| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
1 Section of Pulmonary and
Critical Care Medicine, Findings in recent years strongly suggest that
the stress-inducible gene heme oxygenase (HO)-1 plays an important role
in protection against oxidative stress. Although the mechanism(s) by
which this protection occurs is poorly understood, we hypothesized that
the gaseous molecule carbon monoxide (CO), a major by-product of heme
catalysis by HO-1, may provide protection against oxidative stress. We
demonstrate here that animals exposed to a low concentration of CO
exhibit a marked tolerance to lethal concentrations of hyperoxia in
vivo. This increased survival was associated with highly significant attenuation of hyperoxia-induced lung injury as assessed by the volume
of pleural effusion, protein accumulation in the airways, and
histological analysis. The lungs were completely devoid of lung airway
and parenchymal inflammation, fibrin deposition, and pulmonary edema in
rats exposed to hyperoxia in the presence of a low concentration of CO.
Furthermore, exogenous CO completely protected against
hyperoxia-induced lung injury in rats in which endogenous HO enzyme
activity was inhibited with tin protoporphyrin, a selective inhibitor
of HO. Rats exposed to CO also exhibited a marked attenuation of
hyperoxia-induced neutrophil infiltration into the airways and total
lung apoptotic index. Taken together, our data demonstrate, for the
first time, that CO can be therapeutic against oxidative stress such as
hyperoxia and highlight possible mechanism(s) by which CO may mediate
these protective effects.
oxidative stress; acute respiratory distress syndrome; heme
oxygenase; gaseous molecule; apoptosis
HEME OXYGENASE (HO) catalyzes the first and
rate-limiting step in the degradation of heme to yield equimolar
quantities of biliverdin IXa, carbon monoxide (CO), and iron (3, 14).
Three isoforms of HO exist; HO-1 is highly inducible, whereas HO-2 and HO-3 are constitutively expressed (3, 14, 16). Although heme is the
major substrate of HO-1, a variety of nonheme agents, including heavy
metals, cytokines, hormones, endotoxin, and heat shock, are also strong
inducers of HO-1 expression (3, 14, 26). This diversity of HO-1
inducers has provided further support for the speculation that HO-1,
besides its role in heme degradation, may also play a vital function in
maintaining cellular homeostasis. Furthermore, HO-1 is highly induced
by a variety of agents, including hydrogen peroxide, glutathione
depletors, ultraviolet irradiation, endotoxin, and hyperoxia, causing
oxidative stress (3, 10, 14). One interpretation of this
finding is that HO-1 can serve as a key biological molecule in the
adaptation and/or defense against oxidative stress (1, 3, 13, 21, 22,
25, 28, 29). Our laboratory (13, 19, 21) and others (1) have shown that
induction of HO-1 provides protection both in vivo and in vitro against
oxidative stress.
The mechanism(s) by which HO-1 provides protection against oxidative
stress is poorly understood. Based on the observations that endogenous
induction of HO-1 provides protection against oxidative stress, we
hypothesized that the gaseous molecule CO, a major by-product of heme
catalysis by HO-1, can mediate protective effects against oxidative stress.
CO is a gaseous molecule with known toxicity and lethality to living
organisms (2, 7). However, against this known paradigm of CO toxicity
and on the basis of several key observations, there has been renewed
interest in recent years in CO behaving as a regulatory molecule in
cellular and biological processes. Mammalian cells have the ability to
generate endogenous CO primarily through the catalysis of heme by the
enzyme HO (3, 14). The total cellular production of CO is generated
primarily via heme degradation by HO (15, 27). Moreover, CO, akin to
the gaseous molecule nitric oxide, plays important roles in mediating
neuronal transmission (27, 31) and in the regulation of vasomotor tone
(6, 17, 18). There are no data in the literature substantiating a
protective role for CO in vivo against oxidative stress.
In this study, we demonstrate that animals exposed to a low
concentration of CO exhibit a marked tolerance to otherwise lethal hyperoxia in vivo. This increased survival was associated with a marked
inhibition of hyperoxia-induced lung injury as assessed by pleural
effusion and protein accumulation in the airways. Histological analysis
of the lungs after hyperoxia demonstrates severe lung airway and
parenchymal inflammation, fibrin deposition, and pulmonary edema. In
contrast, the lungs of rats exposed to hyperoxia in the presence of CO
were completely devoid of injury or inflammation. Neutrophil influx
into the airways of the lung, a reliable marker of oxidant-induced lung
injury, and the total lung apoptotic index were strikingly reduced in
animals exposed to hyperoxia in the presence of CO. The modulation of
neutrophil infiltration and apoptosis may represent a possible
mechanism(s) by which CO confers protection against oxidative stress.
Animals and gas exposure.
Pathogen-free male Sprague-Dawley rats (250-300 g) 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 animals were exposed to >98%
O2 or 98%
O2 plus CO mixtures at a flow rate
of 12 l/min in a 3.70-ft3 glass
exposure chamber. The animals were supplied food and water during the
exposures. CO at a concentration of 1% [10,000 parts/million (ppm)] in compressed air was mixed with >98%
O2 in a stainless steel mixing
cylinder before delivery to the exposure chamber. By varying the flow
rates of CO into the mixing cylinder, the concentrations delivered to
the exposure chamber were controlled. Because the flow rate was
primarily determined by the O2
flow, only the CO flow was changed to generate the different
concentrations delivered to the exposure chamber. A CO analyzer
(Interscan, Chatsworth, CA) was used to measure CO levels continuously
in the chamber. Gas samples were taken by the analyzer through a port
in the top of the exposure chamber at a rate of 1 l/min and analyzed by
electrochemical detection, with a sensitivity of 10-600 ppm. CO
levels in the chamber were recorded at hourly intervals, and there were
no changes in chamber CO concentrations once the chamber had
equilibrated. O2
concentrations in the chamber were determined with a gas spectrometer.
Lung tissue preparation. The lungs
were fixed by perfusion with 10% Formalin at 20 cmH2O pressure and embedded in
paraffin. Lung sections of 4-5 µm were mounted onto
slides pretreated with 3-aminopropylethoxysilane (Digene Diagnostics,
Beltsville, MD). The slides were baked for 30 min at 60°C and
washed twice in fresh xylene for 5 min to remove the paraffin. The
slides were rehydrated though a series of graded alcohols and then
washed in distilled water for 3 min before being stained with
hematoxylin and eosin.
Bronchoalveolar lavage fluid
analysis. The animals were anesthesized
with pentobarbital sodium 24 h after 56 h of hyperoxic exposure.
Bronchoalveolar lavage (BAL; 35 ml/kg) was performed four times with
PBS (pH 7.4). The cells were pooled from the lavage fluids and
centrifuged at 1,200 g for 10 min. The
supernatant was discarded, and the cells were resuspended in PBS. Cell
counts were performed with a Neubaur hemocytometer. For differential analysis, samples were cytocentrifuged and stained with Diff-Quik.
Measurement of injury markers. The
rats were removed at 56 h of hyperoxia and anesthetized with
pentobarbital sodium. The pleural effusion was collected by inserting
an 18-gauge needle and a 10-ml syringe through the diaphragm and
withdrawing all fluid present in the pleural cavity. Tin protoporphyrin
(SnPP) was purchased from Protoporphyrins Products (Logan, UT). SnPP was administered to the rats (50 µmol/kg subcutaneously) before hyperoxia and injected daily throughout the duration of exposure. BAL
was performed as described in Bronchoalveolar lavage
fluid analysis, the first lavage sample
was centrifuged at 1,200 g for 10 min,
and the supernatant was assayed for protein albumin as determined with
the bromcresol green kit from Sigma (St. Louis, MO).
Arterial blood oxygen tension and carboxyhemoglobin
determination. Indwelling catheters were surgically
implanted into the carotid arteries of rats anesthetized with 3%
(vol/vol) isoflurane. The animals were secured in jackets and tethers
to allow movement about the cage and access to food and water that were
placed inside the exposure chambers. Polyethylene tubing connected
to the catheter and threaded out through an airtight fitting in the lid
of the chamber was used for continuous heparin infusion throughout the exposure (20 U/ml at 0.1 ml/h) to maintain patency of the vessel. At
each time point, 1 ml of blood was drawn into a heparinized syringe,
sealed, and placed on ice until analyzed for oxygen tension. Arterial
oxygen tension and carboxyhemoglobin were determined with an
Instrumentation Laboratory (Boston, MA) BG3 blood gas analyzer and
CO-oximeter.
Apoptosis by terminal deoxytransferase dUTP nick end
labeling assay and photomicrography. The terminal
deoxytransferase dUTP nick end labeling (TUNEL) method was used for the
apoptosis assay of lung tissue sections as previously described (9,
19). TUNEL reagents including rhodamine-conjugated anti-digoxigenin Fab
fragment were obtained from Boehringer Mannheim (Indianapolis, IN).
Tissue sections were counterstained with 2 µg/ml of
4',6-diamidine-2'-phenylindole dihydrochloride (DAPI;
Boehringer Mannheim) for 10 min at room temperature. Photomicrographs
were recorded on 35-mm film with a Nikon Optiphot microscope and UFX
camera system (Nikon, Melville, NY) and transferred onto a
KodakPhotoCD. The images were digitally adjusted for contrast with
Adobe Photoshop 3.0 (Adobe Systems, Mountain View, CA).
Computer-aided image analysis. To
quantify the extent of apoptosis in the rat lung, samples were studied
by epifluorescence to visualize either TUNEL-positive nuclei (590 nm)
or total DAPI-stained nuclei (420 nm). Images were captured with a
charge-coupled device video camera. The captured images were analyzed
with the Image 1 system (Universal Imaging, West Chester, PA). The
images were digitally thresholded with identical settings for each set
of either DAPI- or TUNEL-fluorescent groups. The total number of cells
(nuclei) or the number of TUNEL-positive cells in each field was
determined in the object-counting mode. At least 100 fields were
analyzed from at least 3 individual animals for each experimental group. The apoptotic index was calculated as the percent of
TUNEL-positive apoptotic nuclei divided by the DAPI-stained nuclei.
Statistical analysis. Data are
expressed as means ± SE. Differences in measured variables between
the experimental and control groups were assessed with Student's
t-tests. Statistical calculations were
performed on a Macintosh personal computer with the Statview II
statistical package (Abacus Concepts, Berkeley, CA). Significant difference was accepted at P < 0.05.
CO induces tolerance to lethal
hyperoxia. We used clinically relevant in vivo models
of oxidative stress to test the hypothesis that CO mediates the
protective effects of HO-1 against oxidative stress. Hyperoxia when
administered to animals produces pathophysiological changes similar to
those seen in human acute respiratory distress syndrome (ARDS) (5, 12).
Choi et al. (4) and others (5) have shown that adult rats
exposed to hyperoxia develop lung edema or pleural effusion by 56 h
that significantly increases between 56 and 66 h. These rats will
uniformly die by 72 h of continuous hyperoxic exposure (4, 5). In this
study, one group of rats was placed in hyperoxia (>98%
O2) alone while the second group of rats was placed in an identical chamber and exposed to the same
levels of hyperoxia in the presence of a low concentration of CO
(50-500 ppm; Table 1). The rats
exposed to hyperoxia alone all died by 72 h, whereas the rats exposed
to hyperoxia in the presence of a low concentration of CO exhibited a
highly significant tolerance to hyperoxia: all animals exposed to
hyperoxia in the presence of CO concentrations of 250-500 ppm were
alive at the 72-h time point (Table 1). This protective effect of CO is
concentration dependent, with effects seen in the range between 50 and
500 ppm. We observed concentration-dependent protection against
hyperoxia at both 72 and 100 h of hyperoxic exposure (Table 1).
(P value for the association between
survival and CO concentration is 0.001 by logistic regression.)
Carboxyhemoglobin levels, a standard measurement of CO levels in the
blood, correlated with the increasing concentrations of CO exposure and
the survival of animals to lethal hyperoxia (Table 1). Rats exposed to
low concentrations of CO (50-500 ppm) alone did not exhibit any
untoward effects.
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
Table 1.
Concentration-dependent protective effects of CO against lethal
hyperoxia
CO provides protection against hyperoxia-induced lung
injury. To assess further the beneficial effects of CO,
we measured the volume of pleural effusion and total protein
accumulation in the airways, both standard and highly reliable markers
of hyperoxic lung injury (4, 5, 12). The rats exposed to hyperoxia alone exhibited an increase in the volume of pleural effusion after 56 h of hyperoxic exposure (Fig.
1A),
whereas in those rats exposed to hyperoxia in the presence of a low
concentration of CO, we observed a marked inhibition in the amount of
pleural effusion (P < 0.0001; Fig.
1A). The rats exposed to hyperoxia
alone exhibited a significant increase in the amount of protein
accumulation into the airways as measured by BAL (Fig.
1B). In contrast, the animals exposed to hyperoxia in the presence of CO exhibited significantly lower levels of protein accumulation
(P < 0.01; Fig.
1B). The amount of pleural effusion
or protein accumulation in the BAL fluid in rats exposed to CO alone
was similar to the level observed in control animals exposed to
normoxia (Fig. 1).
|
Effect of CO on lung histology. We
performed histological analyses to examine further whether a low
concentration of CO attenuated lung injury. There were striking
differences in lung histology between the two experimental groups.
Figure 2 demonstrates normal lung
morphology in control rats exposed to either normoxia (Fig. 2a) or CO alone (Fig.
2b). Marked lung hemorrhage, edema,
alveolar septal thickening, influx of inflammatory cells, and fibrin
deposition were observed in rats exposed to hyperoxia alone (Fig. 2,
c and d). In contrast, the lungs of rats
exposed to hyperoxia in the presence of CO were completely normal
macroscopically and microscopically (Fig. 2,
e and
f ).
|
Effect of exogenous CO on rats whose endogenous HO
enzyme activity was completely inhibited. To examine
whether exogenous CO can provide protection in the absence of
endogenous HO enzyme activity, we administered SnPP (50 µmol/kg), a
potent selective inhibitor of the HO enzyme, before exposing rats to
hyperoxia in the presence of exogenous CO. Otterbein et al. (21)
previously reported that SnPP administered at this dose completely
inhibits HO enzyme activity in tissues including the lung. The rats
exposed to hyperoxia alone exhibited an increase in pleural effusion
compared with the animals exposed to normoxia
(P < 0.0001; Fig.
3). Figure 3 illustrates that rats
pretreated with SnPP exhibited significantly more pleural effusion
compared with rats receiving saline before hyperoxic exposure
(P < 0.0001).
Interestingly, rats pretreated with SnPP exhibited normal lung
morphology devoid of tissue injury, including pleural effusion, when
exposed to hyperoxia in the presence of exogenous CO
(P < 0.0001 compared with rats
treated with SnPP and hyperoxia without CO). No untoward effects were
observed in rats receiving CO or SnPP alone, without any evidence of
pleural effusion accumulation.
|
CO attenuates hyperoxia-induced neutrophil
infiltration into the airways and total lung apoptotic
index. To further investigate a possible mechanism(s)
of CO-mediated protection against hyperoxia, we examined the
inflammatory cell profile in the BAL fluid of animals exposed to
hyperoxia. We hypothesized that CO may mediate the protection against
oxidant tissue injury via inhibition of neutrophil influx into the
airways. The animals exposed to hyperoxia alone demonstrated an
increase in neutrophil influx into the airways as assessed by BAL fluid
analysis (P < 0.007; Fig.
4). In contrast, the rats exposed to
hyperoxia in the presence of CO exhibited significant reductions in
neutrophil influx (P < 0.006; Fig.
4).
|
Another possible mechanism by which CO might exert its salutary effects
would be by modulating apoptosis. We observed that rats exposed to
hyperoxia alone exhibit a highly significant induction in the lung
apoptotic index (7.9 ± 0.3%) compared with that in control rats in
normoxia (0.5 ± 0. 09%; P
<0.0001; Fig. 5). In contrast, the rats
exposed to hyperoxia in the presence of CO demonstrate a significant
reduction in the lung apoptotic index (1.8 ± 0.12%) compared with
that in the animals exposed to hyperoxia alone (7.9 ± 0.3%;
P < 0.001; Fig. 5).
|
| |
DISCUSSION |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
We have shown that exogenous administration of low concentrations of CO can provide protection against oxidative stress in a model of inflammation. It should be noted that the concentration of CO used for these studies, in the order of 50-500 ppm, corresponds to 0.005-0.05% CO, respectively. A concentration of 500 ppm represents one-twentieth of the lethal concentration of CO in our model (data not shown). It is notable that the concentrations of CO used for these studies were even lower (10- to 50-fold) than the doses administered to humans (0.3% CO) to assess the diffusion capacity of the lung, a standard pulmonary function test. Because differences in arterial PO2 levels have been implicated in other models of tolerance to hyperoxia (4), we measured the PO2 content of our experimental groups. No significant difference was observed between the rats exposed to hyperoxia and the rats exposed to hyperoxia in the presence of a low concentration of CO (PO2 502.5 ± 7.4 mmHg for hyperoxia vs. 510.5 ± 11.4 mmHg for hyperoxia and CO; P = not significant).
The precise mechanism(s) by which CO mediates protection is not clear. Our observation that CO attenuated hyperoxia-induced influx of neutrophils into the airways is interesting in that it is well established that neutrophil influx in BAL fluid is of paramount importance in the development of hyperoxia-induced lung injury in in vivo models and in human patients with ARDS (4, 5, 24). Moreover, identical experiments were performed with a second model of oxidant-induced lung injury and inflammation. Lipopolysaccharide administered to rats induces profound neutrophil influx into the airways; however, this neutrophil influx was significantly inhibited in the lungs of rats given lipopolysaccharide and exposed to CO (Otterbein and Choi, unpublished observations). Willis et al. (30) recently reported that HO-1 modulates the inflammatory response in vivo, and a recent report by Soares et al. (23) also showed that HO-1 may modulate the inflammatory response in vivo. The findings of our study may provide a possible mechanism to explain the anti-inflammatory properties of HO-1 as demonstrated by our laboratories (19, 21) and others (23, 30). However, our study with exogenous CO does not directly prove that it is mimicking endogenous CO and cannot be compared with CO produced during heme metabolism by endogenous HO-1. Designing an experiment(s) to show that endogenous CO from HO-1 actually mediates the protective effect of HO-1 in vivo is technically very difficult, perhaps not feasible because current available technology to measure CO in vivo (carboxyhemoglobin assay) is not sensitive enough to detect increased CO levels after HO-1 induction (Otterbein and Choi, unpublished observations). However, our observations that exogenous CO can completely ablate or reverse the increased pleural effusion in rats treated with SnPP and hyperoxia suggest that exogenous CO can provide cytoprotective effects even in conditions when endogenous HO activity is completely inhibited. Nevertheless, the marked protection against hyperoxia-induced lung injury by exogenous CO at low concentrations observed in our study provides one with a suitable in vivo model to further investigate the functional physiological role of CO in oxidant-induced lung injury.
Furthermore, the inhibition of apoptosis by CO may represent an
additional mechanism by which CO provides protection against oxidant-induced injury and inflammation. Although the precise physiological function of apoptosis in the lung has yet to be established, emerging data strongly suggest that the total lung apoptotic index can serve as a useful marker of lung injury in response
to oxidative stress such as hyperoxia (9, 20). Soares et al. (23) also
showed that HO-1 may act as an antiapoptotic molecule in an in vitro
model. We have also shown in vitro that HO-1 can inhibit tumor necrosis
factor-
-induced apoptosis in L929 cells (I. Petrache and A. M. K. Choi, unpublished observations). It seems possible, if
not likely, that CO may be mediating the effects of HO-1 observed in
those studies.
The known observations that CO can avidly bind to heme moieties such as guanylyl cyclase (11) and thereby increase cGMP, similar to the action of nitric oxide, may provide clues to future studies. However, CO could act also via a pathway not involving cGMP as recently described in other in vitro models (8).
We have provided evidence demonstrating that exogenous CO at low concentrations provides protection against hyperoxia-induced lung injury. The concentrations of CO needed to achieve this dramatic therapeutic effect are far less than the known toxic concentrations and even lower than the concentrations used in pulmonary function tests in humans. Although we have not established the precise mechanism by which CO exerts its protective effects against hyperoxic lung injury, the inhibition of neutrophil inflammation and attenuation of total lung apoptotic index represent potential mechanisms to investigate in the future. Our work raises the intriguing possibility for the potential therapeutic use of low concentrations of CO in clinical settings, not only in lung disorders such as ARDS and sepsis but also in a variety of other inflammatory disease states.
| |
ACKNOWLEDGEMENTS |
|---|
We thank Marco Chacon of Paragon BioTechnology (Baltimore, MD) for assistance with tissue sectioning and staining and Dr. Peter Bach for assistance in statistical analysis. We also thank Sandra Beaudouin for assistance in the apoptosis assay.
| |
FOOTNOTES |
|---|
L. E. Otterbein was supported by a National Heart, Lung, and Blood Institute Multidisciplinary Training Grant. A. M. K. Choi was supported by National Heart, Lung, and Blood Institute Grant RO1-HL-55330, an American Heart Association Established Investigator Award, and National Institute of Allergy and Infectious Diseases Grant R01-AI-42365. L. L. Mantell was supported in part by grants from American Lung Association and the Stony Wold-Herbert Fund.
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: 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 (E-mail: augustine.choi{at}yale.edu).
Received 25 November 1998; accepted in final form 4 January 1999.
| |
REFERENCES |
|---|
|
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
|---|
1.
Abraham, N. G.,
Y. Lavrovsky,
M. L. Schwartzman,
R. A. Stoltz,
R. D. Levere,
M. E. Gerritsen,
S. Shibahara,
and
A. Kappas.
Transfecton of the human heme oxygenase gene into rabbit coronary microvessel endothelial cells: protective effects against heme and hemoglobin toxicity.
Proc. Natl. Acad. Sci. USA
92:
6798-6802,
1995
2.
Chance, B.,
M. Erecinska,
and
M. Wagner.
Mitochondrial responses to carbon monoxide toxicity.
Ann. NY Acad. Sci.
174:
193-204,
1970[Medline].
3.
Choi, A. M. K.,
and
J. Alam.
Heme oxygenase-1: function, regulation and implication of a novel stress-inducible protein in oxidant-induced lung injury.
Am. J. Respir. Cell Mol. Biol.
15:
9-19,
1996[Abstract].
4.
Choi, A. M. K.,
S. L. Sylvester,
L. E. Otterbein,
and
N. J. Holbrook.
Molecular responses to hyperoxia in vivo: relationship to increased tolerance in aged rats.
Am. J. Respir. Cell Mol. Biol.
13:
74-82,
1995[Abstract].
5.
Clerch, L. B,
and
D. Massaro.
Tolerance of rats to hyperoxia.
J. Clin. Invest.
91:
499-508,
1993.
6.
Goda, N.,
K. Suzuki,
M. Naito,
S. Takeoka,
E. Tsuchida,
Y. Ishimura,
T. Tamatani,
and
M. Suematsu.
Distribution of heme oxygenase isoforms in rat liver. Topographic basis for carbon monoxide-mediated microvascular relaxation.
J. Clin. Invest.
101:
604-612,
1998[Medline].
7.
Haldane, J. B. C.
Carbon monoxide as a tissue poison.
Biochem. J.
21:
1068-1075,
1927.
8.
Hartsfield, C. L.,
J. Alam,
J. L. Cook,
and
A. M. K. Choi.
Regulation of heme oxygenase-1 gene expression in vascular smooth muscle cells by nitric oxide.
Am. J. Physiol.
273 (Lung Cell. Mol. Physiol. 17):
L980-L988,
1997
9.
Kazzaz, J. A.,
J. Xu,
T. A. Palaia,
L. L. Mantell,
A. M. Fein,
and
S. Horowitz.
Cellular oxygen toxicity-oxidant injury without apoptosis.
J. Biol. Chem.
271:
15182-15186,
1996
10.
Keyse, S. M.,
and
R. M. Tyrrell.
Heme oxygenase is the major 32-kDa stress protein induced in human skin fibroblasts by UVA radiation, hydrogen peroxide, and sodium arsenite.
Proc. Natl. Acad. Sci. USA
86:
99-103,
1989
11.
Kharitonov, V. G.,
V. S. Sharma,
R. B. Pilz,
D. Magde,
and
D. Koesling.
Basis of guanylate cyclase activation by carbon monoxide.
Proc. Natl. Acad. Sci. USA
92:
2568-2571,
1995
12.
Lee, P. J.,
J. Alam,
S. L. Sylvester,
N. Inamdar,
L. E. Otterbein,
and
A. M. K. Choi.
Regulation of heme oxygenase-1 expression in vivo and in vitro in hyperoxic lung injury.
Am. J. Respir. Cell Mol. Biol.
14:
556-568,
1996[Abstract].
13.
Lee, P. J.,
J. Alam,
G. W. Wiegand,
and
A. M. K. Choi.
Overexpression of heme oygenase-1 in human pulmonary epithelial cells results in cell growth arrest and increased resistance to hyperoxia.
Proc. Natl. Acad. Sci. USA
93:
10393-10398,
1996
14.
Maines, M. D.
The heme oxygenase system: a regulator of second messenger gases.
Annu. Rev. Pharmacol. Toxicol.
37:
517-554,
1997[Medline].
15.
Marilena, G.
New physiological importance of two classic residual products: carbon monoxide and bilirubin.
Biochem. Mol. Med.
61:
136-142,
1997[Medline].
16.
McCoubrey, W. K.,
T. J. Huang,
and
M. D. Maines.
Isolation and characterization of a cDNA from the rat brain that encodes hemoprotein heme oxygenase-3.
Eur. J. Biochem.
247:
725-732,
1997[Medline].
17.
Morita, T.,
and
S. Kourembanas.
Endothelial cell expression of vasoconstrictors and growth factors is regulated by smooth muscle cell-derived carbon monoxide.
J. Clin. Invest.
96:
2676-2682,
1995.
18.
Morita, T.,
M. A. Perrella,
M. E. Lee,
and
S. Kourembanas.
Smooth muscle cell-derived carbon monoxide is a regulator of vascular cGMP.
Proc. Natl. Acad. Sci. USA
92:
1475-1479,
1995
19.
Otterbein, L. E.,
J. Alam,
and
A. M. K. Choi.
Gene transfer of heme oxygenase-1 protects rats against hyperoxia (Abstract).
Am. J. Respir. Crit. Care Med.
157:
A56,
1998.
20.
Otterbein, L. E.,
B. Y. Chin,
L. L. Mantell,
L. Stansberry,
S. Horowitz,
and
A. M. K. Choi.
Pulmonary apoptosis in aged and oxygen-tolerant rats exposed to hyperoxia.
Am. J. Physiol.
275 (Lung Cell. Mol. Physiol. 19):
L14-L20,
1998
21.
Otterbein, L. E.,
S. L. Sylvester,
and
A. M. K. Choi.
Hemoglobin provides protection against lethal endotoxemia in rats: the role of heme oxygenase-1.
Am. J. Respir. Cell Mol. Biol.
13:
595-601,
1995[Abstract].
22.
Poss, K. D.,
and
S. Tonegawa.
Reduced stress defense in heme oxygenase 1 deficient cells.
Proc. Natl. Acad. Sci. USA
94:
10925-10930,
1997
23.
Soares, M. P.,
Y. Lin,
J. Anrather,
E. Csizmada,
K. Tajigami,
S. T. Sato,
R. B. Colvin,
A. M. K. Choi,
K. D. Poss,
and
F. H. Bach.
Expression of heme oxygenase-1 (HO-1) can determine cardiac xenograft survival.
Nat. Med.
4:
1073-1077,
1998[Medline].
24.
Steinberg, K. P.,
J. A. Milberg,
T. R. Martin,
R. J. Maunder,
B. A. Cockrill,
and
L. D. Hudson.
Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome.
Am. J. Respir. Crit. Care Med.
150:
113-122,
1994[Abstract].
25.
Taylor, J. L.,
M. S. Carraway,
and
C. A. Piantadosi.
Lung-specific induction of heme oxygenase-1 and hyperoxic lung injury.
Am. J. Physiol.
274 (Lung Cell. Mol. Physiol. 18):
L582-L591,
1998
26.
Tenhunen, R.,
H. S. Marver,
and
R. Schmidt.
The enzymatic catabolism of hemoglobin: stimulation of microsomal heme oxygenase by hemin.
J. Lab. Clin. Med.
75:
410-421,
1970[Medline].
27.
Verma, A.,
D. J. Hirsch,
C. E. Glatt,
G. V. Ronnett,
and
S. H. Synder.
Carbon monoxide: a putative neural messenger.
Science
259:
381-384,
1993
28.
Vile, G. F.,
S. Basu-Modak,
C. Waltner,
and
R. M. Tyrrell.
Heme oxygenase 1 mediates an adaptive response to oxidative stress in human skin fibroblasts.
Proc. Natl. Acad. Sci. USA
91:
2607-2610,
1994
29.
Vile, G. F.,
and
R. M. Tyrrell.
Oxidative stress resulting from ultraviolet A irradiation of human skin fibroblasts leads to a heme oxygenase-dependent increase in ferritin.
J. Biol. Chem.
268:
14678-14681,
1994
30.
Willis, D.,
A. R. Moore,
R. Frederick, R.,
and
D. A. Willoughby.
Heme oxygenase-1. A novel target for the modulation of the inflammatory response.
Nat. Med.
2:
87-90,
1996[Medline].
31.
Zhuo, M.,
S. A. Small,
E. R. Kandel,
and
R. D. Hawkins.
Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus.
Science
260:
1946-1950,
1993
This article has been cited by other articles:
|
|
 |
|
  S. Mizuguchi, J. Stephen, R. Bihari, N. Markovic, S. Suehiro, A. Capretta, R. F. Potter, and G. Cepinskas CORM-3-derived CO modulates polymorphonuclear leukocyte migration across the vascular endothelium by reducing levels of cell surface-bound elastase Am J Physiol Heart Circ Physiol, September 1, 2009; 297(3): H920 - H929. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Scott, M. A. Cukiernik, M. C. Ott, A. Bihari, A. Badhwar, D. K. Gray, K. A. Harris, N. G. Parry, and R. F. Potter Low-dose inhaled carbon monoxide attenuates the remote intestinal inflammatory response elicited by hindlimb ischemia-reperfusion Am J Physiol Gastrointest Liver Physiol, January 1, 2009; 296(1): G9 - G14. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Nemzek, C. Fry, and O. Abatan Low-dose carbon monoxide treatment attenuates early pulmonary neutrophil recruitment after acid aspiration Am J Physiol Lung Cell Mol Physiol, April 1, 2008; 294(4): L644 - L653. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Kirkby, C. Baylis, A. Agarwal, B. Croker, L. Archer, and C. Adin Intravenous bilirubin provides incomplete protection against renal ischemia-reperfusion injury in vivo Am J Physiol Renal Physiol, February 1, 2007; 292(2): F888 - F894. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Basuroy, S. Bhattacharya, D. Tcheranova, Y. Qu, R. F. Regan, C. W. Leffler, and H. Parfenova HO-2 provides endogenous protection against oxidative stress and apoptosis caused by TNF-{alpha} in cerebral vascular endothelial cells Am J Physiol Cell Physiol, November 1, 2006; 291(5): C897 - C908. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Pryor, K. N. Houk, C. S. Foote, J. M. Fukuto, L. J. Ignarro, G. L. Squadrito, and K. J. A. Davies Free radical biology and medicine: it's a gas, man! Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2006; 291(3): R491 - R511. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. W. Ryter, J. Alam, and A. M. K. Choi Heme Oxygenase-1/Carbon Monoxide: From Basic Science to Therapeutic Applications Physiol Rev, April 1, 2006; 86(2): 583 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Kirkby and C. A. Adin Products of heme oxygenase and their potential therapeutic applications Am J Physiol Renal Physiol, March 1, 2006; 290(3): F563 - F571. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Sarady-Andrews, F. Liu, D. Gallo, A. Nakao, M. Overhaus, R. Ollinger, A. M. Choi, and L. E. Otterbein Biliverdin administration protects against endotoxin-induced acute lung injury in rats Am J Physiol Lung Cell Mol Physiol, December 1, 2005; 289(6): L1131 - L1137. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Morse and A. M. K. Choi Heme Oxygenase-1: From Bench to Bedside Am. J. Respir. Crit. Care Med., September 15, 2005; 172(6): 660 - 670. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ghosh, M. R. Wilson, S. Choudhury, H. Yamamoto, M. E. Goddard, B. Falusi, N. Marczin, and M. Takata Effects of inhaled carbon monoxide on acute lung injury in mice Am J Physiol Lung Cell Mol Physiol, June 1, 2005; 288(6): L1003 - L1009. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. D. Filippo, R. Marfella, S. Cuzzocrea, E. Piegari, P. Petronella, D. Giugliano, F. Rossi, and M. D'Amico Hyperglycemia in Streptozotocin-Induced Diabetic Rat Increases Infarct Size Associated With Low Levels of Myocardial HO-1 During Ischemia/Reperfusion Diabetes, March 1, 2005; 54(3): 803 - 810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Guo, A. B. Stein, W.-J. Wu, W. Tan, X. Zhu, Q.-H. Li, B. Dawn, R. Motterlini, and R. Bolli Administration of a CO-releasing molecule at the time of reperfusion reduces infarct size in vivo Am J Physiol Heart Circ Physiol, May 1, 2004; 286(5): H1649 - H1653. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. Sikorski, T. Hock, N. Hill-Kapturczak, and A. Agarwal The story so far: molecular regulation of the heme oxygenase-1 gene in renal injury Am J Physiol Renal Physiol, March 1, 2004; 286(3): F425 - F441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Kaminski, J. A. Belperio, P. B. Bitterman, L. Chen, S. W. Chensue, A. M.K. Choi, S. Dacic, J. H. Dauber, R. M. du Bois, J. J. Enghild, et al. Idiopathic Pulmonary Fibrosis Am. J. Respir. Cell Mol. Biol., September 1, 2003; 29(3): S1 - 105. [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Machado, J. K. Stoller, D. Laskowski, S. Zheng, J. A. Lupica, R. A. Dweik, and S. C. Erzurum Low levels of nitric oxide and carbon monoxide in alpha 1-antitrypsin deficiency J Appl Physiol, December 1, 2002; 93(6): 2038 - 2043. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhang, E. L. Bedard, R. Potter, R. Zhong, J. Alam, A. M. K. Choi, and P. J. Lee Mitogen-activated protein kinases regulate HO-1 gene transcription after ischemia-reperfusion lung injury Am J Physiol Lung Cell Mol Physiol, October 1, 2002; 283(4): L815 - L829. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Barreiro, A. S. Comtois, S. Mohammed, L. C. Lands, and S. N. A. Hussain Role of heme oxygenases in sepsis-induced diaphragmatic contractile dysfunction and oxidative stress Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L476 - L484. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Vulapalli, Z. Chen, B. H. L. Chua, T. Wang, and C.-S. Liang Cardioselective overexpression of HO-1 prevents I/R-induced cardiac dysfunction and apoptosis Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H688 - H694. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Morse and A. M. K. Choi Heme Oxygenase-1 . The "Emerging Molecule" Has Arrived Am. J. Respir. Cell Mol. Biol., July 1, 2002; 27(1): 8 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. B. KHATRI, M. OZKAN, K. MCCARTHY, D. LASKOWSKI, J. HAMMEL, R. A. DWEIK, and S. C. ERZURUM Alterations in Exhaled Gas Profile during Allergen-induced Asthmatic Response Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): 1844 - 1848. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Foresti, H. Goatly, C. J. Green, and R. Motterlini Role of heme oxygenase-1 in hypoxia-reoxygenation: requirement of substrate heme to promote cardioprotection Am J Physiol Heart Circ Physiol, November 1, 2001; 281(5): H1976 - H1984. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Hill-Kapturczak, V. Thamilselvan, F. Liu, H. S. Nick, and A. Agarwal Mechanism of heme oxygenase-1 gene induction by curcumin in human renal proximal tubule cells Am J Physiol Renal Physiol, November 1, 2001; 281(5): F851 - F859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Clayton, M. S. Carraway, H. B. Suliman, E. D. Thalmann, K. N. Thalmann, D. E. Schmechel, and C. A. Piantadosi Inhaled carbon monoxide and hyperoxic lung injury in rats Am J Physiol Lung Cell Mol Physiol, October 1, 2001; 281(4): L949 - L957. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Chapman, L. E. Otterbein, J. A. Elias, and A. M. K. Choi Carbon monoxide attenuates aeroallergen-induced inflammation in mice Am J Physiol Lung Cell Mol Physiol, July 1, 2001; 281(1): L209 - L216. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Donnelly and P. J. Barnes Expression of Heme Oxygenase in Human Airway Epithelial Cells Am. J. Respir. Cell Mol. Biol., March 1, 2001; 24(3): 295 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. TAILLE, R. FORESTI, S. LANONE, C. ZEDDA, C. GREEN, M. AUBIER, R. MOTTERLINI, and J. BOCZKOWSKI Protective Role of Heme Oxygenases against Endotoxin-induced Diaphragmatic Dysfunction in Rats Am. J. Respir. Crit. Care Med., March 1, 2001; 163(3): 753 - 761. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. E. Otterbein and A. M. K. Choi Heme oxygenase: colors of defense against cellular stress Am J Physiol Lung Cell Mol Physiol, December 1, 2000; 279(6): L1029 - L1037. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Merker, B. R. Pitt, A. M. Choi, P. M. Hassoun, C. A. Dawson, and A. B. Fisher Lung redox homeostasis: emerging concepts Am J Physiol Lung Cell Mol Physiol, September 1, 2000; 279(3): L413 - L417. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Petrache, L. E. Otterbein, J. Alam, G. W. Wiegand, and A. M. K. Choi Heme oxygenase-1 inhibits TNF-alpha -induced apoptosis in cultured fibroblasts Am J Physiol Lung Cell Mol Physiol, February 1, 2000; 278(2): L312 - L319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-F. Yet, R. Tian, M. D. Layne, Z. Y. Wang, K. Maemura, M. Solovyeva, B. Ith, L. G. Melo, L. Zhang, J. S. Ingwall, et al. Cardiac-Specific Expression of Heme Oxygenase-1 Protects Against Ischemia and Reperfusion Injury in Transgenic Mice Circ. Res., July 20, 2001; 89(2): 168 - 173. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
) of exogenous CO (250 ppm).
Group 1, control normoxia;
group 2,
O2 for 48 h;
group 3, SnPP plus
O2 for 48 h;
group 4, SnPP plus
O2 for 48 h plus 250 ppm CO;
group 5,
O2 for 48 h plus 250 ppm CO.
Values are means ± SE of 8 rats.
* P < 0.0001 compared with
groups 1,
4, and
5.
** P < 0.0001 compared with
all other groups.
