, which removes the
disorganized proteins to relieve cellular stress[145]. We
demonstrated that both overlaying epithelial cells and fibroblasts in
fibroblastic foci (FF) express both ubiquitin and p62, which appeared to
reflect insufficient autophagy[146]. FF comprised of myofibroblast
accumulations is recognized to be the leading edge of fibrogenesis, and the
number of FF is a potential prognostic measure[147], further
indicating the possible involvement of insufficient autophagy in IPF
pathogenesis.
Interestingly, our in vitro experiments demonstrated that autophagy
inhibition by knock down of LC3B and ATG5 was sufficient to induce
myofibroblast differentiation of -smooth muscle actin (SMA) and type I collagen expressions in lung
fibroblasts even in the absence of TGF-[146]. Furthermore, in
contrast to recent findings[144], TGF- clearly induced autophagy as shown
by increased LC3-II and decreased p62 levels, and autophagy inhibition further
enhanced TGF--induced
myofibroblast differentiation[146]. Therefore, TGF--induced
autophagy may have a negative regulatory role in myofibroblast differentiation,
which is partly consistent with a recent report in primary mouse mesangial
cells[148].
As potential
mechanisms leading to insufficient autophagy in IPF lung, we speculate the
involvement of chronic and latent viral infections, which have been widely
implicated in IPF pathogenesis via chronic inflammation and increased apoptosis
induction[149]. Viral infections have been known to interfere with
autophagy not only to prevent xeophagic degradation but also to modulate immune
responses[41]. Another possibility is aberrant activation of the
PI3K-Akt-S6K1 signal pathway in response to polymerized collagen in IPF
fibroblasts, which is conferred by low PTEN activity[150]. mTOR, a
negative regulator for autophagy, is a part of the PI3K-Akt-S6K1 signaling
pathway, thus it is plausible that low PTEN activity may also be involved in
autophagy inhibition through aberrant mTOR activation. Furthermore, IPF is
recognized to be a disease of aging, and autophagy diminishes with aging[7].
Although it is difficult to distinguish cause from consequence of disease
progression, accelerated cellular senescence in epithelial cells in IPF may
also be involved in the mechanism for insufficient autophagy, although that is
not the case in fibroblasts.
Senescence
Telomeres protect chromosome ends from erosion and shorten with each
cell division, and once a critical length is reached, cells were induced to
cellular senescence or apoptosis. Telomerase restores telomere length, which
consists of two essential components, telomerase reverse transcriptase (TERT)
and telomerase RNA (TERC). Loss-of-function mutations in TERT have been found
in 15% of familial interstitial pneumonia (FIP) and in 3% of sporadic IPF[151,152].
These patients showed significantly shorter telomeres length in peripheral
blood lymphocytes and granulocytes. In sporadic IPF, these mutations are less
common; however, telomere shortening is similar to those of FIP in peripheral
blood leukocytes and alveolar epithelial cells compared with those of healthy
controls[153,154]. Recently, 9 nucleotide polymorphisms including
TERT gene were identified to be associated with IPF susceptibility in Japanese
patients[155].
Telomere
attrition is induced by oxidative stress, smoking as well as aging, which are risk
factors which have been implicated to have a role in the pathogenesis of IPF.
TGF-β plays central roles in fibrogenesis and is highly expressed in lung
tissues of IPF. TGF-β suppresses telomerase expression and may affect telomere
shortening. Weisberg et al demonstrated that the decrease of telomerase
expression was correlated with apoptosis of type II alveolar epithelial cells
in lung tissues from patients with IPF[156]. They suggested that low
ratio of telomerase / apoptosis reduced regenerative capacity in injured lungs,
which subsequently resulted in fibrosis. Zhou et al showed that
telomerase activation ameliorated epithelial cell senescence and lung injury in
bleomycin-induced pulmonary fibrosis in mice, and aged mice were susceptible to
this fibrosis model[157]. Paradoxically, Liu et al
demonstrated that bleomycin-induced pulmonary fibrosis was attenuated in
telomerase-deficient mice, and suggested that inactivation of damaged and
misdirected fibroblasts by senescence due to telomerase deficiency may be
beneficial to the body[158]. Collectively, these results suggest
that telomere shortening rather than telomere gene abnormality itself affects
the pathophysiology of IPF. Since telomere shortening and cellular senescence
is closely associated with each other, and increased cellular senescence is a
major feature of aging, cellular senescence is proposed to be a part of the
pathogenic sequence of IPF.
As the
initiation of epithelial cell damage in IPF, proapoptotic factors such as ROS,
TGFβ, and Fas ligand induce apoptosis in epithelial cells, while resistant
cells against apoptosis or senescence migrate and proliferate to repair damaged
tissues. TGF-β induces cellular senescence as well as apoptosis in bronchial
epithelial cells[146,159]. Regenerated epithelial cells appear
cuboidal metaplasia and bronchiolization and cover remodeled tissues. We have
found accelerated senescence of epithelial cells, including metaplastic cells
and bronchiolization, in active fibrosing lesions of IPF[146].
Furthermore, interleukin (IL)-1β secretion as SASP by senescent HBEC was
sufficient to induce myofibroblast differentiation in lung fibroblasts,
possibly playing a key role in fibrosis development[146] (Figure 1).
Additionally,
we hypothesized that epithelial cell senescence in IPF is at least partly
attributed to insufficient autophagy to relieve ER stress. In the results of
our study, tunicamycin (TM), an inducer of ER stress via disruption of protein
glycosylation, accelerated HBEC senescence especially in the setting of
insufficient autophagy[10]. Interestingly, our in vitro experiments
demonstrated that autophagy inhibition by knock down of LC3B and ATG5 was
sufficient to induce myofibroblast differentiation indicated by -smooth muscle
actin (SMA) and type I collagen expression in lung fibroblasts even in the
absence of TGF-β[10]. Taken together, insufficient autophagy may be
an underlying mechanism of accelerated epithelial cell senescence and
myofibroblast differentiation in IPF pathogenesis. Considering the insufficient
autophagy and cellular senescence, we demonstrated that immunohistological
staining of p21 and SA-βGal staining were prominent in only epithelial cells
covering actively fibrosing lesions, including FF. In contrast, no cellular
senescence was observed in fibroblasts regardless of whether the fibrosis was
mild or severe, suggesting that autophagy regulation of cellular senescence is
a cell-type specific[10].
Collectively,
it is plausible that accelerated senescence of epithelial cells plays a role in
IPF pathogenesis through perpetuating abnormal epithelial-mesenchymal
interactions by SASP such as IL-1β secretion. Cellular senescence and
insufficient autophagy has been implicated in the pathogenesis of IPF as well
as COPD. Cellular senescence in epithelial cells from patients with IPF has
characteristics of premature senescence but also programmed senescence, which
is also involved in embryonic organogenesis, which may be distinct from
cellular senescence involved in COPD pathogenesis[160].
conclusion
An aging society has problem with various diseases associated with
aging. In particular, lung diseases have much attention because COPD,
pneumonia, and lung cancer are speculated to be third, fourth, and fifth,
leading cause of death in the world, respectively. Autophagy is responsible not
just for simple homeostatic energy supply but also for elimination of aggregate
prone proteins, damaged organelles, and intracellular microbes and also for
regulation of innate and adaptive immunity as a central component of the
integrated stress response. Autophagy is a dynamic process and may rapidly
change its status, which can be influenced by not only disease activity but
also environmental stresses. Additionally, the regulatory role of autophagy can
be dependent on stages in disease development and the pathogenic involvement
may be different in a cell-type specific manner.
Cellular
senescence is the most closely associated with aging processes, therefore,
therapies targeting cellular senescence should be important strategies against
various lung diseases. Cellular senescence is thought to be caused by
insufficient regulatory mechanisms of homeostasis. Classic “free radical
hypothesis” means that ROS induces cellular senescence. Many reports have shown
that mitochondrial dysfunction leads to cellular senescence due to excessive
ROS production. The treatment strategy against cellular senescence through
induction of autophagy, especially mitophagy, may be promising against lung
diseases associated with aging (Figure 2).
Recent
advances in autophagy and senescence shed more light on understanding the
pathogenesis of variety of pulmonary diseases and may lead to the development
of new therapeutic options. For future directions, the development of proper
biomarkers reflecting autophagy status and senescence is warranted to precisely
evaluate autophagy and senescence status during disease progression. It is also
warranted to establish novel therapeutic approaches to achieve optimal levels
of autophagy status and cellular senescence.
CONFLICT OF
INTERESTS
The Author has no conflicts of interest to declare.
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Peer reviewer: Marco Malavolta,
INRCA, Scientific and Technological Pole, via Birarelli 8, Ancona,
60121, Italy.
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