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Abstract |
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Abstract
Introduction
Materials and Methods
Results
Discussion
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Mechanical ventilation has become an indispensable therapeutic modality for patients with respiratory failure. However, a serious potential complication of MV is the newly recognized ventilator-induced acute lung injury. There is strong evidence suggesting that matrix metalloproteinases (MMPs) play an important role in the development of acute lung injury. Another factor to be considered is extracellular matrix metalloproteinase inducer (EMMPRIN). EMMPRIN is responsible for inducing fibroblasts to produce/secrete MMPs. In this report we sought to determine: (1) the role played by MMPs and EMMPRIN in the development of ventilator-induced lung injury (VILI) in an in vivo rat model of high volume ventilation; and (2) whether the synthetic MMP inhibitor Prinomastat (AG3340) could prevent this type of lung injury. We have demonstrated that high volume ventilation caused acute lung injury. This was accompanied by an upregulation of gelatinase A, gelatinase B, MT1-MMP, and EMMPRIN mRNA demonstrated by in situ hybridization. Pretreatment with the MMP inhibitor Prinomastat attenuated the lung injury caused by high volume ventilation. Our results suggest that MMPs play an important role in the development of VILI in rat lungs and that the MMP-inhibitor Prinomastat is effective in attenuating this type of lung injury.
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Introduction |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Over the last 40 yr, mechanical ventilation (MV) has become an indispensable therapeutic modality for patients
with respiratory failure. However, it was quickly recognized that MV per se could lead to a number of serious
complications. Initially, the focus of the research in such
injury was primarily on the role of pressure and volume
causing barotrauma leading to the clinical conditions of
pneumothorax and pneumomediastinum (1). More recently, the concept that the stretching of the lung by mechanical ventilation with high tidal volumes may lead to
acute lung injury, with severe damage to the alveolar-capillary barrier and pulmonary edema, has emerged (1, 2)
and has been coined "volutrauma." This type of lung injury is characterized by an increased endothelial and epithelial barrier permeability in the lung. The mechanism of
such an increase in permeability is not well understood.
Recently, it was reported that MV may play a role in initiating and propagating an inflammatory response in the
lung by increasing the release of cytokines (such as tumor
necrosis factor [TNF]-
and interleukin [IL]-1
) from the
lung (3).
Matrix Metalloproteinases (MMPs) are a family of enzymes that degrade components of the extracellular matrix. The 72 kD gelatinase A (MMP-2), is the most widely distributed of all the MMPs (4), and is expressed constitutively by a number of cells, including endothelial and epithelial cells. The 92 kD gelatinase B or MMP-9 (103 kD in rat) is produced by several types of inflammatory cells, including PMNs and alveolar macrophages, as well as stimulated connective tissue cells. Gelatinase A, along with gelatinase B, plays an important role in pericellular basement membrane turnover by degrading type IV collagen, a main component of the basement membrane.
There is strong evidence that MMPs play an important role in the development of acute lung injury. There is also evidence that recombinant tissue inhibitor of MMPs (TIMP-2) suppressed immune complex-induced high permeability pulmonary edema in rats in vivo (5) and that a synthetic MMP inhibitor protected rat lungs from oxidant-induced injury (6).
Extracellular matrix metalloproteinase inducer
(EMMPRIN), previously known as tumor collagenase stimulatory factor (TCSF), is a 58-kD plasma membrane glycoprotein identified originally in carcinoma cells (7, 8). Cell
surface and released EMMPRIN are responsible for inducing peritumor fibroblasts to produce/secrete MMPs (9,
10). EMMPRIN also enhances endothelial cell production of stromelysin-1, collagenase-1, and gelatinase A (manuscript submitted). EMMPRIN has no mitogenic activity
and therefore differs from most well characterized cytokines, such as interleukin (IL)-1, tumor necrosis factor
(TNF)-, and transforming growth factor (TGF)- (8).
EMMPRIN has not only been identified by immunohistochemistry and in situ hybridization in malignant cells,
but has also been localized in alveolar macrophages in the
lungs of patients with cancer (11). Therefore, there is a
possibility that EMMPRIN may have a function in acute
lung injury by stimulating lung fibroblasts and endothelial
cells to secrete MMPs, leading to the increased permeability and lung injury.
In this study we sought to examine if MMPs and EMMPRIN play an important role in the development of ventilator-induced lung injury (VILI) in a rat lung preparation, and whether this lung injury could be prevented by the MMP inhibitor Prinomastat (AG3340). Prinomastat, a potent inhibitor of gelatinases A and B, collagenase-3, and MT1-MMP, has broad antitumor and anti-angiogenic activity (12).
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Materials and Methods |
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Abstract
Introduction
Materials and Methods
Results
Discussion
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Animal Preparation
Sprague-Dawley rats weighing 200-250 g were anesthetized with urethane (1.3 g/kg) and pentobarbital (30 mg/kg). The animals were tracheostomized and ventilated with a small animal respirator (Harvard Apparatus, South Natick, MA). Animals were given pancuronium (4 mg/kg) and the peak airway pressure (PAW) was monitored throughout the experiment with a differential transducer.
Experimental protocol. The animals were divided into the following experimental groups: high volume ventilation (20 ml/kg tidal volume, no PEEP, 25 br/min), with room air for 4 h (n = 6); low volume ventilation (7 ml/kg tidal volume, +2 cm H2O PEEP, 40 br/min) with room air for 4 h (as a control, n = 6); and unventilated animals (as a control, anaesthetized only, n = 6). In another group of animals, the rats were subjected to high volume ventilation for 1, 2, and 3 h (3 rats in each group) and the lungs removed for in situ hybridization.
Assessment of lung injury. The severity of lung injury was assessed by the following criteria: (i) the degree of lung weight gain, the main index of pulmonary edema, was measured from the wet/dry weight ratio. The right hilum was ligated and the right lung removed after the experiment, then weighed (wet weight) and dried in a 70°C oven until weight is constant (dry weight); (ii) bronchoalveolar lavage fluid (BALF) protein content; 3 × 5 ml of saline was used to lavage the lungs, through the endotracheal catheter. The lavage fluid was then centrifuged and the protein content of the supernatant was assayed (13).
Assessment of Gelatinase Induction, Release, and Activation
Samples obtained from BALF at the end of the experiment (1, 2, 3 and 4 h) were compared for the presence of gelatinases by gelatin zymography as described perviously (14). Precast gelatin gels with minimal lot to lot variability were purchased from NOVEX, San Diego, CA.
To verify that gelatinase B identified in the BALF is activated, we used conditioned media from macrophages isolated from rat spleen and activated with APMA (2 mM for 3 h at room temperature) as a control. The BALF and macrophage conditioned media were then compared by zymography (figure not shown).
Immunoblotting of Proteins
To identify specific MMPs detected on zymograms, immunostaining for gelatinases A and B was performed. Immunoblotting for MMPs was performed using affinity-purified rabbit or sheep polyclonal antibodies (15) directed against purified proteins or synthesized peptides as previously described (10). Mouse monoclonal antibody to rat EMMPRIN (OX-47) was purchased from Serotec Ltd. (Oxford, UK) (16).
Labeling of Riboprobes
Antisense and sense digoxigenin (DIG)-labeled RNA probes were synthesized by reverse transcribing 1 µg of cDNA from a PCR reaction that had used gene-specific primers that contain either the T7 or T3 phage promoter sequence followed by 20-25 bases of the mRNA sequence. The PCR primers used were as follows: Gelatinase A (399-bp product, sense, 5'-TAATACGACTCACTA TAGGGAGACACCATCGCCCATCATCAAGT-3'; antisense, 5'-AATTACCC TCAC TAAAG GGAGATGGATTCGAGAA AAGCGCAGCGG-3') Gelatinase B (305-bp product; sense, 5'-TAATACGACTCAC TATAGGGAGAGCTC TAGGC TACA GCTTTGCTG-3'; antisense, 5'-AATTACCCTCACTAAAGG GAGAGTCGCCTTCGAAGGTTTGGAAT-3'); MT1-MMP (339-bp product; sense, 5'-TAATACGACTCACTATAGGGA GAATTCGGAAAGCCTTCCGAGTATG-3'; antisense, 5'-A ATTAC CCTCACT AAAGGG AGATGATGGCGG AGGGG TCGTTGGA-3'); EMMPRIN (397-bp product; sense, 5'-TAATA CGACTCACTATAGGGAGATCCTGCATCTTCCTTCCTGAGCC-3'; antisense, 5'-AATTACCCTCATAAAGGGAGAATGCCCA GGAAGGGCCAGAGGGC-3'). In vitro transcription of the amplified DNA template used the digoxigenin system RNA labeling kit (Boehringer-Mannheim, Mannheim, Germany) (17). Labeled probe was purified according to Panoskaltsis-Mortari and Bucy (18), and stored in 10-µl aliquots at -80°C.
In Situ Hybridization
Serial sections of paraffin-embedded rat lung were cut at 5 µm. After deparaffinization, slides were prepared for in situ hybridization according to manufacturer's method (Boehringer Mannheim) (19). The RNA probes were then heat denatured at 80°C for 5 min, and added to the slides at a concentration of 400 ng/ml. Slides were hybridized overnight (> 16 h) at 50°C in a moisture chamber containing 50% formamide/5× SSC.
The next day, the slides were washed and processed for immunodetection using the Boehringer-Mannheim Wash and Block Set (19). The color reaction was stopped by incubating the slides in 10 mM Tris-HCl, pH 8/1mM EDTA, for 5 min with shaking, and the slides mounted in aqueous mounting medium. The slides were reviewed and the number of positive cells/unit area was documented.
TNF- Immunoassay
Samples of BALF from rats treated with normal volume ventilation, high volume ventilation, or high volume ventilation after treatment with Prinomastat were examined for immunoreactive
TNF- content using a rat TNF- ELISA kit from R&D Systems,
Minneapolis, MN. The BALF was diluted 1:2, 1:4, and 1:8 utilizing the kit's calibrator diluent as per the manufacturer's instructions. The concentration of TNF- in each sample was determined by comparing ELISA optical density reading versus a
standard curve generated using the rat TNF- provided with the
kit. This kit recognizes the cleaved 157 amino acid active form of
TNF-.
Treatment with the MMP Inhibitor Prinomastat
Prinomastat, 3(S)-2,2-dimethyl-4-{4-pyridin-4-yloxy-benzenesulfonyl}-thimorphonline-3-carboxylic acid hydroxyamide (Mr 423.5), was obtained as a white powder from Agouron Pharmaceuticals Inc. (San Diego, CA). An aqueous solution was prepared by dissolving Prinomastat in 1 N HCl and acidified water, pH 2.3. Control solutions without Prinomastat were also prepared. The solutions were sterilized by filtration. We prepared a fresh drug solution approximately every 14 d. Animals were injected either with 100 mg/kg Prinomastat or vehicle control, intraperitoneally once daily for 2 d before the experiment, and at 2 h before the experiment.
The rats were divided into three groups of six rats each: (i) rats ventilated with high volume ventilation (20 ml/kg, no PEEP); (ii) rats pretreated with Prinomastat and then ventilated with high volume ventilation (20 ml/kg, no PEEP); and (iii) rats ventilated with low volumes (7 ml/kg + 2 cm H2O PEEP). At the end of 4 h the animals were killed and the BALF for protein content was obtained as described above. The lungs were then removed and wet/dry weight ratio measured as described above; in situ hybridization was performed.
Statistical Analysis
The differences between groups were compared using a one-way ANOVA, followed by an intergroup analysis using the Student- Newman-Keuls test (20). P < 0.05 was considered significant.
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Results |
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Materials and Methods
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High-Volume Ventilation Causes Acute Lung Injury
High-volume ventilation leads to acute lung injury as manifested by the increase in airway PAW, the wet/dry lung weight ratio, and the protein content in BALF.
The PAW increased from 53.2 ± 3.9 cm H2O at initiation of ventilation to 67.7 ± 6.2 cm H2O at the end of the experiment (4 h) in the group ventilated with high volume. In the low-volume ventilation group, by contrast, the PAW increased from 14.0 ± 1.8 to 18.2 ± 1.1 cm H2O at the end of the 4 h.
The wet/dry weight ratio was increased to 11.2 ± 0.5 by high-volume ventilation as compared with 9.2 ± 0.4 (Figure 1A, P < 0.0001) in the low-volume ventilation group. High-volume ventilation caused an increase in BAL protein content from 1.3 ± 0.1 mg/ml in rats ventilated with low volume to 12.7 ± 2.1 mg/ml (Figure 1B, P < 0.0001).
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Hematoxylin-eosin (H&E) staining of the lungs at l h (Figure 2, Panel 2) and 4 h (Figure 2, Panel 3) show evidence of injury at 4 h, with loss of architecture, alveolar filling, and alveolar collapse. H&E staining of lung tissues from lungs of rats pretreated with Prinomastat and ventilated with high-volume ventilation for 4 h show preserved architecture with mild alveolar wall thickening (Figure 2, Panel 4).
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VILI Increases Expression of Gelatinases in Rat Lungs
In rat lungs subjected to high-volume ventilation, in situ hybridization performed on sections from these lungs revealed an increased amount of gelatinase A, gelatinase B, and MT1-MMP mRNA synthesis (Figure 3) as compared with rat lungs subjected to low tidal volume ventilation. The increased gelatinase A mRNA was identified in vascular endothelial cells, airway epithelial cells, and mononuclear cells in the interstitium (Figure 3). Gelatinase B mRNA activity was located in type II pneumocytes, airway epithelial cells, and vascular endothelial cells (Figure 3). An increased amount of MT1-MMP mRNA was identified in vascular endothelial cells and bronchial epithelial cells (Figure 3).
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The increase in mRNA of gelatinase A and gelatinase B (as manifested by the number of positive cells) started at ~ 1 h of high-volume ventilation and continued to increase throughout the 4 h. The increase in MT1-MMP mRNA was less evident at 1 h than at 4 h.
VILI Increases the Release of Gelatinases in BALF
The zymogram of the BALF in animals ventilated with low volume displayed weak gelatinolytic bands in the typical doublet form seen with murine gelatinase A at 74 and 72 kD (progelatinase A) (21). In contrast, BALF from animals ventilated with high volume displayed intense gelatinolytic bands of activity at 74 and 72 kD (progelatinase A), 62 kD (activated gelatinase A), and at 103 kD murine progelatinase B (22) and activated gelatinase B (Figure 4).
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The Matrix Metalloproteinase Inhibitor Prinomastat Attenuates VILI in Rats
Pretreatment with the MMP inhibitor Prinomastat significantly abrogated the increase in wet/dry weight ratio caused by high-volume ventilation from 11.2 ± 0.5 to 8.9 ± 0.3 (Figure 1A, P < 0.01), markedly attenuated the increase in BAL protein content caused by high-volume ventilation from 12.7 ± 2.1 to 2.5 ± 1.0 mg/ml (Figure 1B, P < 0.01), and prevented the release and activation of gelatinases A and B in the BALF in treated animals (Figure 4). In situ hybridization showed that Prinomastat did not affect the increased expression of gelatinase A mRNA, gelatinase B mRNA, and MT1-MMP mRNA in lungs of rats treated with high-volume ventilation (Figure 3).
TNF- Is Increased in BALF of Rats with VILI
In rats ventilated with low tidal volume ventilation, the TNF-
in the BALF at the end of 4 h was 3.86 ± 0.45 pg/ml (n = 7). In animals subjected to high tidal volume ventilation, there
was an increase in the TNF- level in the BALF to 67.3 ± 11.28 pg/ml at 4 h (n = 4). Pretreatment with Prinomastat in
rats ventilated with high-volume ventilation attenuated the
increase in TNF- to 10.4 ± 2.71 pg/ml (n = 6, P < 0.001; Figure 5A). In another experiment, the BALF collected after 1, 2, 3, and 4 h of high-volume ventilation was analyzed for immunoreactive TNF-; TNF- remains low in BALF at 1, 2, and 3 h (n = 3 in each group) and increases only at 4 h of
high-volume ventilation (Figure 5B).
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EMMPRIN Is Increased in Lung Tissues and BALF from Rats with VILI
To investigate the possibility that EMMPRIN may play an important role in inducing the increases in the gelatinases in acute lung injury, we evaluated EMMPRIN in BAL and tissues from the lungs of rats ventilated with the different ventilation strategies described above. In situ hybridization revealed an increased amount of EMMPRIN mRNA in alveolar macrophages and airway epithelial cells of rats ventilated with high volumes as compared with low-volume ventilation (Figure 2). This increase in EMMPRIN mRNA was prominent at ~ 1 h after high volume ventilation with the number of positive cells for EMMPRIN per unit area being 3-fold more than the gelatinase A positive cells at 1 h. However, at 4 h the number of cells positive for gelatinase A was ~ 3-fold more than the cells positive for EMMPRIN, suggesting that EMMPRIN upregulation occurred before gelatinase A and may have influenced the gelatinase A upregulation. Prinomastat did not affect this increase in EMMPRIN mRNA.
Immunoblotting of BALF revealed a large increase in EMMPRIN in rats ventilated with high- as compared with low-volume ventilation (Figure 6A). The biologically active form of EMMPRIN is the 58 kD glycosylated form, while the 31 kD nonglycosylated form is inactive (9). In Figure 5A, there are bands at 116 and 174 kD that are presumed dimers and trimers of the 58 kD glycosylated form. Immunoblotting of BALF obtained from rats after 1, 2, 3 (n = 3 in each group), and 4 h of ventilation with high volume (20 ml/kg, no PEEP, n = 6) revealed a progressive increase in immunoreactive EMMPRIN, with the greatest increase occurring between 2 and 3 h (Figures 6B and 6C).
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Discussion |
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Abstract
Introduction
Materials and Methods
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Discussion
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VILI is recognized as a major complication in patients
with acute lung injury and ARDS requiring mechanical
ventilation. The results of this study indicate that gelatinases play an important mediator role in the development
of this type of lung injury in rats. We have also shown that
the MMP inhibitor Prinomastat is an effective modulator
of this injury. Furthermore, our results also suggest that
EMMPRIN and TNF- play an integral part in the mechanism leading to development of VILI in the rat.
High-volume ventilation leads to an increase in expression and release of gelatinases from epithelial and endothelial cells in the lung. The cause of this increase is most likely due to the mechanical stress on these cells. There is increasing evidence that cyclic mechanical stress affects the release and activation of MMPs, and plays an important role in the regulation of extracellular matrix remodeling. Cyclic mechanical stress causes: (1) the upregulation, release, and activation of gelatinase B and gelatinase A from cultured chondrocytes (23); (2) MT1-MMP expression that leads to the activation of gelatinase A in cardiac fibroblasts (24); (3) a decrease in gelatinase A release from rat glomerular mesangial cells at 48 h but an increase in gelatinase A release at 72 h (25); and (4) the activation of human alveolar macrophages in vitro and their release of gelatinase B (26). Furthermore, cyclic mechanical stress has been shown to inhibit airway epithelial repair and prevent prostanoid synthesis (27, 28).
Tremblay and colleagues have suggested that high tidal
volume mechanical ventilation may play a role in initiating
and propagating an inflammatory response in the lung by
increasing the release of the cytokines TNF- and IL-1
from the lung, thus suggesting a mechanism for the development of VILI (3). The MMP inhibitor Prinomastat potently inhibits gelatinase A, gelatinase B, and collagenase-3,
supporting the contention that some or all of these MMPs
may also mediate the inflammation and lung injury in this acute lung injury model. However, the protective effect of
Prinomastat pretreatment may not be entirely due to inhibition of MMPs, although MMP activities are clearly inhibited by treatment with Prinomastat. Prinomastat potently
inhibits gelatinase A and B, collagenase-3, and MT1-MMP
with IC50 values in the pM range in an enzymatic assay employing tight binding kinetics (Shalinsky, 1999). Prinomastat can also inhibit TNF--converting enzyme (TACE),
a metalloproteinase of the Adamalysin/ADAM family (29)
activity with an IC50 of 40 nM when tested in an enzymatic
assay. In a cell-based assay, Prinomastat weakly inhibits
TACE activity with an IC50 of 5 µM (D. Shalinsky, personal communication). In vivo studies of Prinomastat on
TACE activity have not been conducted. Our results show
that pretreatment with Prinomastat in animals that received
high-volume ventilation both protected the lung from VILI
and reduced the TNF- concentration found in the BAL.
Taken together, the data suggest that the beneficial effects
of Prinomastat in this model of acute lung injury may be
due to direct inhibition of MMP activities or indirectly by
inhibiting TACE. Further studies are required to fully elucidate the mechanism(s) responsible for the efficacy of this drug.
Our in situ data show that Prinomastat had no effect on the mRNA expression of any of the MMPs examined in lungs subjected to high-volume ventilation. The decrease in the release of gelatinase A and gelatinase B into the BALF in these animals may be due to the reduction in lung injury, thereby decreasing the capillary-epithelial permeability.
EMMPRIN has not only been identified by immunohistochemistry and in situ hybridization in malignant cells, but has
also been localized to alveolar macrophages in the lungs of patients with cancer (11). In addition, EMMPRIN (also known
as M6 antigen) has been identified in granulocytes of patients
with rheumatoid arthritis (10). We have demonstrated increased levels of EMMPRIN in BAL and tissues of rats subjected to VILI. Our data suggest that EMMPRIN mRNA increased in lung tissue subjected to high-volume ventilation.
The increased EMMPRIN mRNA in injured lung tissue appears to have preceded the increase in gelatinase A mRNA.
Increased EMMPRIN in the BALF also preceded the increase
in TNF-, thereby supporting the notion that EMMPRIN may
upregulate gelatinase A production in inflammation, as previously reported in cancer (8). The central importance of EMMPRIN in lung injury cannot be confirmed without an effective means of inhibiting EMMPRIN. It is interesting to note
that we have also identified EMMPRIN in BAL of patients with ARDS (Foda and Zucker, unpublished observation).
The data presented herein serves to emphasize the
complex pathophysiology of acute lung injury. Although it
is customary to try to identify a single disease mediator, it
seems likely that both EMMPRIN and TNF- participate
in the upregulation of MMPs. Perhaps this explains why
inhibitors of a single mediator such as TNF-, while successful in some animal models, has not been clinically successful in improving survival of ARDS (30).
In conclusion, our results suggest that MMPs play an important role in the development of VILI in rats and that the MMP inhibitor Prinomastat is an effective modulator of this type of lung injury. These findings support the notion that MMP inhibitors may be useful therapeutically in patients at risk for developing VILI.
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Footnotes |
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Address correspondence to: Hussein D. Foda, M.D., Pulmonary and Critical Care Medicine SUNY at Stony Brook, Health Science Center, Stony Brook, NY 11794-8172. E-mail: hfoda{at}mail.som.sunysb.edu
(Received in original form March 12, 2001 and in revised form July 26, 2001).
Abbreviations: bronchoalveolar lavage fluid, BALF; extracellular matrix metalloproteinase inducer, EMMPRIN; interleukin, IL; matrix metalloproteinase, MMP; TNF--converting enzyme, TACE; tumor necrosis factor-, TNF-; ventilator-induced lung injury, VILI.
Acknowledgments: This work was supported by funds from the VA Research Enhancement Award Program REAP, NIH Grant HL-646340 from NHLBI (H.D.F), Grant-in-aid from the American Heart Association (H.D.F.), VA Merit Review Grant (S.Z.), and Department of Defense Breast Grant DAMD 17-95-5017 (S.Z.).
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References |
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Materials and Methods
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Discussion
References
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