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4 Section of Pulmonary and
Critical Care Medicine, Yale University School of Medicine,
New Haven 06250 and Veterans Affairs Connecticut Health System,
West Haven, Connecticut 06516;
1 Division of Pulmonary and
Critical Care Medicine, The Johns Hopkins University School of
Medicine, Baltimore, Maryland 21205;
2 Departments of Pediatrics and
Pulmonary and Critical Care Medicine, Accumulating evidence demonstrates that genotoxic
and oxidant stress can induce programmed cell death or apoptosis in
cultured cells. However, little is known about whether oxidative stress resulting from the deleterious effects of hyperoxia can induce apoptosis in vivo and even less is known regarding the functional significance of apoptosis in vivo in response to hyperoxia. Using hyperoxia as a model of oxidant-induced lung injury in the rat, we show
that hyperoxic stress results in marked apoptotic signals in the lung.
Lung tissue sections obtained from rats exposed to hyperoxia exhibit
increased apoptosis in a time-dependent manner by terminal transferase
dUTP nick end labeling assays. To examine whether hyperoxia-induced
apoptosis in the lung correlated with the extent of lung injury or
tolerance (adaptation) to hyperoxia, we investigated the pattern of
apoptosis with a rat model of age-dependent tolerance to hyperoxia. We
show that apoptosis is associated with increased survival of aged rats
to hyperoxia and with decreased levels of lung injury as measured by
the volume of pleural effusion, wet-to-dry lung weight, and
myeloperoxidase content in aged rats compared with young rats after
hyperoxia. We also examined this relationship in an alternate model of
tolerance to hyperoxia. Lipopolysaccharide (LPS)-treated young rats not
only demonstrated tolerance to hyperoxia but also exhibited a
significantly lower apoptotic index compared with saline-treated rats
after hyperoxia. To further separate the effects of aging and
tolerance, we show that aged rats pretreated with LPS did not exhibit a
significant level of tolerance against hyperoxia. Furthermore, similar
to the hyperoxia-tolerant LPS-pretreated young rats, the nontolerant LPS-pretreated aged rats also exhibited a significantly reduced apoptotic index compared with aged rats exposed to hyperoxia alone. Taken together, our data suggest that hyperoxia-induced apoptosis in
vivo can be modulated by both aging and tolerance effects. We conclude
that there is no overall relationship between apoptosis and tolerance.
programmed cell death; oxidative stress; lung injury
THE LUNG IS A MAJOR TARGET ORGAN for oxidant injury by
hyperoxia (6, 7). Patients suffering from pulmonary diseases including
adult respiratory distress syndrome and emphysema require supplemental
O2 therapy to maintain lung
function, which further increases the oxidant burden of the lung (9,
14). It is believed that the damaging effects of hyperoxia are mediated
by reactive oxygen species (ROS) including superoxide and hydroxyl
radicals and hydrogen peroxide, which are generated by the incomplete
reduction of O2 (12, 19).
Oxidative stress resulting from these ROS can cause cellular damage by
oxidizing nucleic acids, proteins, and membrane lipids. Cells have
evolved both nonenzymatic and enzymatic antioxidant defenses to
detoxify ROS to defend against the deleterious effects of hyperoxia
(13, 23). Nonenzymatic defenses include vitamins C and E and
sulfhydryl-containing glutathione (3). Enzymatic antioxidant defenses
against hyperoxia include superoxide dismutase, catalase, and
glutathione peroxidase (3). When these antioxidant defenses become
overwhelmed by the oxidative stress of hyperoxia, the resultant cell
injury can lead to cell death.
Cell death from oxidative stress can occur via cell necrosis or
apoptosis (11, 27, 34). Cell necrosis is a mode of cell death that
occurs exclusively in environmental disruption apart from physiological
conditions, resulting in inflammatory reactions caused by cell lysis
and release of intracellular contents into the extracellular space
(11). Cell necrosis is always pathological. Programmed cell death or
apoptosis, on the other hand, is a gene-regulated process in which a
coordinated series of morphological changes such as nucleus and
chromatin condensation, cell membrane blebbing, and fragmentation of
the cell into membrane-bound apoptotic bodies occurs, resulting in cell
death (28, 30). Removal of apoptotic bodies by phagocytosis by
neighboring cells, in particular macrophages, occurs without
disturbance to the tissue architecture and without initiating
inflammation. Apoptosis is often a physiological process, especially important during embryogenesis, organ atrophy, and normal adult tissue turnover (8). However, accumulating evidence suggests that genotoxic and oxidant stress can induce cell death via
apoptosis (8, 10, 18).
A recent study (18) suggests that cultured pulmonary cells can also
undergo apoptosis after oxidant stress, yet little is known about
apoptosis from oxidant stress in the lung in vivo. What is the
functional significance of apoptosis in vivo after hyperoxic stress?
Does apoptosis represent a mere marker of cell and tissue injury after
oxidant injury, or does it play a role in adaptation or defense against
hyperoxic stress in vivo? We attempted to address these questions by
utilizing various in vivo models of tolerance to hyperoxia. We show
that hyperoxia exposure in vivo can indeed cause a significant level(s)
of apoptosis in the rat lung. Using two distinct in vivo models of
tolerance to hyperoxia, we show that apoptosis in the rat lung can be
regulated by both aging and tolerance effects and that there is no
clear relationship between apoptosis and tolerance to
hyperoxia.
Animals and O2 exposure.
Virus-free 6- and 24-mo-old male Fischer 344 rats and 2-mo-old
Sprague-Dawley rats were purchased from Harlan Sprague Dawley (Indianapolis, IN) and allowed to acclimate on arrival for 7 days before experimentation. The animals were fed rodent chow and water ad
libitum. All experimental protocols were approved by the Animal Care
and Use Committee, The Johns Hopkins University School of Medicine
(Baltimore, MD). The animals were exposed to hyperoxia (>99%
O2 at a flow rate of 12 l/min) in
a 3.70-ft3 glass exposure chamber.
The chamber was humidified for 10-15 min at the start of the
exposure. Food and water were provided ad libitum during the exposure.
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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RESULTS |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Hyperoxia induces apoptosis in the rat lung. To determine whether hyperoxia can induce apoptosis in vivo, lung sections were obtained from rats exposed to either normoxia or hyperoxia and analyzed for apoptotic signals by in situ TUNEL assay, which labels the 3'-COOH ends of DNA cut by endonucleases that are activated during apoptosis (31). Figure 1A illustrates the lack of apoptotic signals in the lungs from rats exposed to air alone. In contrast, a marked increase in TUNEL-positive cells was observed in lungs from rats exposed to hyperoxia (Fig. 1B).
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Effect of acquired (age-induced) tolerance to hyperoxia on apoptosis. To examine whether hyperoxia-induced apoptosis in the rat lung correlated with the extent of lung injury or tolerance (adaptation) in response to hyperoxic stress, we investigated the pattern of apoptosis using a rat model of tolerance to hyperoxia. Choi et al. (4) have previously reported that the rats exhibit increased tolerance (increased survival) to hyperoxia as they age normally. The young rats (2-6 mo old) succumbed to continuous hyperoxia exposure by 72 h, whereas the aged rats (24 mo old) survived up to 92 h of continuous hyperoxia exposure (P < 0.05) (4). We then used this model to examine whether apoptosis is modulated by age-induced acquired tolerance to hyperoxia. Lung sections were obtained from young (2-mo-old) and aged (24-mo-old) rats exposed to air or hyperoxia and then analyzed for apoptosis by TUNEL assay. Figure 2 demonstrates the kinetics of increase in TUNEL-positive cells after 24, 48, and 61 h of hyperoxia exposure in young (2-mo-old) and aged (24-mo-old) rats. In the young rats, we did not observe increased TUNEL-positive cells at either 24 or 48 h of hyperoxia exposure (Fig. 2, E and F, respectively) but detected a marked increase in apoptotic cells at 61 h of hyperoxia exposure (Fig. 2G). In the aged rats, we did not detect any evidence of apoptotic signals at 24 h of hyperoxia exposure (Fig. 2A) as in the young rats (Fig. 2E). However, we observed a marked increase in TUNEL-positive cells at 48 h of hyperoxia (Fig. 2B), with a sustained increase at 61 and 96 h of hyperoxia exposure (Fig. 2, C and D, respectively). Figure 2H illustrates DAPI fluorescence of the same lung section shown in Fig. 2D (TUNEL stain) to demonstrate the total number of nucleated cells.
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We then quantitated the level of apoptosis in these lung sections by determining the apoptotic index (number of TUNEL-positive cells/number of DAPI-stained cells). As shown in Fig. 3, the apoptotic index increased with advancing exposure in both exposed groups but increased more rapidly in the aged (tolerant) rats.
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Hyperoxia-induced apoptosis is associated with increased survival and decreased lung injury in acquired tolerance to hyperoxia. Based on our observation that apoptosis was associated with increased survival in the acquired model of tolerance to hyperoxia (earlier onset and higher level of apoptosis in the aged tolerant rats), we then examined whether apoptosis was associated with a decreased level of lung injury. The young rats (2 mo old) exhibited increased signs of lung injury as measured by an increased volume of pleural effusion and wet-to-dry lung weight after 48 h of hyperoxia (Fig. 4, A and B, respectively) at a time point where only negligible levels of apoptotic signals were observed (Figs. 2 and 3). In contrast, the aged rats (24 mo old) exhibited a significantly decreased level of lung injury compared with the young rats as measured by the volume of pleural effusion, wet-to-dry lung weight, and MPO content after 48 h of hyperoxia (Fig. 4, D-F, respectively). Interestingly, at this time point, the aged rats exhibited significant levels of apoptotic signals (Figs. 2 and 3).
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Effect on chemical tolerance to hyperoxia on apoptosis. Based on the observation that apoptosis in the rat lung was associated with decreased lung injury and increased survival in a model of acquired tolerance to hyperoxia (aging), we chose to test this relationship in an alternate model of tolerance to hyperoxia. We used the established model of LPS-induced tolerance (chemical tolerance) to hyperoxia (7, 29). Young rats (2 mo old) pretreated with LPS exhibited a marked increased survival to hyperoxia (Fig. 5) compared with control rats pretreated with saline before hyperoxia exposure. Lung sections were obtained from these tolerant rats and assayed for apoptotic signals by TUNEL assay. As shown in Fig. 6, young rats exposed to hyperoxia alone demonstrated a marked increase in the apoptotic index. However, young rats pretreated with LPS not only demonstrated a tolerance to hyperoxia but also exhibited a significantly reduced apoptotic index compared with rats exposed to hyperoxia alone (Fig. 6). To separate the effects of aging and tolerance, we performed an identical experiment in the aged rats (24 mo old). In contrast to the young rats, aged rats pretreated with LPS did not exhibit a significant level of tolerance against hyperoxia (Fig. 5). Furthermore, lung sections were obtained from these nontolerant LPS-treated aged rats and assayed for apoptotic signals by TUNEL assay. As shown in Fig. 6, aged rats exposed to hyperoxia alone demonstrated a marked increase in the apoptotic index. However, similar to the tolerant LPS-treated young rats, the nontolerant LPS-treated aged rats exhibited a significantly reduced apoptotic index compared with aged rats exposed to hyperoxia alone (Fig. 6). Interestingly, aged rats treated with LPS alone also exhibited increased apoptosis after hyperoxia (Fig. 6).
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Direct exposure of cultured cells to oxidants such as hydrogen peroxide, ionizing irradiation, various superoxide-generating agents, and glutathione depletors can cause cell death via the induction of apoptosis, depending on the dose (8, 18, 26, 32). Although the biochemical and molecular mechanisms by which oxidants mediate apoptosis in cells are not clearly understood, recent reports that Bcl-2 prevents apoptosis by an antioxidant pathway at the sites of oxygen radical formation (15, 17) and that antioxidants such as N-acetyl-L-cysteine and thioredoxin (25) prevent apoptosis strongly suggest that oxidants may serve as key signaling molecules in the development of apoptosis in cultured cells. Surprisingly, although the damaging effects of hyperoxia in the lung are in part mediated by superoxide and hydroxyl radicals and hydrogen peroxide, the products of which can induce apoptosis in various cell types (8, 18, 32), hyperoxia exposure does not cause apoptosis in cultured lung cells (18). For instance, Kazzaz et al. (18) recently reported that hyperoxia causes cell death via necrosis and not apoptosis in pulmonary A549 epithelial cells. Our laboratory has also observed that hyperoxia causes cell necrosis and not apoptosis in other cell types such as human bronchial epithelial cells (Choi, unpublished data). Little is known regarding the effects of hyperoxia on apoptosis in the lung in vivo. In contrast to cultured cells that do not undergo apoptosis in response to hyperoxia (18), we hypothesized that hyperoxia induces apoptosis in the lung in vivo and that a clear functional relationship exists between apoptosis and tolerance to hyperoxia. We decided to investigate this relationship between hyperoxia and apoptosis in vivo.
This study clearly shows that hyperoxia induces apoptosis in the rat
lung in a time-dependent manner in contrast to absence of apoptosis in
cultured cells exposed to the same concentration of hyperoxia (>95%
O2). Several possibilities exist
to underlie this disparate observation between in vitro lung cultured
cells and in vivo lung tissue. 1)
The lack of hyperoxia-induced apoptosis in cultured lung cells may
reflect cell specificity because there are recent reports of vascular
endothelial cells and lymphoblastoid cells exhibiting susceptibility to
hyperoxia-induced apoptosis (1, 5).
2) The ability of hyperoxia to
induce apoptosis in the lung in vivo may reflect the effect of systemic
mediators released during the inflammatory phase of hyperoxic lung
injury, which may be responsible for inducing apoptosis rather than
hyperoxia itself. For example, tumor necrosis factor-
, a potent
inducer of apoptosis in various cell types, is released in vivo during hyperoxia (16). 3) The
susceptibility of lung cells in vivo to undergo apoptosis may reflect
the effect of the quiescent state of the cells in vivo compared with
the more proliferative state of cultured cells growing in cultured
conditions.
The functional significance of apoptosis in the lung in vivo is not clearly understood. Mantell et al. (22) reported in a mouse model of hyperoxia that the level of hyperoxia-induced apoptosis correlated with the extent of lung injury. Using an inbred (rather than acquired) model of tolerance, they reported higher levels of apoptosis in a sensitive strain of mouse and lower apoptosis in a resistant strain. This suggests that apoptosis may serve as a marker of cell and tissue injury. Our data, however, do not support our hypothesis that there is a clear functional relationship between hyperoxia and apoptosis. This simple relationship, however, was not observed in our age-dependent rat model of hyperoxia. We observed that the increased apoptotic index of lungs from the age-dependent tolerant rat is inversely proportional to the extent of lung injury and is associated with increased survival. This relationship may reflect the effects of the aging process and not of tolerance; however, the increased level of apoptosis observed in the aged tolerant rats was associated with decreased lung injury in the aged rats as determined by pleural effusion volume, wet-to-dry lung weight, and MPO determination in this study and decreased albumin levels in bronchoalveolar lavage fluid (4) after hyperoxia. These studies may suggest that the apoptosis in the lung may represent a physiological process that is pivotal in protecting the lung from oxidant injury. However, a recent study (22) showed that neonatal rabbits that are tolerant to hyperoxia exhibited significantly less apoptosis than the more susceptible adult rabbits after hyperoxia. This observation supports the formal possibility that the hyperoxia-induced apoptosis can also be regulated by the aging process independent of the tolerance effect.
The complexity of the functional role of apoptosis in lung injury is further highlighted by our observations that in contrast to the age-dependent tolerance model, the apoptotic index of the lung is not associated with survival in the LPS-induced tolerance model of hyperoxia in young rats. For example, LPS-induced hyperoxia-tolerant young rats exhibited a significantly reduced level of apoptosis than saline-treated rats after hyperoxia, although baseline levels were similar. These observations suggest that in some cases apoptosis may represent a marker of tissue injury rather than a marker of tolerance. However, we observed similar attenuation of apoptosis in LPS-treated old rats, which were not tolerant to hyperoxia. These apparently conflicting results highlight the difficulty of interpreting a simple role for apoptosis in the rat lung after hyperoxia. It seems likely that a greater knowledge of the cell types undergoing apoptosis during lung injury will lead to a better understanding of the role(s) for apoptosis in lung injury. The antioxidant manganese superoxide dismutase in response to an LPS stimulus contributes significantly to the protective effect of LPS against hyperoxia (7, 29) in young rats. Although no direct evidence exists that manganese superoxide dismutase can attenuate the apoptosis in the lung, accumulating evidence suggests that antioxidants may play vital roles in attenuating the apoptotic process (15, 25).
Although one cannot yet confidently determine the cell type responsible for the apoptotic signals in TUNEL assays of lung tissue sections, increased apoptosis in the aged-tolerant rats coincided with significantly decreased lung MPO after hyperoxia, suggesting that neutrophil clearance by apoptosis may represent one major mechanism of increased survival in the aged rats. Interestingly, a study (24) involving patients with human adult respiratory distress syndrome demonstrated that the apoptotic process was more prominent during the repair phase than the acute phase of this syndrome, suggesting that apoptosis serves as a beneficial process in the resolution of acute lung injury.
It is generally thought that apoptosis occurs without eliciting an
inflammtory response, whereas cell or tissue necrosis can cause
inflammation (8, 33). However, our studies challenge this paradigm in
that the inflammatory response (neutrophil and macrophage), as
determined by bronchoalveolar lavage analysis, was similar in both the
young and aged rats after hyperoxia (4). However, we observed marked
differences in the kinetics and extent of apoptosis between the young
and aged rats. Recent reports (2, 32) also suggested that apoptosis
induced by tumor necrosis factor- and X-irradiation in cultured
cells can be inhibited by the transcription factor nuclear factor-
B
(NF-B). Interestingly, we did not observe differences in the
induction of NF-B activation in vivo in the lungs after hyperoxia in
both tolerance models (age and LPS) (4; Choi, unpublished
data) that may reflect differences between the in vivo and
in vitro systems or may represent stimulus specificity. Interestingly,
Li et al. (21) recently reported that apoptosis can occur in the
absence of NF-B activation in cultured epithelial cells after
hydrogen peroxide treatment and that the hyperoxic induction of NF-B
fails to protect cultured cells from death.
In summary, our study demonstrates that hyperoxia in vivo can induce apoptosis in the rat lung. Furthermore, these studies strongly suggest that apoptosis is not a universal indicator of tolerance to hyperoxia and that the functional significance of apoptosis in vivo after hyperoxic oxidant stress largely depends on the mechanism of tolerance, whether chemically induced or acquired by aging. The complex regulation of hyperoxia-induced apoptosis by both aging and tolerance poses a challenge to a straightforward assessment of the physiological function of apoptosis in lung injury. Further investigations leading to the identification of cell types undergoing apoptosis in these models of tolerance to hyperoxia will be helpful in delineating the functional significance of apoptosis in oxidant-injured lung.
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ACKNOWLEDGEMENTS |
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A. M. K. Choi was supported by National Heart, Lung, and Blood Institute First Award R29-HL-55330 and National Institute of Allergy and Infectious Diseases Grant RO1-AI-42365. S. Horowitz was supported in part by Basic Research Grant 1-FY96-0752 from the March of Dimes Birth Defects Foundation and grants from the National Institutes of Health and Winthrop-University Hospital.
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FOOTNOTES |
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Address for reprint requests and present address of A. M. K. Choi: Section of Pulmonary and Critical Care Medicine, Yale Univ. School of Medicine, 333 Cedar St., LCI 105, New Haven, CT 06520.
Received 17 July 1997; accepted in final form 20 March 1998.
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L. L. Mantell, T. H. Shaffer, S. Horowitz, R. Foust III, M. R. Wolfson, C. Cox, P. Khullar, Z. Zakeri, L. Lin, J. A. Kazzaz, et al. Distinct patterns of apoptosis in the lung during liquid ventilation compared with gas ventilation Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L31 - L41. [Abstract] [Full Text] [PDF]
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E. Marchi, W. Liu, and V. C. Broaddus Mesothelial cell apoptosis is confirmed in vivo by morphological change in cytokeratin distribution Am J Physiol Lung Cell Mol Physiol, March 1, 2000; 278(3): L528 - L535. [Abstract] [Full Text] [PDF]
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I. Petrache, M. E. Choi, L. E. Otterbein, B. Y. Chin, L. L. Mantell, S. Horowitz, and A. M. K. Choi Mitogen-activated protein kinase pathway mediates hyperoxia-induced apoptosis in cultured macrophage cells Am J Physiol Lung Cell Mol Physiol, September 1, 1999; 277(3): L589 - L595. [Abstract] [Full Text] [PDF]
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C. E. Howlett, J. S. Hutchison, J. P. Veinot, A. Chiu, P. Merchant, and H. Fliss Inhaled nitric oxide protects against hyperoxia-induced apoptosis in rat lungs Am J Physiol Lung Cell Mol Physiol, September 1, 1999; 277(3): L596 - L605. [Abstract] [Full Text] [PDF]
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L. E. Otterbein, L. L. Mantell, and A. M. K. Choi Carbon monoxide provides protection against hyperoxic lung injury Am J Physiol Lung Cell Mol Physiol, April 1, 1999; 276(4): L688 - L694. [Abstract] [Full Text] [PDF]
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L. L. MANTELL, S. HOROWITZ, J. M. DAVIS, and J. A. KAZZAZ Hyperoxia-induced Cell Death in the Lung-the Correlation of Apoptosis, Necrosis, and Inflammation Ann. N.Y. Acad. Sci., January 1, 1999; 887(1): 171 - 180. [Abstract] [Full Text] [PDF]
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, Young rats pretreated
with saline before hyperoxia exposure; 
, young rats pretreated with
LPS before hyperoxia exposure; 
, aged rats pretreated with saline
before hyperoxia exposure; 
, aged rats pretreated with LPS before
hyperoxia exposure. P < 0.001 for
young LPS-treated vs. young saline-treated rats after hyperoxia.
