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Department of Medicine, Division of Pulmonary and Critical Care Medicine, The Johns Hopkins Medical Institutions at the Asthma and Allergy Center, Hopkins Bayview Medical Center, Baltimore, Maryland 21224
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We previously found that
increased intravascular pressure decreased ischemic lung injury by a
nitric oxide (NO)-dependent mechanism (Becker PM, Buchanan W, and
Sylvester JT. J Appl Physiol 84: 803-808, 1998).
To determine the role of cyclic nucleotides in this response, we
measured the reflection coefficient for albumin (
alb),
fluid flux (
), cGMP, and cAMP in ferret lungs
subjected to either 45 min ("short"; n = 7) or 180 min ("long") of ventilated ischemia. Long ischemic lungs had
"low" (1-2 mmHg, n = 8) or "high" (7-8 mmHg, n = 6) vascular pressure. Other long
low lungs were treated with the NO donor
(Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA-NONOate; 5 × 10
4 M, n = 6) or
8-bromo-cGMP (5 × 104 M, n = 6).
Compared with short ischemia, long low ischemia decreased alb (0.23 ± 0.04 vs. 0.73 ± 0.08;
P < 0.05) and increased (1.93 ± 0.26 vs. 0.58 ± 0.22 ml · min1 · 100 g1;
P < 0.05). High pressure prevented these changes. Lung
cGMP decreased by 66% in long compared with short ischemia. Lung cAMP did not change. PAPA-NONOate and 8-bromo-cGMP increased lung cGMP, but
only 8-bromo-cGMP decreased permeability. These results suggest that
ischemic vascular injury was, in part, mediated by a decrease in cGMP.
Increased vascular pressure prevented injury by a cGMP-independent mechanism that could not be mimicked by administration of exogenous NO.
cGMP; cAMP; lung injury; reflection coefficient; filtration coefficient
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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ISCHEMIA-REPERFUSION LUNG injury is characterized by increased pulmonary vascular permeability and edema (28) and occurs following medical (44) and surgical (18) thrombolysis, cardiopulmonary bypass (35), and lung transplantation (2). Although the clinical manifestations of lung dysfunction are observed following reperfusion, experimental evidence suggests that the injury begins during the ischemic phase (6, 7). For example, we demonstrated increased pulmonary vascular permeability to water and protein in isolated ferret (6) and sheep (30) lungs following 180 and 75 min of ischemia, respectively. The mechanism of the increased vascular permeability in ischemic lungs is unclear, but the detection of reactive oxygen species (ROS) (1) and lipid peroxidation products (7, 14) and a protective effect of ROS scavengers (7) suggests that a component of the injury may be oxidant mediated.
Several investigators have found that subjecting the ischemic pulmonary
vasculature to mechanical strains can have an ameliorating effect on
the injury following reperfusion (3, 26, 39). For example,
either ventilatory stretch (with or without oxygen) or increased static
intravascular pressure during ischemia attenuated the increased
vascular permeability after reperfusion (39). We extended
these findings by demonstrating that these mechanical stimuli
attenuated the increased vascular permeability caused by pulmonary
ischemia before reperfusion. Specifically, ventilation for 75 min of
ischemia prevented the decrease in the reflection coefficient for
albumin (alb) that occurred in statically inflated ischemic lungs (30). Statically inflated ischemic
lungs had a marked decrease in peripheral lung cGMP concentration,
whereas ventilated lungs did not, suggesting that the protective effect of ventilatory stretch may have been mediated by maintenance of endothelial cGMP concentrations (30). Interestingly, the
protective effects of ventilation on alb and lung cGMP
were not blocked by inhibition of nitric oxide (NO) synthase,
suggesting that NO-induced stimulation of soluble guanylate cyclase
(GC) was not involved (30). Ventilatory lung stretch was
not protective after 180 min in ischemic ferret lungs, although the
combination of ventilation and increased static vascular pressure
blocked the increased vascular permeability at this time point
(5). Unlike the effect of ventilatory stretch, the
protective effect of increased vascular pressure was prevented by the
administration of a NO synthase inhibitor, suggesting that hoop
stretch of the vasculature attenuated injury via NO release
(5).
On the basis of these observations, we hypothesized that 1)
the increased vascular permeability observed after 180 min of ventilated ischemia with low vascular pressure would be accompanied by
a decrease in lung cGMP concentration, 2) treatments
designed to increase lung cGMP concentration would attenuate the
increase in vascular permeability, and 3) the protective
effect of increased static vascular pressure would be associated with
sustained levels of lung cGMP concentration. To address these
hypotheses, we measured lung cyclic nucleotide concentrations,
alb, and fluid flux () in
ventilated ferret lungs subjected to 180 min of ischemia in the
presence or absence of increased static vascular pressure or an NO
donor compound. These results were compared with measurements made
after 45 min of ischemia. An additional group of 180 min ischemic lungs
was treated with 8-bromo-cGMP, a cell-permeant cGMP analog, to
determine whether directly increasing lung cGMP concentration could
also mimic the effect of increased intravascular pressure.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Preparation. Adult male ferrets were anesthetized with pentobarbital sodium (50 mg/kg ip). After tracheostomy, mechanical ventilation was begun with room air at a tidal volume of 12 ml/kg body wt and respiratory rate of 20 breaths/min. An abdominal aortic catheter was placed through a midline incision, heparin (1,000 U/kg iv) was administered, and the ferrets were rapidly exsanguinated. Ventilation was adjusted to 10 breaths/min with 95% O2-5% CO2 and positive end-expiratory pressure of 3 mmHg. These settings were constant for the remainder of the experiment. The pulmonary artery and left atrium were cannulated, and the lungs were excised. The pulmonary vasculature was flushed with 50 ml of PSS containing 3 g/dl albumin, 2 g/dl Ficoll, and no glucose as previously described (6).
Effects of ischemic time and intravascular pressure.
After the lungs were flushed of residual blood, intravascular pressure
(Piv) was controlled by connecting the vascular cannulas to
a pressurized reservoir containing the same flush solution, and airway
and vascular pressures were measured by Statham model P50 transducers
referenced to the level of the lung hilum. The temperature was
maintained at 37°C by enclosing the lungs in plastic and submerging
them in a water bath. The lungs were then subjected to either 45 min
("short"; n = 7) or 180 min ("long";
n = 26) of ischemia while maintaining vascular pressure
at either 1-2 mmHg ("low" Piv) or 7-8 mmHg
("high" Piv). Lungs subjected to short low
Piv ischemia (n = 7) were compared with
groups of long low Piv (n = 8) and long
high Piv (n = 6) lungs. In additional groups of long low Piv lungs, the NO donor
(Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA-NONOate; 5 × 104 M, n = 6) or
the cell-permeant analog of cGMP, 8-bromo-cGMP (5 × 104 M, n = 6), was added to the PSS
solution instilled into the lungs at the start of ischemia. The
PAPA-NONOate and 8-bromo-cGMP were obtained from Sigma Chemical (St.
Louis, MO) and prepared fresh daily.
alb,
which was estimated by the filtered volumes method modified for a
nonflowing system as previously described (6). Hct and
albumin concentration were determined in duplicate for each sample, and
alb was estimated iteratively from the relationship
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(1) |
Hct0 )/Hct0, C represents albumin concentration, and
C0 and Hct0 represent initial reservoir values.
To measure water permeability, we performed an additional analysis of
the Hct vs. vascular volume relationship obtained for the measurement
of alb. The amount of erythrocyte-free fluid that left
the lung per unit period of time can be determined by
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(2) |
was chosen as the
time spent at Piv of 30 mmHg, because the contribution to
filtration made by the short times (
5 min) at the lower levels of
Piv was trivial, based on our previous measurements of
filtration coefficient (Kf) in this
preparation (5). An estimate of filtration time, and
therefore , could not be determined in the six lungs
that had a Piv of 30 mmHg for less than 10 min, because of
the significant contribution of the lower Piv levels to
filtration.
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Cyclic nucleotide measurements. Lung biopsies were immediately frozen in liquid nitrogen for later determination of cAMP and cGMP by enzyme immunoassay (Cayman Chemical, Ann Arbor, MI). Cyclic nucleotides were measured in an additional group of lungs (n = 3) subjected to minimal ischemia (<15 min) to estimate in vivo lung concentrations.
Statistical analysis.
The pulmonary vascular permeability and cyclic nucleotide data were
analyzed by a one-factor ANOVA. The cyclic nucleotide data were not
normally distributed and thus were transformed to logarithms before
statistical analysis. When significant (P 0.05)
variance ratios were obtained, least-significant differences were
calculated to allow comparison of individual means. Values presented in
the text are means ± SE. Differences were considered significant
when P 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Compared to short ischemic lungs, long low Piv
ischemia caused a decrease in alb (0.23 ± 0.04 vs. 0.73 ± 0.08) and an increase in
(1.93 ± 0.26 vs. 0.58 ± 0.22 ml · min1 · 100 g1;
P < 0.05), indicating increases (P < 0.05) in vascular permeability to protein and water, respectively (Fig.
2). Treatment with 8-bromo-cGMP attenuated the increase in protein permeability as evidenced by a
alb value of 0.36 ± 0.04, which was greater
(P < 0.05) than long low Piv ischemia.
8-Bromo-cGMP treatment did not decrease compared
with untreated long low Piv lungs, although there was a
trend in this direction (P = 0.09). The NO donor
PAPA-NONOate had no effect on vascular permeability (Fig. 2), whereas
the increased static vascular pressure in the long high Piv
lungs prevented the increases in protein and water permeability
(alb = 0.65 ± 0.07, = 0.89 ± 0.32 ml · min1 · 100 g1; P < 0.05).
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As shown in Fig. 3, lung cGMP
concentration in short ischemic lungs (0.21 ± 0.06 ng/g) fell
within the 95% confidence intervals for lungs subjected to minimal
ischemia, whereas lung cGMP concentration was significantly decreased
by long low Piv and long high Piv ischemia
(0.07 ± 0.01 and 0.04 ± 0.01 ng/g, respectively) compared with short ischemic lungs. Both NO- and 8-bromo-cGMP-treated lungs had
increased lung cGMP concentration compared with long low
Piv lungs. Lung cAMP concentration, which averaged
1.28 ± 0.11 ng/g, did not differ between groups (Fig. 3).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Increasing evidence suggests that mechanical perturbations of the
pulmonary vasculature during ischemia have a protective effect on
the vascular permeability changes following ischemia and reperfusion of
the lung (37, 39). We have been interested in the
increased vascular permeability that occurs during lung ischemia before
reperfusion (6). As shown in Fig. 2, subjecting ferret
lungs to 180 min of warm, ventilated ischemia (long ischemia) decreased
alb compared with 45 min of ischemia (short ischemia), indicating an increase in protein permeability. The alb
is a dimensionless index that describes the ability of the vascular endothelium to maintain an oncotic pressure gradient during convective fluid movement; a alb value of 0 indicates free movement
of albumin across the vessel wall, whereas a alb value
of 1 indicates impermeability to albumin. We have found
alb to be a useful vascular injury index, because it is
sensitive to small changes in vascular permeability and is not affected
by changes in vascular surface area (43). Long low
Piv ischemia also increased vascular permeability to water
as evidenced by an increase in in the current study
(Fig. 2) and Kf in a previous study
(6). We previously showed that alb and
Kf following short ischemia were not different
from a separate group of minimally ischemic ferret lungs,
suggesting that, in the presence of continued ventilation and low
Piv, ischemic vascular injury occurred at a time between 45 and 180 min of ischemia (6). These data are similar to our
experience with the effect of ischemia on vascular permeability in
ventilated sheep lungs where 75 min of low Piv ischemia was
also associated with normal values of alb and
Kf (29, 30).
Effect of ischemia on lung cyclic nucleotide concentrations.
The first objective of the current study was to determine the
relationship between lung cyclic nucleotide concentration and vascular
permeability in the ventilated ischemic ferret lung. As shown in Fig.
3, the 68% increase in vascular permeability (change in
alb) in the long ischemic lungs was associated with a
66% decrease in lung cGMP concentration compared with short ischemic
lungs which, in turn, were not different from minimally ischemic lungs.
Ischemia had no effect on lung cAMP concentration, suggesting that the
effect of ischemia on lung cGMP concentration was not a manifestation
of nonspecific cellular injury. We recently reported a selective
decrease in lung cGMP concentration in ischemic sheep lungs
(30). In that study, 75 min of ischemia under conditions of static inflation and low Piv caused a 99% decrease in
lung cGMP concentration without altering lung cAMP concentration. The decrease in cGMP was associated with an increase in vascular
permeability to protein and water. Ventilation attenuated both the
decrease in cGMP and the increase in vascular permeability without
altering pulmonary capillary blood gas tensions, suggesting that
ventilatory lung stretch delayed ischemic vascular injury possibly
by maintaining pulmonary endothelial concentrations of cGMP. In support
of this hypothesis, treatment of statically inflated ischemic lungs
with sodium nitroprusside, an NO donor, restored normal levels of both cGMP concentration and vascular permeability (30). The
current data extend these findings by suggesting that the protective
effect of ventilation on lung cGMP concentration in low Piv
ischemic lungs becomes ineffective between 75 and 180 min of ischemia, coincident with the time that vascular permeability increases.
Effect of NO and 8-bromo-cGMP on vascular permeability and lung
cGMP concentration.
To determine whether the decrease in cGMP observed in the long low
Piv lungs was responsible for the increase in vascular permeability, we attempted to restore cGMP levels back to the normal
range by administering the NO donor compound PAPA-NONOate. PAPA-NONOate
spontaneously releases NO in a first order process with a half-life of
~15 min at physiological pH and temperature (17). As
shown in Figs. 2 and 3, generation of NO within the pulmonary
vasculature restored normal lung cGMP concentration without
ameliorating the increased pulmonary vascular permeability. There are
several possible explanations for this result, specifically: 1) the decreased lung cGMP concentration was a marker of
ischemic injury but was not a cause of increased vascular permeability; 2) NO failed to increase cGMP in critical endothelial or
subendothelial compartments despite an increase in whole lung cGMP
concentration; 3) the duration of the cGMP response was
inadequate to sustain protection to the end of the protocol because NO
production stopped or PDE activity increased; and 4) a
separate injurious effect of NO occurred countering cGMP-mediated
protection. When NO concentrations exceed a critical level, protective
antioxidant effects or cGMP-mediated actions may be overwhelmed by NO
toxicity (17). The toxic effects of excess NO may be
mediated by the generation of additional ROS (25) such as
peroxynitrite or may occur through oxidant-independent pathways
(17). To address this possibility, we treated two
additional long low Piv lungs with 10 µM PAPA-NONOate.
Vascular permeability in these lungs remained elevated as evidenced by
an average alb of 0.16 (data not shown), suggesting that
the lack of protection conferred by PAPA-NONOate was not due to NO toxicity.
alb accompanied by an
increase in lung cGMP concentration, indicating a cGMP-induced decrease
in protein permeability. Treatment with 8-bromo-cGMP did not decrease
, however, suggesting that water permeability was
unaffected. A change in protein but not water permeability is
consistent with the theory that different-sized pores are responsible
for the movement of water and protein across the microvascular barrier
of the lung (41). An increase in the number of large pores
responsible for protein conductance could theoretically decrease
alb without affecting (41,
43).
As mentioned above, cGMP administration has been shown to attenuate
several forms of oxidant injury including ischemia-reperfusion lung
injury (33), hydrogen peroxide-induced liver injury
(8), and hydrogen peroxide-induced protein permeability in
pulmonary artery (40) and aortic endothelial monolayers
(21). Administration of cGMP has been less successful in
preventing increases in pulmonary endothelial permeability that were
not mediated by ROS such as thrombin (27), phorbol
myristate acetate (9), and protamine (13),
perhaps suggesting that cGMP interferes at a relatively proximal,
ROS-dependent step in the pathway mediating the increase in
permeability. In this regard, it was interesting to note that the
effect of 8-bromo-cGMP on vascular permeability in the long low
Piv group in the current study (Fig. 2) was nearly
identical to the previously reported effect of adding superoxide
dismutase and catalase to the vascular flush solution of long low
Piv lungs which caused alb to increase from
0.19 to 0.32 (7). One explanation for this result was that
only a small component of the ischemic injury present at 180 min was
oxidant-mediated and thus responsive to antioxidants or cGMP. The
absence of a correlation between vascular permeability and lipid
peroxidation in lungs subjected to varying ischemic times
(7) supports this conclusion.
Potential downstream targets for cGMP include cGMP-dependent protein
kinases (PKG), cGMP-regulated ion channels, and cGMP-regulated PDE
(20). The precise mechanisms underlying the antioxidant properties of cGMP remain poorly understood, but the ability to reverse
the protective effects of 8-bromo-cGMP on reperfusion lung injury with
an inhibitor of PKG (33) suggests that this may be the
most important downstream pathway in ischemia-reperfusion lung injury.
Moreover, PKG activity was recently reported in pulmonary microvascular
endothelial cells (11). The potential targets and effects
of PKG are numerous (11), but the specific mechanisms mediating the protection conferred by cGMP remain poorly understood. For example, one of the proteins phosphorylated by PKG,
vasodilator-stimulated phosphoprotein (VASP), is associated with focal
adhesions, where it interacts with cytoskeletal structures
(12). Although the role of VASP in regulating endothelial
barrier function is not known, phosphorylation of VASP or other
cytoskeletal-associated proteins could explain the ability of cGMP to
inhibit hydrogen peroxide-induced actin stress fiber formation in
cultured endothelial cells (21). PKG modulates ion
channels (42), ion pumps (42), and other
second messenger pathways (36), however, so many possible protective mechanisms exist. Finally, the studies demonstrating a
predisposition toward oxidant injury in cells with decreased cGMP
(15, 24) suggest that PKG may be an important
regulator of cellular antioxidant enzyme function.
Effect of increased Piv on vascular permeability and
lung cGMP concentration.
As shown previously (5), increasing static vascular
pressure during 180 min of ischemia to a level above end-expiratory airway pressure prevented the increase in protein permeability observed
in ischemic lungs with low vascular pressure (Fig. 2). Increased
Piv did not attenuate the increase in
Kf in our previous study, although there was a
trend for a decreased Kf in the high Piv lungs. As shown in Fig. 2 in the current study, high
Piv significantly decreased , suggesting
a protective effect on water permeability. Schutte et al.
(39) recently showed in isolated rabbit lungs that an
increased Piv (3-4 mmHg) during 120 min of ischemia
prevented an increased Kf following reperfusion.
Although the mechanism of this effect was not determined, protection
occurred in the presence or absence of ventilatory lung motion during
ischemia (39), suggesting that the effect was mediated by
vascular distention rather than enhanced ventilatory motion of blood
between the alveolar and extra-alveolar vessels. We were able to block
the protective effect of high Piv on ischemic vascular
injury by NG-nitro-L-arginine methyl
ester (L-NAME), an NO synthase inhibitor, but not
D-NAME, its inactive isomer, suggesting that vascular distension preserved barrier function through increased NO production (5). Moreover, the inhibition caused by L-NAME
was reversed by adding excess L-arginine, confirming the
specificity of the effect. On the basis of these data, we expected to
see an increase in cGMP concentration in long high Piv
lungs compared with long low Piv lungs. As shown in Fig. 3,
however, lung cGMP concentration was decreased in both groups despite
their differences in vascular permeability. The interpretation of this
result depends on the ability of the whole lung measurement of cGMP to
detect small changes within a single cellular compartment of the lung.
Given that many investigators routinely use PDE inhibitors in their experimental systems to allow detection of small changes in cellular cyclic nucleotide concentrations, it may not be surprising that we were
unable to see a difference in the absence of PDE inhibition. Moreover,
pulmonary vascular endothelial cells were shown to transport cGMP into
the vascular lumen of perfused lungs under conditions of increasing
vascular distension at constant flow (4), suggesting an
additional pathway for loss of endothelial cGMP. On the other hand, it
is also possible that NO was generated in the alveolar capillary bed by
vascular distension and prevented the adverse affects of ischemia
without a concomitant change in cGMP concentration. When generated in
small concentrations, NO has been shown to have potent antioxidant
properties not dependent on the generation of cGMP (10,
17). Moreover, cultured rat pulmonary microvascular endothelial
cells did not express sGC (34) and thus were not capable
of an NO-induced increase in cGMP concentration. It is not known
whether these cultured cells accurately reflected their in vivo
counterparts or whether ferret lung is similar to rat lung in this regard.
Measurement of .
We used the profile of increased Hct values in the sequential vascular
volume samples to calculate . As an index of water conductance, this measurement has both advantages and disadvantages compared with a Kf value determined from
measuring lung weight. The advantages include the ability to measure an
index of water conductance that is not affected by changes in vascular
volume or loss of edema fluid from the lung surface. Both of these
factors influence the gravimetric measurement of
Kf (16, 31). The disadvantages of
the measurement include an underestimation of
maximal fluid conductance if red blood cells remain trapped in the
pulmonary vasculature from the most injured regions or significant
hemorrhage occurs.
Summary. Three hours of low Piv ischemia in ventilated ferret lungs caused an increase in vascular permeability that was associated with a decrease in lung cGMP (but not cAMP) concentration. Lungs subjected to shorter ischemic times had no change in either permeability or cGMP concentration. Restoration of lung cGMP concentrations with 8-bromo-cGMP, but not an NO donor, significantly attenuated the increase in permeability. Increased static pulmonary vascular pressure prevented the increase in vascular permeability but did not affect the decrease in cGMP concentration. We conclude that the increase in vascular permeability caused by 180 min of ischemia in ventilated lungs was mediated in part by a decrease in lung cGMP. Increased Piv prevented injury by a cGMP-independent mechanism that could not be mimicked in low Piv lungs by exogenous NO.
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ACKNOWLEDGEMENTS |
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We thank Wendy Buchanan and Teresa Privett for expert technical assistance, Dr. Solbert Permutt for helpful discussions, and Wanda Moran for excellent secretarial support.
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FOOTNOTES |
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This work was supported by National Heart, Lung, and Blood Institute Grants HL-50504 (to D. B. Pearse) and HL-02933 (to P. M. Becker) and by a Grant-In-Aid and Established Investigator Award (to D. B. Pearse) from the American Heart Association (AHA) with funds contributed in part by the AHA, Maryland Affiliate.
Address for reprint requests and other correspondence: D. Pearse, Division of Pulmonary and Critical Care Medicine, Hopkins Bayview Medical Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224 (E-mail: dpearse{at}welch.jhu.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.
Received 16 March 2000; accepted in final form 19 May 2000.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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