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1 Washington University School of Medicine, St. Louis 63110; 2 St. Louis University, St. Louis, Missouri 63103; and 3 Vanderbilt University School of Medicine, Nashville, Tennessee 37240
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Recent studies have demonstrated significant synergistic physiological and biochemical effects between low-dose endotoxin (Etx) administration and oleic acid (OA)-induced canine lung injury. To evaluate whether this interaction depends on Etx priming of some key cell population, we compared the effects of giving low-dose Etx both after as well as before inducing lung injury with OA. In addition to hemodynamic and blood-gas measurements, positron emission tomographic imaging was used to measure edema accumulation and intrapulmonary blood flow distribution. Biochemical measurements of the stable metabolites of prostacyclin and thromboxane were obtained as well as measurements of isoprostanes and reactive sulfhydryls as evidence for possible concomitant oxidant production. We found that the physiological and biochemical effects of low-dose Etx developed 30-45 min after its administration, regardless of whether Etx was administered before or after OA. No increase in either isoprostane or reactive sulfhydryl production after Etx and/or OA was detected. These data suggest that the synergistic effect of low-dose Etx and OA-induced lung injury is not due to a priming effect of Etx.
positron emission tomography; pulmonary edema
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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THE INJECTION OF OLEIC ACID (OA) into the pulmonary circulation is one of the most commonly used experimental models of acute lung injury (19). The injury, at least initially, appears to be the result of a direct interaction between OA and pulmonary endothelial cell membranes; i.e., injury is not initiated by inflammatory cells or their products. Nevertheless, small doses of endotoxin (Etx), which by themselves are largely devoid of systemic or pulmonary hemodynamic effects, can markedly alter the physiological expression of lung injury after OA administration, including a failure to develop otherwise characteristic pulmonary hypertension, a failure to redistribute pulmonary blood flow away from edematous lung regions, and the development of systemic hypotension (7). These effects (i.e., effects of low-dose Etx in this model) appear to be mediated by enhanced arachidonic acid release in the presence of upregulated cyclooxygenase-2 (COX-2), which results in increased prostacyclin production (9).
This sequence of events, namely Etx administration followed by OA-induced injury, suggests a priming effect of Etx on some cell population, which then modifies the response to OA. Certainly, there is ample evidence that Etx can prime circulating inflammatory or endothelial cells, thereby greatly enhancing the production of various prostanoids (15, 23, 24, 27, 30). Whether the effects of low-dose Etx on the OA model involve priming effects on inflammatory cells (circulating or resident in the lung) or on other cell populations (e.g., the endothelium) has not been determined.
Priming has been defined as a sequence of events in which a first stimulus influences an intermediate step used by a second stimulus (13). Furthermore, the response to the two stimuli should be different from any sequential response to the same stimulus. By some definitions, the priming signal should be distinct from the second signal (13). Accordingly, we proposed that low-dose Etx (the first stimulus) can influence the regulation of the inducible form of COX-2 (the intermediate step), which, in the presence of acute lung injury (the second stimulus), results in the production of prostacyclin that far exceeds that observed in the absence of low-dose Etx. The physiological and thus clinical consequences of this sequence of events are a dramatic worsening of gas exchange and systemic hemodynamics.
By the above definition, the priming stimulus must come before the second stimulus. It would be expected, then, that reversing the order of the stimuli should alter the expression of their combined effects if priming per se is the operative mechanism. Thus, assuming that the effects of Etx in this model necessarily depend on Etx-induced priming of a critical cell population, we hypothesized that low-dose Etx administered after OA would have little to no effect on prostanoid production, gas exchange, or hemodynamics beyond that caused by OA alone.
As part of these experiments, we also took the opportunity to more carefully characterize the temporal development of the physiological and biochemical effects of the Etx-OA interaction, including biochemical probes for evidence of oxidant production, which would potentially provide additional clues about the mechanism underlying the Etx effect.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal preparation. These studies were approved by the Washington University School of Medicine Animal Studies Committee. Twenty-six healthy mongrel dogs (weight range = 18.0-22.6 kg; mean 19.8 ± 1.1 kg) were anesthetized with pentobarbital sodium (25 mg/kg) administered via a forelimb peripheral vein, intubated with no. 9 cuffed endotracheal tube (Mallinckrodt, St. Louis, MO), and ventilated with a Harvard pump respirator (Harvard Apparatus, South Natick, MA) with the following settings: fraction inspired oxygen of 1.0, tidal volume of 15 ml/kg, and rate adjusted to a normal arterial partial pressure of CO2 (PaCO2) at baseline. Positive end-expiratory pressure was set to 0 cmH2O.
Instrumentation was performed in a sterile fashion with animals fixed in the supine position. After percutaneous insertion of bilateral femoral 8.5-Fr introducer sheaths (Baxter Heathcare, Irvine, CA), a 7.5-Fr balloon-tipped pulmonary artery catheter (Baxter) and a 110-cm 7.0-Fr pigtail catheter (Cook, Bloomington, IN) were positioned in the pulmonary artery under fluoroscopic guidance for hemodynamic monitoring and blood withdrawal, respectively. An external jugular 6.0-Fr introducer (Cook) was inserted percutaneously, and radionuclides were administered via a 5-cm length of infant feeding tube placed in this introducer sheath. A 20-gauge arterial catheter (Arrow International, Reading, PA) was percutaneously inserted into a femoral artery by using a Seldinger technique for continuous blood pressure monitoring and blood sampling. Catheter patency was maintained using intermittent heparinized saline flushes. Cardiac output was measured by the thermodilution technique (difference of 2 successive measurements <5%) by using a cardiac output computer (American Edwards Laboratories, Irvine, CA). Pressure transducers (Baxter) were calibrated to the center of the lateral chest and connected to a Mennen model 742 monitor (Mennen, Clarence, NY) for monitoring of systemic and pulmonary arterial pressures and periodic wedge pressure measurement. Continuous systemic and pulmonary arterial pressures were recorded with the use of a MacIntosh 165B portable computer with AcqKnowledge 3.5.5 software (BIOPAC Systems, Santa Barbara, CA). Blood gases were analyzed by using an Instrumentation Laboratories (Lexington, MA) model 1630 blood-gas analyzer. A transurethral bladder catheter was placed in all animals.Position emission tomography techniques.
Regional pulmonary blood flow and regional lung water content were
measured by using positron emission tomography (PET) imaging techniques. In general, PET is used to measure the tissue concentration and distribution of a positron-emitting radionuclide, which in the present study was simply H215O. The
activity data measured with PET, when combined with blood activity
(used as a reference) and analyzed with an appropriate compartmental
mathematical model, yield tomographic images representative of
pulmonary blood flow. In the present study, these measurements were
obtained with a Siemens/CTI ECAT EXAC HR plus 962 scanner, a
63-plane positron camera with an axial sampling of 2.43 mm, isotropic
resolution of 4.6 mm, and a 15 × 56-cm field of view. Because the
pattern of pulmonary blood flow in normal dogs (as measured with PET
imaging) is well established in this model
(7-9), we only obtained pulmonary blood flow data
once, ~2 h after lung injury (Table
1).
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Image analysis. Our methods for image analysis have also been described in detail elsewhere (21, 22). To evaluate the relationship of pulmonary blood flow to anatomic position within the lung, the pulmonary blood flow data in each image pixel are sorted by bins along a ventral-dorsal gradient. Arbitrarily, data were divided into 20 bins stacked vertically in the ventral-dorsal direction so that each bin contained 20-25 pixels, which could then be averaged. By keeping the number of bins per region and the number of tomographic slices per dog constant, we could average bin values across dogs, which allows comparisons between experimental groups. To quantify perfusion redistribution, we calculated and summed the fractional pulmonary blood flow in the six most dorsal bins. Reliably, these bins represent the edematous lung regions after OA injury (7-9). The average value for each group was compared. A significantly reduced fractional blood flow to these six image bins compared with normal, uninjured lungs represents perfusion redistribution away from the edematous lung region.
Experimental protocols.
Five groups of five to six dogs each were studied (Table 1). In
the normal group, animals were anesthetized and instrumented as
described above, but no experimental interventions were performed. In
the Etx-only group, 15 µg/kg Escherichia coli Etx
(Fisher Scientific, Pittsburgh, PA) was injected into the central
venous circulation after baseline measurements. After this, no other
interventions were performed. This dose of Etx is known to inhibit
perfusion redistribution during acute lung injury without significant
systemic hemodynamic changes (7, 9, 26, 28). In the
OA-only group, the only experimental intervention (other than placebo
administration) was 0.08 ml/kg OA infused into the central venous
catheter. In the Etx
OA group, Etx was injected via the central
venous catheter, followed 30 min later by OA. Finally, in the OAEtx
group, OA was administered after baseline data were obtained. The
animals were then watched for ~2 h, after which Etx was administered
as above, and the animals were watched for ~1 h more. At the end of
each study, animals were euthanized with additional pentobarbital sodium followed by 20 ml of saturated KCl. Time 0 in each
group was the time of OA administration (or placebo as appropriate; Table 1).
Biochemical analyses.
Blood was drawn at baseline, before each intervention (Etx or OA
administration, PET imaging) and at selected times between interventions, which resulted in a blood sample being drawn
approximately every 30 min during the experimental observation period.
In group OAEtx, blood was drawn more frequently (approximately every
15 min) for ~1 h after Etx administration. Blood was drawn into tubes containing EDTA (1 mg/ml) and indomethacin (5 µg/ml) and then was
centrifuged immediately at 1,800 g for 10 min at 5°C. The plasma was removed and stored frozen at 
80°C until assay.
and thromboxane B2
(TxB2), respectively. The methods used to make these
measurements have been reported previously (7).
Evidence for possible oxidant production was obtained by measuring
plasma reactive sulfhydryl (RSH) and 8-iso-PGF2
concentrations. A reaction with 5,5'-dithiobis(2-nitrobenzoic acid) was
used to determine the plasma oxidant-RSH content, by using previously described methods (11). Because 99% of plasma RSH groups
are protein associated, the RSH content was normalized for total
protein, as measured by the biuret reaction technique, to account
for any protein concentration differences among animals.
F2-isoprostanes were quantified in plasma by employing a
stable isotope-dilution mass-spectrometric assay as previously
described (14). The precision of the assay is ±6%, and
the accuracy is 96%.
Statistical analysis. Data are presented as means ± SD. Statistical significance was determined by one- or two-way ANOVA as appropriate (including algorithms for repeated measures when needed) by using the General Linear Models Procedure of the Statistical Analysis System (SAS, Cary, NC). Because of the large number of possible interactions and comparisons with a relatively small number of animals per experimental group, we limited statistical testing either to a comparison of mean values among the groups at the end of each experiment or to a comparison of final values to baseline values within any one group. We accepted P < 0.05 as indicating statistical significance.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Hemodynamic, blood-gas, and PET data.
In the normal group, cardiac output, systemic and pulmonary
artery blood pressures, and blood gases were stable throughout the
experimental observation period (Table
2, Fig.
1).
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OA groups. The pH
fell significantly from baseline in each group, and the level reached
in the EtxOA and OAEtx groups was significantly lower than in the
OA-only group (Table 2). PaCO2 rose significantly from
baseline only in the EtxOA and OAEtx groups (Table 2). Overall,
these hemodynamic and blood-gas changes are similar to previously
reported effects of OA (7, 9).
Mean arterial blood pressure fell in all experimental groups (Fig. 1).
Note that, after the initial interventions were completed by 0.5 h, the mean arterial blood pressure was stable in all experimental groups for over 90 min. However, in animals given both low-dose Etx and
OA, regardless of whether they were given at the beginning or at the
end of each study, the fall in blood pressure was greater. Importantly,
the additional fall in blood pressure in the OAEtx group did not
occur until after administration of low-dose Etx (Fig. 1).
By the end of each study, pulmonary artery pressure increased
significantly only in the group given OA alone (Fig.
2). Stated differently, low-dose Etx
alone had no effect on pulmonary artery pressure and prevented or
reversed the pulmonary hypertension that otherwise developed in
OA-treated animals.
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Etx group before Etx
administration) showed perfusion redistribution away from the dorsal
edematous lung regions (Fig. 4). In contrast, animals given Etx plus OA
showed no perfusion redistribution. Once again, as with the development
of pulmonary hypertension, low-dose Etx both prevented and essentially
reversed this otherwise physiological response to lung injury.
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Etx group before Etx administration) showed moderate decreases
in oxygenation. As with mean arterial blood pressure, oxygenation was
basically stable for over 90 min after the initial set of interventions. However, animals given both low-dose Etx and OA showed
marked worsening of oxygenation compared with those animals given OA
only (either the OA-only group or those animals in the OAEtx group
before Etx administration). As one would predict from the perfusion
patterns observed in the OAEtx group (Fig. 4), the greater
deterioration in oxygenation in this group did not occur until after
administration of Etx.
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Biochemical measurements.
Of the various biochemical measurements obtained, the most
profound changes occurred in the plasma concentrations of
6-keto-PGF1 (Fig. 6).
Animals given OA alone (OA-only group and the OAEtx group before Etx
administration) showed no increase in 6-keto-PGF1 concentrations. Animals given low-dose Etx alone showed a modest increase in 6-keto-PGF1 concentrations during
approximately the first hour after administration. After this time, the
increase in 6-keto-PGF1 concentrations were sustained
but did not increase further.
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concentrations for at least
2.5-3 h after both drugs were administered and achieved levels
that were 10-15 times greater than those observed at baseline or
at the same time in the normal group (Fig. 6). Likewise, in animals
given Etx after OA, 6-keto-PGF1 concentrations rose rapidly and dramatically to levels that were comparable to the OAEtx
group at the same time (Fig. 6).
The data presented in Fig. 6 also provide interesting insights into the
kinetics of the Etx-OA intervention. The initial increase in
6-keto-PGF1 concentrations in the Etx-only and EtxOA groups takes 30-60 min to develop. In the OAEtx group, blood for 6-keto-PGF1 measurements was obtained approximately
every 15 min after Etx was given. No increase in
6-keto-PGF1 concentrations was observed at the 15-min
time point (data not shown). However, by 30-45 min,
6-keto-PGF1 concentrations were always dramatically increased. At the same time, we observed marked deterioration in
oxygenation (Fig. 5) and a fall in systemic and pulmonary arterial blood pressures (Fig. 1). The abrupt onset of these physiological changes is graphically illustrated by serial data from one animal in
the OAEtx group (Fig. 7).
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OA groups but were not different from the normal or OA-only
groups by the end of the experiment. In the OAEtx group, the
TxB2 concentration after Etx was 448 ± 166 pg/ml
blood, which was significantly higher than the concentration in the
OA-only group (238 ± 292 pg/ml blood).
Evidence for oxidant production as a possible mediator of the Etx-OA
interaction was sought by measuring 8-iso-PGF2 and RSH
concentrations in circulating blood. Unfortunately, the RSH measurements could not be performed in the three groups receiving OA
because of hemolysis in virtually all these samples. In the Etx-only
group, however, there was no evidence of signficant oxidant production
with this assay (no significant change over time or compared with data
from the normal group).
Supporting these limited observations are the serial measurements of
8-iso-PGF2 concentrations. By the end of the experiment, the 8-iso-PGF2 concentrations were slightly but
statistically higher only in the EtxOA group and then only compared
with the OAEtx group (Fig. 8). This
tendency was not seen until approximately the last hour of experimental
measurements (data not shown). In other words, the kinetics of the
increase in 8-iso-PGF2 concentrations were delayed
compared with the development of increased 6-keto-PGF1 concentrations.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In several previous studies, our laboratory has reported a striking synergistic effect between low-dose Etx and OA-induced injury (7-9). At least one set of consequences of this synergism is apparently mediated by COX-2-driven increases in prostacyclin production (9), the results of which are prevention of pulmonary hypertension, prevention of the normally expected redistribution of regional pulmonary blood flow away from edematous lung regions, markedly worsening oxygenation, and the development of systemic hypotension. It is important to keep in mind that the dose of Etx used in this study was at least 30-60 times less than that usually used to cause experimentally-induced septic shock in dogs (3). When administered alone, this dose of Etx has minimal cardiovascular effects, no effect on lung water accumulation, and no effect on gas exchange (Table 2, Figs. 1-5).
The current study extends this previous work by showing that 1) the mechanism for the Etx-OA-injury interaction is inconsistent with the phenomenon of priming as an underlying mechanism, 2) the onset of effects from this interaction follows a predictable time delay of ~30-45 min after both drugs are administered, and 3) the interaction may be independent of (i.e., is not mediated by) increased oxidant production.
Priming. In our previous studies, low-dose Etx was used primarily to ablate intrapulmonary perfusion redistribution in an effort to discern its importance to maintaining gas exchange (7-9). Because low-dose Etx has also been used in numerous studies to prevent the development of hypoxic pulmonary vasoconstriction (25, 26, 28), we speculated that the effects of Etx in this setting implied that the mechanism underlying perfusion redistribution in this model was also hypoxic pulmonary vasoconstriction. Regardless of its intended purpose in these previous studies, Etx was always administered before OA administration. When we discovered that the effects of Etx were apparently mediated by COX-2-driven increases in prostacyclin production (9), we further speculated that Etx primed lung cells (most likely the endothelium) to increase COX-2 production, which, in the presence of increased arachidonic acid release secondary to OA-induced lung injury, resulted in markedly increased prostacyclin production.
Clearly, others have shown that Etx, including low doses or concentrations of Etx, can alter cellular responses to a subsequent challenge with higher doses of Etx or to a new exposure to exotoxin, platelet activating factor, or arachidonic acid, among other secondary stimuli, and result in increased eicosanoid production (1, 4, 5, 15, 23, 24, 27, 30). However, these other studies have not altered the sequence of first and second stimuli, so whether they indeed involve priming or synergy is not always clear. As stated previously, priming has been defined as a sequence of events in which a first stimulus influences an intermediate step used by a second stimulus. Obviously, the temporal relationship between the first and second stimuli is inherent in such a definition. Thus a straightforward test of priming in our case was to simply reverse the order of the two stimuli (low-dose Etx and OA administration). Because the physiological and biochemical consequences were the same regardless of order, the interaction must not depend on Etx priming of a specific cell population.Temporal relationships. The administration of low-dose Etx ~2 hrs after fully developed and stable lung injury (time periods from 1.0-3.0 h in Figs. 1 and 5) allowed us to better define the temporal development of this interaction. Previously (7, 9), when we administered the Etx just 30 min before OA, the interpretation of subsequent physiological changes was confounded by the progressive changes in edema accumulation, intrapulmonary hemodynamics, and gas exchange that take place during the first 90-120 min in this model. Furthermore, previous biochemical measurements had been obtained only at the time of PET imaging, which resulted in only two to three observations per experiment.
In the present study, the effects of administering low-dose Etx were not immediate, but required a predictable period of 30-45 min before becoming apparent (Figs. 6 and 7). To the extent that the Etx-OA interaction is dependent on COX-2 activation (generally thought to be inducible and not constitutively expressed), this time interval may seem short. However, recent in vitro data have shown that a variety of inflammatory mediators, including lipopolysaccharide, can indeed lead to substantial COX-2 activation in as little as 30 min (16). Furthermore, Ermert et al. (5) have shown that COX-2 may be constitutively expressed in rat lung. Thus COX-2-mediated production of prostacyclin is still a plausible explanation for the low-dose Etx-OA injury interaction.Biochemical mechanisms. Cyclooxygenase is not thought to be rate limiting in eicosanoid production, so an increase in prostacyclin production, although possibly dependent on upregulation of cyclooxygenase, implies additional release of arachidonic acid. It is possible that OA injury involves increased arachidonic acid release, which, in the presence of upregulated cyclooxygenase, combines to produce increased prostacyclin production. A recent study in rats showed that 6 h of lipopolysaccharide infusion alone had relatively little effect on prostacyclin production, but that concentrations rose rapidly after a source of arachidonic acid was provided (10). Another recent study showed that many of the physiological consequences of OA injury can be prevented by a phospholipase A2 specific inhibitor, presumably by reducing arachidonate release (6). The results of the current study are consistent with these observations.
Because prostacyclin synthase (the terminal enzyme in prostacyclin production) activity is largely limited to endothelium, it is reasonable to assume that these cells must ultimately be responsible for the increased prostacyclin production seen in the current studies. However, the source of increased cyclooxygenase expression could be circulating inflammatory cells, inflammatory cells that have become trapped in the lung as a result of endothelial injury, or endothelium in the lung or elsewhere. If lung endothelium is not the source of increased cyclooxygenase activity, a mechanism for delivering the intermediate product PGH2 must be identified, and examples of transcellular transport of eicosanoids have been described (12). Although OA injury itself does not require inflammatory cells to develop (19), inflammatory cells clearly do become sequestered and migrate into the lung after OA injury. The effects of Etx on endothelium (if any in the context of this study) may be a direct one or may involve intermediate products of inflammatory cells, such as oxygen-free radicals, tumor necrosis factor-
, or
platelet-activating factor among others, all of which have been
implicated in cascades of events that culminate in increased eicosanoid
production. Such participation by inflammatory cells, if required,
could help explain some or all of the temporal delay that was observed
after Etx administration before physiological and biochemical changes
became manifest. In the current study, however, we failed to find any
convincing evidence that increased oxidant production was at all
involved in explaining the Etx-OA interaction. Indeed, what evidence
for increased oxidant production was obtained came only after several
hours of exposure to both Etx and lung injury and clearly after the
increase in prostacyclin concentrations was already present. Although
such inferences from biochemical measurements obtained in plasma are
not definitive, they do point away from oxidant production as a likely
explanation for the Etx-OA interaction.
Clinical implications.
The so-called "two hit" hypothesis is one commonly invoked paradigm
used to explain the pathogenesis of acute respiratory distress syndrome
(ARDS) and associated other multiorgan system dysfunctions
(2). The hypothesis claims that sequential inflammatory insults are often required for organ injury to become manifest. Priming
of inflammatory cells by cytokines or other mediators is an intrinsic
part of this paradigm. If one keeps in mind that the results of the
current study may differ if retested in other species or other models
of lung injury, our data do suggest that alternative scenarios could
also be important. Our results suggest that small, intermittent,
circulating concentrations of Etx can substantially affect the
physiological consequences of already established and apparently stable
lung injury. What appears to be relatively mild noncardiogenic edema
can quickly change to a clinical picture of severe hypoxemia and
systemic hypotension (changes after Etx in the OAEtx group in Figs.
1, 5, and 7). Of course, it is not known whether a comparable
phenomenon occurs in ARDS, nor, if it does, exactly how low a
concentration of Etx would trigger these events.
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ACKNOWLEDGEMENTS |
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This work was supported in part by National Heart, Lung, and Blood Institute Grants HL-32815 and HL-52675 and National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-48831 and DK-26657. Dr. Morrow is a recipient of a Burroughs Wellcome Clinical Scientist Award in Translational Research.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. P. Schuster, Pulmonary and Critical Care Division, Washington Univ. School of Medicine, 510 S. Kingshighway, Univ. Box 8225, St. Louis, MO 63110 (E-mail: schusted{at}msnotes.wustl.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 13 December 2000; accepted in final form 27 July 2001.
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TOP
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METHODS
RESULTS
DISCUSSION
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