1Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224; and 2Department of Chest Medicine, Faculty of Medicine, Ankara University, 06100 Ankara, Turkey
Submitted 12 February 2003 ; accepted in final form 15 May 2003
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ABSTRACT |
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multiorgan system dysfunction; interleukin-6; tumor necrosis factor-; vascular endothelial growth factor; vascular endothelial growth factor receptor-2
Many prior animal models evaluating ventilator-associated lung injury have focused on determining the effects of VT higher than those used conventionally to ventilate patients in the intensive care unit (ICU), as these conventional ventilatory strategies do not cause significant injury during short periods of mechanical ventilation of healthy animals, whereas more recent studies have focused on the mechanisms of the protective effects of decreased ventilatory stretch in acute lung injury (15). Several of these prior studies have suggested that proinflammatory cytokines and chemokines are released into the circulation with high VT ventilation (19, 48), although this finding remains controversial (51). Clinically, however, it has also been recognized that patients with ARDS are at increased risk for systemic multiorgan failure (41).
We were therefore interested in determining whether a protective VT strategy attenuates production of mediators that could predispose to both lung injury and remote organ dysfunction and whether systemic organs are differentially susceptible to the effects of VT on inflammation. Our goal in this study was to establish an in vivo murine model of ventilator-associated lung injury, mimicking the protective ventilatory protocols currently in use in the ICU, and to evaluate the effects of mechanical ventilatory strategy on expression of mediators causing vascular leak and/or inflammation, in the lung and in organs remote to the lung. Understanding the molecular and cellular consequences of mechanical ventilation and defining specific pathways mediating the beneficial effects of protective ventilatory protocols will lead to the development of more refined strategies to prevent ventilator-associated injury and associated nonpulmonary organ dysfunction in critically ill patients with respiratory failure.
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METHODS |
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Male C57B/6 mice (6-9 wk old) were utilized for these studies. Animals were anesthetized with acepromazine (10 mg/ml)-ketamine (100 mg/ml) (10:1, 0.03 ml ip). After endotracheal intubation, mechanical ventilation was initiated (Harvard Apparatus, Boston, MA), and pancuronium bromide (1 mg/kg ip) was administered. Additional anesthetic was given throughout the protocol as needed. The femoral artery was cannulated for measurement of systemic arterial pressure and arterial blood gas analysis at the termination of the experimental protocol. Heparinized saline was constantly infused (0.4 µl/min) to maintain patency of the femoral arterial line. All of the experiments described in this manuscript were approved by the Animal Care and Use Committee at the Johns Hopkins University School of Medicine.
Protocols
Effects of VT on lung injury in healthy mice. After anesthesia, mice were randomized to mechanical ventilation with either conventional, high (high VT, 17 ml/kg, n = 14) or protective, low (low VT, 6 ml/kg, n = 12) VT. Respiratory frequency was set at 150 or 300 breaths/min for high and low VT groups, respectively. These ventilatory parameters were based on plethysmographic estimates of VT (5-15 ml/kg) and respiratory frequency (120-300 breaths/min) in awake, spontaneously ventilating mice (46, 47), and preliminary studies were performed to ensure that the minute ventilation chosen for each experimental condition would maintain PCO2 in a normal range (25-35 mmHg) (38) during the first 30 min of the mechanical ventilatory period. Because FIO2 requirements are usually increased in mechanically ventilated patients, we chose to study the effects of VT in mice ventilated with FIO2 of 1.0. Positive end-expiratory pressure (PEEP) was 3 cmH2O in both groups. The mice were covered throughout the experiment to maintain body temperature. Systemic arterial and airway pressures were continuously monitored throughout the 4-h period of mechanical ventilation (Grass model 7; Grass Instruments, Quincy, MA) with Statham P50 transducers.
After 4 h, separate groups of lungs were excised for measurement of wet/dry lung weight (n = 4/group), snap-frozen in liquid nitrogen (n = 4/group), and fixed for histological evaluation (n = 4/group), or bronchial lavage was performed (n = 4-6/group). In the groups where lungs were snap-frozen, both kidneys and the liver were also rapidly excised and snap-frozen in liquid nitrogen for measurement of cytokine concentration. Arterial blood gas measurements were made via an automated blood gas analyzer (Instrumentation Laboratories, Lexington, MA) in all mice except those undergoing bronchial lavage or intratracheal fixation. Results were compared with mice spontaneously ventilating room air (control, n = 14).
Effects of VT on lung injury after acid aspiration. In a concurrent, second series of experiments to determine whether the effects of mechanical ventilation were altered by the administration of a concurrent inflammatory stimulus, mice received intratracheal hydrochloric acid (HCl, 0.2 N diluted with PBS to pH = 1.5) instilled in 20-µl increments for a total of 80 µl. The animals were then ventilated for 4-5 min with a standard protocol (VT of 12.5 ml/kg, frequency 150 breaths/min) to achieve similar distribution of HCl. As above, FIO2 was maintained at 1.0 throughout the experiment, and PEEP of 3 cmH2O was added. Animals were randomized to 4 h of mechanical ventilation with high (high VT + HCl, n = 13) or low (Low VT + HCl, n = 12) VT, using the same ventilatory parameters described above. After 4 h of mechanical ventilation, lung injury was assessed in separate groups of mice by measurement of bronchial lavage protein and cell count (n = 4-5/group), lung wet/dry wt ratio (n = 4/group), or histological evaluation (n = 4/group), or the lungs, kidneys, liver, and heart were snap-frozen for measurement of cytokine concentration (n = 4/group). Terminal arterial blood gas measurements were made as described above, and results were compared with mechanically ventilated and spontaneously breathing animals from the first series of experiments.
To evaluate the potential contribution of respiratory acidosis associated with low VT on ventilator-associated injury, an additional group of mice was ventilated with high VT following HCl administration, but respiratory frequency was decreased to 90-100/min to match minute ventilation in the low VT + HCl group. After 4 h, animals were killed, and either lung lavage protein concentration and cell count (n = 3) or lung wet/dry weight (n = 3) was determined.
Measurements
Assessment of acute lung injury. Acute lung injury was assessed by analysis of bronchial lavage protein concentration and cell counts, measurement of lung wet/dry wt ratios, and histological evaluation. Bronchial lavage was performed as described by Walters et al. (53). In brief, 0.5 ml of saline (37°C) was instilled through the endotracheal tube, and then the fluid was slowly withdrawn. After the amount of fluid recovered was recorded, an aliquot of lavage fluid was diluted 1:1 with trypan blue (GIBCO-BRL) for estimation of total cell count by a hemocytometer (Hausser Scientific). The remainder of the lavage fluid was centrifuged, and the supernatant was stored at -20°C until measurement of protein concentration was made by Bradford assay (Bio-Rad Laboratories, Hercules, CA). For measurement of wet/dry lung weight, lungs were rapidly excised separately and immediately weighed on pretared plates for determination of wet weight. The lungs were then dried in an oven (Fisher Isotemp, 65°C) and weighed daily for determination of dry weight and calculation of lung wet-to-dry ratios. For histological evaluation, lungs were fixed by intratracheal instillation (25 cmH2O) of 0.2% agarose then submerged in fresh 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.2) for 12-36 h (4°C). Blocks were embedded in paraffin then sectioned (0.5 µM) and stained with hematoxylin and eosin.
Measurement of cytokine concentration. Frozen tissue samples were
solubilized by homogenization in lysis buffer containing PMSF and leupeptin,
and protein concentration were determined (Bio-Rad Protein Assay, Bio-Rad
Laboratories) by comparison with BSA standards. TNF-, IL-6, and VEGF
protein expression was determined with commercially available sandwich ELISA
kits (R&D Systems, Minneapolis, MN). Samples were then resolved by SDS
polyacrylamide gel electrophoresis as previously described by Laemmli
(22). After electrophoresis,
the proteins were transferred onto polyvinylidene difluoride membranes, and
membranes were stained with the rabbit anti-human antibodies against VEGF
receptor-2 (VEGFR2/KDR; Santa Cruz Biotechnology, Santa Cruz, CA). This
antibody recognizes 195- and 235-kDa forms of VEGFR2. After washing away the
primary antibody, we used peroxidase-conjugated avidin secondary antibody for
visualization. To control for differences in protein concentration between
samples or loading errors, we stripped and reprobed blots for
-actin
expression.
Statistical Analysis
Results presented represent means ± SE. Differences between groups
in arterial blood gas parameters, lung wet/dry weight, lung lavage protein
concentration and cell count, and IL-6, VEGF, and TNF- concentration
were compared by one-way analysis of variance. Repeated-measures analysis of
variance was used for the comparison of mean arterial and peak airway pressure
data. When significant variance ratios were obtained, least-significant
differences were calculated to allow comparison of individual group means.
Differences were considered significant for P
0.05.
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RESULTS |
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As shown in Fig. 1A, peak airway pressure averaged 18.4 ± 4.5 and 6.9 ± 1.0 mmHg in the high and low VT groups, respectively. There were no significant differences in mean arterial pressure between the groups throughout 4 h of mechanical ventilation (Fig. 1B). Similarly, pulmonary vascular permeability, assessed by measurement of lung wet/dry wt ratio (Fig. 2A), did not differ between healthy mice ventilated with high or low VT and was not increased over values obtained from spontaneously ventilating control mice. Although bronchial lavage protein concentration (Fig. 2B) and total cell count (Fig. 3A) increased slightly in the high VT group, these differences did not achieve statistical significance. Histological evaluation of lungs from healthy mice following 4 h of mechanical ventilation did not demonstrate evidence of edema formation or inflammation, compared with control mice (data not shown). Arterial blood gas analysis demonstrated the presence of a moderate respiratory acidosis in mice ventilated with low VT, compared with the high VT group, although this difference was not statistically significant (Table 1). Oxygenation did not differ between groups.
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Effects of VT on Lung Injury After Acid Aspiration
Shown in Fig. 1A, peak airway pressure during the first 30-45 min of mechanical ventilation was slightly higher in acid-injured lungs compared with healthy mice, regardless of VT. As in healthy mice, VT did not alter mean arterial pressure during 4 h of mechanical ventilation (Fig. 1B). However, in contrast to healthy mice, VT did alter manifestations of lung injury following acid aspiration. Pulmonary vascular permeability, evaluated by estimation of lung wet/dry wt ratio (Fig. 2A) and lung lavage protein concentration (Fig. 2B), increased significantly after acid aspiration in mice ventilated with high VT, compared with control animals or healthy mice ventilated with high VT. Shown also in Fig. 2, low VT ventilation after acid aspiration completely attenuated the increased wet/dry lung weight and lavage protein concentration seen in the high VT + HCl group. Total cell count in bronchial lavage fluid was also significantly lower in the low VT + HCl group compared with high VT + HCl (Fig. 3B). Absolute cell counts in lung lavage were lower in all mice mechanically ventilated after acid aspiration compared with control, spontaneously ventilated mice, either secondary to dilutional effects or HCl-mediated cellular degradation. Histological evaluation confirmed the presence of pulmonary edema following acid aspiration in mice ventilated with high, but not low, VT. As shown in Fig. 4 microscopically, this injury was manifest by the accumulation of fluid in the perivascular space and proteinaceous material in air spaces.
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Arterial blood gas analysis demonstrated a significant respiratory acidosis in mice ventilated with low VT for 4 h after acid aspiration, compared with healthy mice ventilated with low VT, as well as mice ventilated with high VT following HCl administration (Table 1). Also shown in Table 1, PO2 did not differ after 4 h of mechanical ventilation in the low VT + HCl group. All anesthetized, mechanically ventilated mice exhibited a comparable, mild metabolic acidosis independently of VT or the administration of HCl.
Because it has been suggested that respiratory acidosis may attenuate
ventilator-associated lung injury
(5), we ventilated an
additional group of HCl-treated mice with high VT but decreased
respiratory frequency (F = 90-100 breaths/min) to allow the
development of hypercapnia. Although matching minute ventilation did not
achieve as significant a degree of respiratory acidosis in this group (pH 7.15
± 0.03, PCO2 47 ± 7 mmHg) as in low
VT + HCl mice, values for lung wet/dry weight (5.55 ± 0.05)
and lung lavage protein concentration (1.39 ± 0.33 mg/ml) and cell
count (3.2 ± 1.1* 104 cells/ml) were comparable
with those seen in the high VT + HCl group and remained
significantly elevated (P 0.05 for all three parameters)
compared with low VT + HCl animals.
Cytokine Concentration
Shown in Table 2, concentrations of IL-6 in the lung, liver, or kidney were not significantly altered by high or low VT ventilation in healthy mice, compared with control, spontaneously ventilating animals. In contrast, IL-6 was significantly increased in the lung, liver, and kidney of mice ventilated with high VT after HCl administration, whereas low VT ventilation after acid aspiration significantly attenuated increased IL-6 concentrations in all three of these organs. Unlike hepatic and renal measurements, cardiac IL-6 concentrations in acid-injured mice were not significantly altered by mechanical ventilation with either high or low VT.
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Also shown in Table 2, VEGF concentration tended to increase in lungs from mechanically ventilated animals compared with control but did not appear to vary as a function of delivered VT, and differences did not achieve statistical significance (P = 0.09). Interestingly, there was a suggestion of a negative correlation between lung VEGF concentration and arterial PCO2 (R2 = 0.58, P = 0.08) following 4 h of mechanical ventilation in mice receiving intratracheal HCl, such that VEGF concentration tended to decrease as PCO2 increased, but this relationship did not achieve statistical significance.
In contrast to the lung, VEGF protein concentration increased significantly in the liver and kidney of healthy mice after both high and low VT ventilation, compared with control. As in healthy animals, VEGF concentration in kidney was significantly increased after 4 h of either high or low VT ventilation in acid-injured lungs. In contrast, low VT attenuated the increase in liver VEGF protein concentration seen in animals ventilated with high VT following acid aspiration. Mechanical ventilation with either high or low VT did not alter cardiac VEGF concentration following acid aspiration. Unlike the lung, VEGF expression in the liver or kidney did not correlate with arterial PCO2 (R2 = 0.15, P = 0.45 for liver; R2 = 0.14, P = 0.48 for kidney). However, there was a significant positive correlation between VEGF and IL-6 expression in both the liver and kidney after mechanical ventilation of acid-injured mice (R2 = 0.61, P = 0.003 for liver; R2 = 0.32, P = 0.05 for kidney). Mechanical ventilation with either high or low VT after acid aspiration had no significant effect on cardiac VEGF concentration.
TNF- levels were below the limits of detection for the assay in all
organs from spontaneously ventilating mice. Similarly, no TNF-
was
detected in lungs from healthy mice ventilated with either high or low
VT for 4 h or from the liver, kidney, or heart in any mechanically
ventilated animals. Three of four mice ventilated with high VT
following HCl administration had detectable levels of TNF-
in lung
homogenate (mean concentration 16 ± 9 pg/mg protein), whereas only one
of four mice ventilated with low VT after acid aspiration had
measurable amounts of pulmonary TNF-
(mean concentration 8 ± 10
pg/mg protein).
Although VT did not appear to influence VEGF expression, Western blot analysis suggests that VEGFR2 expression did vary with delivered VT after acid aspiration. Shown in Fig. 5, VEGFR2 was upregulated in the lung, liver, and kidney of mice ventilated with high VT after HCL administration, compared with the low VT + HCl and control groups. As with VEGF, changes in VEGFR2 expression were not seen in the heart. No differences in VEGFR2 expression were seen following mechanical ventilation of healthy mice (data not shown).
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DISCUSSION |
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To evaluate the effects of ventilation-protective strategies on systemic organ inflammation, we established a model of this phenomenon in intact mice. This model will allow the study of genetically modified animals in future experiments, to determine the role of specific mediators involved in the development of ventilator-associated lung and systemic organ dysfunction. Because we wanted to mimic the range of VT used in the clinical ICU in this murine model, we chose a low VT that was at the lower end of values for VT reported in unanesthetized, spontaneously breathing mice and a high VT that was slightly above the reported upper limit for spontaneous VT (46, 47). Lung lavage cell count and protein concentration were not significantly increased in the high VT group, suggesting that a short (4 h) duration of mechanical ventilation with high or low VT did not cause lung injury in healthy mice. These findings are in accordance with many prior reports (3, 14, 35, 54).
In contrast, if animals received intratracheal HCl just before 4 h of mechanical ventilation, significant lung injury developed in mice ventilated with a conventional, high VT strategy. Low VT ventilation under these circumstances significantly attenuated evidence of both increased pulmonary vascular permeability and alveolar inflammation. These findings are similar to a recent report that ventilation with a VT of 6 or 3 ml/kg offered significant protection from acid aspiration lung injury in rats, compared with a traditional, 12 ml/kg VT strategy (15). In this prior study, acid aspiration lung injury was allowed to mature for 2 h before the initiation of mechanical ventilation, leading to a more pronounced degree of acute lung injury, and circulating markers of both endothelial and epithelial injury were reduced in the low VT groups.
In our study, differences in lung injury between high and low VT acid-injured mice were not explained by altered hemodynamics, as mean arterial pressure did not differ between the groups. Both decreased cyclic stretch (49) and acidosis (5) have been suggested as mediators of protection from acute lung injury induced by mechanical ventilation. Low VT ventilation following acid aspiration was associated with a significant respiratory acidosis compared with the high VT + HCl and low VT groups. PCO2 also increased significantly in mice mechanically ventilated after acid aspiration with a high VT strategy but decreased respiratory frequency, compared with the high VT + HCl group, without concomitant attenuation of lung injury. However, because we were unable to achieve as severe a degree of respiratory acidosis in this latter group, we cannot exclude contributions of both acidosis and decreased ventilatory stretch to the protective effects of low VT ventilation in this model. All of the mechanically ventilated mice in this study developed a comparable, mild metabolic acidosis, perhaps related to relative hypotension, induced by the anesthetic agents and/or increased pleural pressures secondary to positive pressure ventilation.
The mechanisms by which increased cyclic stretch generate injury, or
decreased cyclic stretch affords protection from injury, have recently been
the focus of intensive investigation
(3,
5,
11,
15,
19,
50). Our results suggest that
lung concentration of IL-6 increased significantly if mice were ventilated
with a high VT following acid aspiration, compared with healthy
mice subjected to high VT ventilation, or low tidal ventilation of
animals following HCl aspiration. This change in IL-6 expression was mirrored
by a trend toward increased lung expression of TNF-. IL-6 is generally
considered a proinflammatory, injurious cytokine, although its role may depend
on the type of lung injury
(39). In vitro studies have
demonstrated that IL-6 causes increased endothelial permeability
(13,
25), and several investigators
have noted a correlation between plasma IL-6 and outcome in ARDS
(55) and sepsis
(1,
56). In addition, IL-6 may
alter neutrophil deformability
(43) and surface
L-selectin expression
(44), thereby potentially
increasing both pulmonary neutrophil sequestration and demargination of
circulating neutrophils.
The present study confirms the findings of several previous studies in
isolated lungs from healthy animals, which demonstrated increased release of
multiple cytokines and chemokines, including TNF- and IL-6, into lung
perfusate or bronchoalveolar lavage (BAL) fluid
(19,
48,
50) as VT was
increased. On the other hand, other investigators could not find increased
proinflammatory cytokines in BAL fluid or plasma following high VT
ventilation of healthy or injured lungs
(35,
51). We did not measure
increased IL-6 or TNF-
in lungs from healthy mice ventilated with high
or low VT, suggesting that acid aspiration in some way primed the
lung to increase cytokine expression in response to increased ventilatory
stretch.
No significant differences in pulmonary concentrations of VEGF, a potent mediator of increased vascular permeability, were seen as a function of VT or acid aspiration. VEGF protein concentration in lung tissue homogenates tended to increase in all mechanically ventilated animals compared with spontaneously breathing, control mice. Because lung epithelial cells represent the primary source of VEGF production in the lung, we might predict VEGF concentration would decrease following acid aspiration, as a result of epithelial injury. Interestingly, there was a suggestion of a negative correlation between VEGF protein expression in lung homogenates and PCO2, such that VEGF expression decreased as PCO2 increased. This is in contrast to a recent study by D'Arcangelo and colleagues (12), which demonstrated evidence of increased expression of VEGF in response to acidosis in bovine aortic endothelial cells in vitro. A relationship between VEGF expression and acidosis was not seen for liver or kidney VEGF expression from the same mice. Because VEGF was measured in whole tissue homogenates, this may reflect differing volumes of cell compartments expressing VEGF in these organs (27). Alternatively, it is possible that acidosis elicits tissue-specific responses. Because VEGF is a significant mediator of increased vascular permeability, any attenuation of pulmonary VEGF expression by acidosis suggests a potential mechanism by which low VT ventilation might limit ventilator-associated lung injury.
Although we were unable to detect an effect of VT on lung VEGF
concentration, pulmonary VEGFR2 expression did increase with high
VT ventilation after acid aspiration. Although expression of IL-6
(31,
32) and TNF-
(31,
32,
52,
57) was not consistently
upregulated by cyclic stretch in vitro, expression of both VEGF
(18,
24,
28,
34,
45,
58) and VEGFR2
(45) increased in response to
stretch in multiple cell types both in vitro and in vivo. In addition, in
vitro studies suggest that IL-6 and TNF-
both upregulate VEGF
expression (9,
16), and TNF-
may
upregulate (17) or
downregulate (33) VEGFR
expression.
In addition to demonstrating that ventilatory strategy altered pulmonary cytokine concentrations, our results suggest that VT delivered during mechanical ventilation following an inflammatory lung insult altered cytokine expression in systemic organs. IL-6 concentration significantly increased in both the liver and kidney of mice ventilated with a high VT strategy following acid aspiration, whereas low VT ventilation completely attenuated systemic IL-6 expression. Similarly, increased hepatic and renal VEGFR2 expression was attenuated by low VT ventilation in acutely injured lungs. This was also true of hepatic VEGF expression, whereas kidney VEGF expression increased comparably with both high and low VT ventilation. These findings suggest the release of humoral factor(s) from inflamed lungs subjected to increased ventilatory stretch, which selectively activate proinflammatory pathways at sites remote to the lung. Interestingly, mechanical ventilation of healthy mice led to increased VEGF concentration in both the liver and kidney, even in the absence of lung injury. The mechanism of this response is not known and will be investigated in future studies. Our data are supported by the recent report by Choi et al. (6), which demonstrates increased serum VEGF concentration in response to high (20 ml/kg) VT ventilation in healthy rats, although serum VEGF levels in spontaneously ventilating controls are not presented in that study. Also of note, no significant changes in cardiac IL-6, VEGF, or VEGFR2 expression were found in mechanically ventilated mice, suggesting that systemic tissues may respond differentially to the effects of mechanical ventilation. Because of its anatomic location in the thorax, the heart is exposed to different mechanical forces during positive pressure ventilation, and it is interesting to speculate as to whether this may account for our findings.
Our data also suggest that expression of VEGF correlated with IL-6 expression in both liver and kidney of mice mechanically ventilated after acid aspiration. We suspect this may represent a common stimulus regulating the expression of these proteins, rather than a causal relationship between increased IL-6 and VEGF expression. IL-6 and VEGF have both been suggested as mediators of increased permeability and/or vascular remodeling in a number of disorders, including metastatic cancer (30, 37), ovarian hyperstimulation syndrome (36), Castleman's disease (20), and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome (23). In many of these studies, IL-6 and VEGF expressions were significantly linked. Both IL-6 and VEGF may promote a procoagulant state, by increasing expression of tissue factor on endothelial cells and/or monocytes (7, 8, 21, 26, 29, 40). Increased tissue factor expression is thought to play a significant role in the development of multiorgan system failure in sepsis and acute lung injury (1, 55, 56). Of note, prior studies suggest that IL-6 and VEGF regulate both endothelial barrier dysfunction and tissue factor expression by different mechanisms. This suggests the possibility that IL-6 and VEGF might act synergistically to potentiate lung injury and/or systemic organ dysfunction.
In summary, we have established a model of ventilator-associated lung injury in intact mice and demonstrated that a short period of mechanical ventilation with a conventional, high VT strategy causes both increased pulmonary vascular permeability and hepatic and renal, but not cardiac, inflammation. This effect was dependent on presence of a localized pulmonary inflammatory stimulus (acid aspiration) and did not occur after mechanical ventilation of healthy mice. Low VT ventilation after acid aspiration significantly attenuated lung injury and pulmonary IL-6 and VEGFR2 concentration but had no effect on pulmonary VEGF. In addition, ventilation of acid-injured lungs with a protective VT strategy attenuated increased hepatic and renal IL-6 and VEGFR2 expression but reduced VEGF expression only in the liver. These data suggest that mechanical ventilatory strategy may differentially mediate inflammation in systemic organs, raising the possibility of discrepant end-organ susceptibility to the harmful effects of mechanical ventilation.
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DISCLOSURES |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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