INVITED REVIEW
Heme oxygenase: colors of defense against cellular stress
Leo E.
Otterbein1 and
Augustine M. K.
Choi1,2
1 Division of Pulmonary, Allergy, and Critical Care
Medicine, University of Pittsburgh School of Medicine, Pittsburgh,
Pennsylvania 15213 and 2 Division of Pulmonary and Care
Medicine, Yale University, New Haven, Connecticut 06520
 |
ABSTRACT |
The
discovery of the gaseous molecule nitric oxide in 1987 unraveled
investigations on its functional role in the pathogenesis of a wide
spectrum of biological and pathological processes. At that time, the
novel concept that an endogenous production of a gaseous substance such
as nitric oxide can impart such diverse and potent cellular effects
proved to be very fruitful in enhancing our understanding of many
disease processes including lung disorders. Interestingly, we have
known for a longer period of time that there exists another gaseous
molecule that is also generated endogenously; the heme oxygenase (HO)
enzyme system generates the majority if not all of the endogenously
produced carbon monoxide. This enzyme system also liberates two other
by-products, bilirubin and ferritin, each possessing important
biological functions and helping to define the uniqueness of the HO
enzyme system. In recent years, interest in HO has emerged in numerous
disciplines including the central nervous system, cardiovascular
physiology, renal and hepatic systems, and transplantation. We review
the functional role of HO in lung biology and its real potential
application to lung diseases.
carbon monoxide; oxidative stress; acute lung injury; stress
response genes
 |
INTRODUCTION |
OVER ONE HUNDRED AND FIFTY YEARS AGO,
a scientist by the name of Virchow (106)
recognized that there was an association between hemoglobin breakdown
and biliverdin. It was not until 1926, however, that this
association was more formally established by Mann et al.
(56). But certainly the manifestations of this metabolic process were recognized hundreds if not thousands of years earlier because the catabolism of heme is the only biological process in humans
that is colorimetric. After receiving a blow to the skin, primitive man
would have observed shortly thereafter a bruise that was black or
purple. These are colors of heme, released into the dermis from
pulverized erythrocytes. The black hue (heme) gradually transformed to
green, the color of biliverdin, and finally to yellow, the color of
bilirubin, the concluding product of this elegant enzymatic reaction.
To this day, investigators have been intrigued by the role of this end
product as well as that of ferritin, the iron storage protein in the
cell induced by the release of free iron and carbon monoxide (CO) and
released in equimolar concentrations as heme anabolism transpires (see
Fig. 1).
 |
HEME OXYGENASE |
Heme oxygenase (HO) was originally identified in 1968 and 1969 by
Tenhunen et al. (100, 101) in seminal papers where
they characterized the enzyme HO as well as its cellular localization. HO catalyzes the first and rate-limiting step in the degradation of
heme. Via oxidation, HO cleaves the
-meso carbon bridge of b-type
heme molecules to yield equimolar quantities of biliverdin IXa, CO, and
free iron. Biliverdin is subsequently converted to bilirubin via the
action of biliverdin reductase, and free iron is promptly sequestered
into ferritin. To date, three isoforms (HO-1, HO-2, and HO-3) that
catalyze this reaction have been identified (1, 54, 60,
61). HO-1 is a 32-kDa protein that is inducible by numerous
stimuli (Table 1) and is the principal
focus of this review. HO-2 is, for the most part, a constitutively
synthesized 36-kDa protein existing primarily in the brain and testes.
HO-3, a recently cloned gene product 33 kDa in size, also catalyzes heme degradation but much less than HO-2. Under physiological conditions, HO activity is highest in the spleen where senescent erythrocytes are sequestered and destroyed, but its activity has also
been observed in all systemic organs.
Although heme is the typical HO-1 inducer, studies by Keyse and Tyrrell
(41), Maeshima et al. (53), and Vile
and Tyrrell (105) demonstrated that HO enzyme
activity could also be stimulated by a variety of nonheme products
including ultraviolet irradiation, endotoxin, heavy metals, and
oxidants such as hydrogen peroxide. One common feature of these
inducers is their capacity to generate reactive oxygen species. Thus
these studies not only demonstrated that HO-1 can be induced by agents
causing oxidative stress but also supported the speculation that HO-1
can function as a cytoprotective molecule against oxidative stress.
Indeed, ample evidence currently supports the notion that HO-1 serves
to provide potent cytoprotective effects in many in vitro and in vivo
models of oxidant-induced cellular and tissue injury.
 |
INDUCTION OF HO-1 EXPRESSION |
Table 1 illustrates a list of the agents that when administered to
cells or animals result in an increase in HO-1 expression. The list
represents a wide variety of nonheme inducers of this enzyme, the scope
of such indexes giving rise to a fundamental question as to the
functional role(s) of the increased levels of this ubiquitous enzyme.
Although the function of this enzyme is still incompletely understood,
accumulating evidence to date strongly suggests that the endogenous
induction of HO-1 provides potent cytoprotective effects in various in
vitro and in vivo models of cellular and tissue injury (34, 75,
93). This evolving paradigm is further supported by observations
made in the HO-1-deficient [HO-1(
/
)] mouse and human. Poss and
Tonegawa (80, 81) in 1997 generated HO-1(
/
) mice by
targeted deletion of the mouse HO-1 gene. The majority of these
HO-1(
/
) mice do not survive to term, and the mice that do survive
to adulthood are abnormal and die within one year of birth (80,
81). These adult mice exhibit growth retardation and
normochromic, microcytic anemia. Kidneys and livers from these mice
show evidence of iron deposition, and as these HO-1(
/
) mice
age, they also demonstrate an increased presence of chronic
inflammation characterized by hepatosplenomegaly, leukocytosis, glomerulonephritis, and hepatic periportal inflammation. These authors also reported that cells obtained from these mice are more
susceptible to oxidative stress induced by endotoxin. A recent report
(111) demonstrating the first identified case of a
HO-1-deficient human patient lends additional support to the evolving
paradigm that HO-1 serves to provide cytoprotection against oxidative
stress. This patient exhibited similar phenotypic alterations as those observed in the HO-1(
/
) mice, including growth retardation, anemia,
leukocytosis, and increased sensitivity to oxidant stress.
The critical importance of HO is also demonstrated by recent reports
(47, 65) that HO expression is
conserved evolutionarily. It has been detected in prokaryotic bacteria
as well as in plants and fungi. This conservation suggests that HO may
play a role in diverse species as a modulator of cellular homeostasis,
serving not only to degrade heme but also, via one or more of its
catabolic by-products, to regulate a variety of critical cellular
processes. For example, in plants, it is believed that HO possesses
dual functions, one that generates tetrapyrroles and another that
recycles heme and chlorophylls, both being important after damage to
the photoreactive centers (65). In most bacteria, iron is
required for survival and is particularly essential for pathogens to
cause disease. To circumvent the low concentration of free
extracellular iron, pathogenic bacteria have developed sophisticated
mechanisms by which to acquire iron from iron-containing proteins found
in their hosts. One such mechanism exploits a bacterial heme
degradation enzyme similar to HO (47). In contrast to the
mammalian HO, the primary purpose of which is to maintain iron
homeostasis, the purpose of the bacterial HO is to release iron from
heme so that the iron may be immediately utilized. Such conservation
among species that express and regulate this enzyme gives credence to the belief that HO is critically important in maintaining cellular homeostasis.
Table 2 illustrates a list of
disease states that have been associated with the increased expression
of HO-1. Most recently, Schipper et al. (87) have
described the use of HO-1 expression as an indicator of cellular stress
and injury. Plasma and cerebrospinal fluid samples collected
from Alzheimer's patients were analyzed by ELISA for HO-1 induction
and found to be elevated in the blood of pathologically confirmed
Alzheimer's patients (87). Although oxidative stress has
been well described as a potent inducer of HO-1, this study presented
the first reported evidence that suggested that HO-1 expression can be
used as a diagnostic tool to evaluate patients with this disease.
Indeed, these authors proposed that HO-1 levels can be used as a
biological marker to diagnose and monitor those with this disease.
Investigators (37, 77) have reported
using the detection of CO as a measurable marker in the exhaled breath
of patients as an index of oxidative stress and inflammation. Bilirubin
has also been used as a marker of liver injury and neonatal jaundice
for years and continues to provide valuable information as a biological
marker.
 |
MECHANISM(S) OF CYTOPROTECTION BY HO-1 |
The increased expression of HO-1 levels in a variety of
pathological states begs the question as to the functional role for this heme catalyzing enzyme. Keyse and Tyrrell (40,
41), followed shortly thereafter by Nath et al.
(66), demonstrated in critical studies that HO-1 provided
cytoprotection against oxidative stress, particularly if HO-1 was
induced before the stress. These two studies prompted increased
investigations of this enzyme in disorders that do not relate to heme
catabolism. Ample evidence now strongly suggests that HO-1 can function
as a critical cytoprotective molecule. The mechanism(s) by which HO-1
can mediate these cytoprotective functions is not clear. However, the
three major catalytic by-products, CO, ferritin, and bilirubin may
represent potential targets.
CO.
CO is one of the most commonly encountered toxic agents because it
interferes with O2 delivery to cells and tissues. It is, after carbon dioxide (CO2), the most abundant atmospheric
pollutant, emanating slowly from natural sources such as volcanoes and
forest fires but more rapidly and abundantly as a by-product of
industrial and technological activity (e.g., the combustion engine). In
1857, Claude Bernard described the affinity of CO for
hemoglobin, thus initiating research that eventuated in an essentially
universal scientific tenet assigning CO to the category of poisons and
toxins that later came to include arsenic, nicotine, and opium. Before this time, it was common practice in Europe to pacify infants by
holding them over a fire where CO-induced cerebral anoxia could exert
its sedating and soothing effects. Since Bernard's discovery of the
CO-hemoglobin affinity, the particulars of that association as well as
its lethal consequences have been well delineated. In 1927, Nicloux
discovered a baseline carboxyhemoglobin level in dogs and concluded
that CO originated in the body itself. A year earlier, in 1926, Campbell was already calling the gas a "poison," a label that over
the years has become as essential and self-evident a feature of its
conceptualization as its atomic structure. In 1972, Weinstock and Niki
observed, with a palpable trace of ironic understatement: "Carbon
monoxide may be the basis of energy metabolism in some extraterrestrial
civilization. Certainly endogenous CO metabolism is of less importance
to life on earth."
The dangers of CO have been well defined. By binding avidly to
hemoglobin, it replaces O2, induces general hypoxia,
increases the stability of oxyhemoglobin by shifting the dissociation
curve to the left, and impedes O2 delivery to the tissues.
Furthermore, dissociation of CO2 is impaired, thus
producing an increase in blood CO2 levels and removing the
reflex stimulus to the respiratory centers in the brain. In addition,
because no change occurs in the dissolved O2 levels in the
blood, the carotid sinus detects no disparity because it responds only
to partial pressure; so it likewise sends no signals to the respiratory
centers of the brain that would otherwise force the individual to
breathe more often to increase the blood O2 levels.
Because of its strong affinity for hemoglobin, the primary toxic effect
of CO is hypoxia or anoxia. Increases in combustion through the use of
fossil fuels over the past century and consequent increases in CO
levels in the atmosphere have heightened public awareness of exposure
to this gas and its noxious potential. The Environmental Protection
Agency via various media instills in the public mind a need to avoid
this gas, recommending elaborate protective alarms and detectors and
publishing allowable exposure limits. The number of studies
investigating these issues, particularly those relating to the toxic
effects of CO, is immense. In 1970, the New York Academy of Sciences
held a symposium on the physiological effects of exposure to this gas
to address these issues. Toxicologists have outlined quite precisely
the pathophysiological effects resulting from exposure to CO as shown
in Table 3.
Among all the negative connotations associated with this gaseous
molecule, evidence accumulating in the past five years is beginning to
shed new light on this historically categorized poison. At high
concentrations, CO is unquestionably lethal. But recent studies
(55, 64, 104) consistently support the emerging idea that
CO at low concentrations exerts distinctly different effects on
physiological and cellular functions, this revelation motivating the
need to reevaluate its role.
Certainly, contemporary neurobiologists and vascular biologists believe
it is important in their systems. The pioneering work of Snyder et al.
(92) and Morita and Kourembanas (62) have clearly shown that CO generated from HO, the primary if not exclusive source of CO generation in the body, can regulate vasomotor tone as
well as neurotransmission. These findings provided the first evidence that this simple gaseous molecule could impart critical biological functions akin to NO. Just as NO functions as a signaling molecule, so does CO play an important role in regulating
vasomotor tone by promoting vasorelaxation (84).
Furthermore, Yet et al. (114) have also observed that
HO-1(
/
) mice exhibited a maladaptive response to chronic
hypoxia, with the development of right ventricular infarcts and
organized mural thrombi resulting in pulmonary hypertension (114). This regulatory function may indeed account for the
anti-inflammatory effects of HO-1 expression in endothelial and smooth
muscle cells because vasorelaxation may allow maintenance of blood flow
at sites of inflammation, such relaxation countering those effects of
coagulation and thrombosis that can lead to anoxia and tissue necrosis.
These effects of CO are mediated through the activation of guanylyl
cyclase on the binding of CO to the heme moiety of this enzyme and
subsequent cGMP generation (12). But the vasodilator function of CO is thought to be 50-100 times less potent than that
of NO based on the capacity of both molecules to activate guanylyl
cyclase, the common mediator of these molecules in modulating smooth
muscle cell relaxation and vasodilatation (113). However, the relative inefficiency of CO in binding guanylyl cyclase may be
largely neutralized because although NO is extremely reactive and
labile, CO is chemically very stable. Unlike NO, CO reacts exclusively
with heme and thus can accumulate in the cell to levels that are
presumably much higher then those of NO. CO may also possess
anti-inflammatory effects such as the capacity to inhibit platelet
activation or aggregation through activation of guanylyl cyclase and
subsequent generation of cGMP. Furthermore, CO when administered
exogenously to rats or mice at very low concentrations can provide
protection in models of lung injury (72, 73).
Recent studies also suggest that changes in CO measurements in exhaled
breath are indicative of increased HO-1 activity and cellular stress
and therefore can be correlated with the severity of some disease
processes. For example, Paredi et al. (77) and Yamara et
al. (113) have shown increased CO in the breath of patients with disease processes as diverse as asthma and diabetes (77, 113).
Biliverdin and bilirubin.
Bilirubin is the most abundant endogenous antioxidant in mammalian
tissues, accounting for the majority of the antioxidant activity of
human serum (32). Bilirubin has been shown to be a potent
antioxidant in the brain, acting to scavenge peroxyl radicals as
efficiently as
-tocopherol or vitamin E (94). Bilirubin is best known, however, as a potentially toxic agent that accumulates in the serum of neonates, causing jaundice. In high concentrations, it
deposits in selected brain regions to elicit neurotoxicity associated
with kinicterus (33). On the other hand, neonatal jaundice
could also have a protective effect for the infant arriving for the
first time into an unsterile environment. In a recent report,
Vachharajani et al. (103) observed that administration of
biliverdin to rats modulates lipopolysaccharide-induced P- and
E-selectin expression in the vascular system, providing evidence that
bilirubin is able to modulate this inflammatory response regardless of
the influences of HO-1, CO, and/or ferritin (103).
Biliverdin administration to rodents has also recently been shown to
provide protection in a rat model of ischemic heart injury (103). Another report by Dore et al. (25)
further demonstrated that bilirubin manifests cytoprotective properties
in a model of hydrogen peroxide-induced oxidative injury to neurons as
does a report by Clark et al. (18) who showed that
bilirubin administration in a model of ischemic heart injury is
protective, suggesting that this end product of heme catabolism is more
than a waste product that simply requires elimination.
Ferritin.
The release of free iron (its two free electrons capable of generating
the vicious hydroxyl radical) through Fenton chemistry with the
superoxide radical is rapidly sequestered into the iron storage protein
ferritin (Fig. 1). Such sequestration can itself lower the prooxidant
state of the cell by removing the free iron (8). Vile and
Tyrrell (105) showed that ferritin levels increase in the
presence of oxidative stress such as ultraviolet irradiation. This
HO-1-dependent release of iron also results in the upregulation of
ferritin, which might provide protection after irradiation. Eisenstein
et al. (27) clearly showed that ferritin is increased in
tandem with HO-1 and decreased with inhibition in HO-1 activity. Balla
et al. (9) also showed that induction of ferritin was cytoprotective in a model of oxidant stress, demonstrating that cytotoxicity was greatly reduced and occurred independently of HO-1
activity. Finally, Otterbein et al. (71), in a model of endotoxic shock, demonstrated that when iron is chelated by the exogenous iron chelator desferoxamine, no ferritin is induced and
protection is ablated.
Another recent report (10) demonstrated that
overexpression of HO-1 also upregulates and interacts with an iron
ATPase present in the endoplasmic reticulum. This iron pump is thought
to limit intracellular iron content once HO-1 activity is upregulated. This limiting effect may be particularly important when cells are
exposed to high levels of heme that increase HO-1 activity, thus
generating high levels of intracellular free iron. The ability of cells
expressing HO-1 to decrease iron content has recently been suggested to
account in large measure for the antiapoptotic effects of HO-1
(15, 78, 89). Other molecules that chelate intracellular
free iron are also thought to prevent apoptosis, suggesting that
upregulation of ferritin by HO-1 may have a similar effect in
preventing apoptosis.
 |
HO-1 EXPRESSION IN THE LUNG |
Like many of the organ systems affected by the pathologies listed
in Table 2, the lung is no exception with regard to the induction of
HO-1. The induction of HO-1 has been demonstrated in many models of
lung injury including hyperoxia, endotoxemia, bleomycin, asthma, acute
complement-dependent lung inflammation, and heavy metals. The
physiological function of this robust HO-1 induction primarily points
to the cytoprotective effects of HO-1. In an in vitro model of
oxidative stress with stably transfected HO-1-overexpressing pulmonary
epithelial cells, Lee et al. (48) demonstrated that these
cells exhibited increased resistance to hyperoxic cell injury. Similar
protective effects of HO-1 were also observed by Suttner et al.
(98) in rat fetal lung cells exposed to hyperoxia. In
studies by Petrache et al. (78) and Soares et al.
(93), HO-1 also prevented tumor necrosis factor (TNF)-
-mediated apoptosis in fibroblasts and endothelial cells, respectively. Such findings further substantiated the involvement of
HO-1 in cytoprotection. These findings, however, are not without controversy. Dennery et al. (21) demonstrated that
HO-2-null mice were sensitized to hyperoxia-induced oxidative injury
and mortality despite increased HO-1 expression. Furthermore, Suttner and Dennery (97) have also observed that moderate
overexpression of HO-1 in fibroblasts is protective against oxidative
injury, whereas high levels of HO-1 expression can be associated with significant O2 cytotoxicity. These authors speculate that
the accumulation of reactive iron released from the catalysis of heme may impart cellular cytotoxicity.
Rodent models of septic shock and hyperoxic lung injury represent two
clinically relevant research models in the study of lung injury. Each
provides pertinent information that can lead to a better understanding
of clinical disease because although they diverge in terms of their
relative cytotoxic etiologies and tissue injury dynamics, they are
closely intertwined at the intracellular level. Both generate enormous
amounts of reactive oxygen species that represent the fundamental
underlying mechanisms responsible for tissue injury. Otterbein and
colleagues (71, 72, 74) have demonstrated that HO-1
induction correlated with cytoprotection against oxidative stress in
vivo. Using hyperoxia as a model of acute respiratory distress syndrome
in rats, they hypothesized that the exogenous administration of HO-1 by
gene transfer would confer protection against oxidant-induced tissue
injury. Adenoviral gene transfer of HO-1 (Ad5-HO-1) into the lungs of
rats resulted in increased expression of HO-1 and, more importantly, a
marked resistance to hyperoxic lung injury (74). Rats
treated with Ad5-HO-1 showed reduced levels of hyperoxia-induced
pleural effusion, neutrophil alveolitis, and bronchoalveolar lavage
protein leakage. Furthermore, rats treated with Ad5-HO-1 showed
increased survivability against hyperoxic stress versus those treated
with the vector control virus AdV-
Gal. These data are supported by
Taylor et al. (99), who demonstrated that intratracheal
administration of hemoglobin, a major inducer of HO-1, also provided
protection from hyperoxic lung injury. They concluded, however, that
the protection was perhaps conferred via ferritin and not directly by
HO-1.
In view of the observations that exogenous administration of HO-1 via
transgene delivery provided cytoprotection against hyperoxia in rats,
Otterbein et al. (75) then examined whether exogenous CO
could impart similar cytoprotective effects. Indeed, CO at low
concentrations [10-500 parts/million (ppm)], well tolerated both
by rodents and cells, provided protective effects against hyperoxia
similar to those observed in the transgene studies (104). Previous work by Stupfel and Bouley (96) had clearly shown
that rodents can be exposed to 500 ppm CO continuously for up to 2 yr
without deleterious effects on multiple physiological and biochemical parameters. Based on these studies and many others, concentrations chosen for exposures ranged from 50 to 500 ppm. Rats exposed to hyperoxia in the presence of a low concentration of CO (250 ppm) were
similarly protected from hyperoxic stress, with reduced markers of
injury and increased survivability. These studies strongly suggested
that CO exerted its protective effects via anti-inflammatory and/or
antiapoptotic effects.
These results provided the direction for the next series of studies in
which an attempt was made to delineate the potential mechanism(s) by
which CO provided cytoprotection against oxidative stress. Otterbein et
al. (73) hypothesized that CO mediated the
anti-inflammatory effects, thus providing the potent cytoprotection. This hypothesis was tested in vivo in mice and in vitro in RAW 264.7 macrophage cells. CO inhibited the lipopolysaccharide-induced proinflammatory cytokines TNF-
, interleukin (IL)-1
, and
macrophage inflammatory protein (MIP)-1
but augmented the
anti-inflammatory cytokine IL-10 expression in vitro.
Likewise, inhibition of the proinflammatory cytokine TNF-
and
augmentation of the cytokine IL-10 were also observed in vivo.
Because of the evidence that cGMP serves as an important mediator
involved in CO and NO signaling in other model systems, in particular
the central nervous system and vascular cells, Otterbein et al.
(73) examined whether CO mediated the anti-inflammatory
effects via the guanylyl cyclase/cGMP pathway. Interestingly, cGMP was
not involved, but rather the observed anti-inflammatory effects of CO
were dependent on the mitogen-activated protein kinase kinase
(MKK-3)/p38 mitogen-activated protein kinase pathway. Further
studies (73) to corroborate the involvement of
p38 in the mechanism producing the CO effects were performed in mice
deficient in MKK-3, the major upstream kinase activator of p38.
Endotoxin administration to MKK-3-deficient mice exposed to air
resulted in the inhibition in TNF-
as expected but with no
additional inhibition when exposed to CO. Further examination revealed
that IL-10 levels were not augmented in the presence of CO in these
mice as observed in the wild-type littermates. These findings confirmed
the involvement of the MKK-3/p38 pathway in the effects observed with CO.
 |
CONCLUSIONS |
Although the mechanism(s) mediating HO-1-induced cytoprotection
remains elusive, recent data point to one of the by-products of heme
catabolism [CO, Fe2+ (ferritin), or bilirubin] as
potential mediators of HO-1 cytoprotection. Even though each product
has been shown to be protective, it could indeed be a combination of
the three by-products that act adaptively to protect the cell and
tissue from further insult. Although progress has been made in our
understanding of the function of HO-1 after oxidative stress, there is
much work to be done to delineate more clearly the role of HO-1
induction in lung biology and pathology. The players (CO, ferritin, and
bilirubin) have been identified, but the destinies and interactions
among these characters remain elusive; gas molecules, metal ions, and
organic antioxidants, all intermingling within the cellular milieu
affecting biological processes, all categorically toxic, all possess
some manner of physiological function in the vastly complex cellular
and molecular environment. At some point, investigators may fully
understand the interplay of these characters and, most importantly, the
mechanism by which this remarkable enzyme invokes the colors of defense against a plethora of insults. And hopefully, in the near future, this
knowledge will help in the discovery of novel therapeutic modalities
with which to treat acute lung injury as well as a multitude of other
disease states.
 |
ACKNOWLEDGEMENTS |
The work by A. M. K. Choi was supported by National
Heart, Lung, and Blood Institute Grants HL-55330 and HL-60234; National Institute of Allergy and Infectious Diseases Grant AI-42365; and an
American Heart Association Established Investigator Award.
 |
FOOTNOTES |
Address for reprint requests and other correspondence: A. M. K. Choi, Division of Pulmonary, Allergy, and Critical Care
Medicine, Univ. of Pittsburgh School of Medicine, MUH, NW 628, 3459 Fifth Ave., Pittsburgh, PA 15213 (E-mail:
choiam{at}msx.upmc.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
 |
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