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ABSTRACT |
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METHODS
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Using a rat model of acid-induced lung injury, we tested the hypothesis that tidal volume reduction at the same level of PEEP (10 cm H2O) would diminish the degree of pulmonary edema by attenuating injury to the alveolar epithelial and endothelial barriers. Tidal volume reduction from 12 to 6 to 3 ml/kg significantly reduced the rate of lung water accumulation from 690 µl/h to 310 µl/h to 210 µl/h. Ventilation with either 6 or 3 ml/kg reduced endothelial injury equally as measured by plasma vWf:Ag and permeability to albumin. Plasma RTI40, a marker of type I epithelial cell injury, decreased 46% when tidal volume was reduced from 12 to 6 ml/kg and decreased an additional 33% with 3 ml/kg (p < 0.05). The rate of alveolar epithelial fluid clearance was significantly faster in the 3-ml/kg group (24 ± 7%/h) compared with 6 ml/kg (15 ± 11%/h) and 12 ml/kg (3 ± 6%/h). We conclude that low tidal volume ventilation protects both the alveolar epithelium and the endothelium in this model of acute lung injury. The additional decrease in pulmonary edema with a tidal volume of 3 ml/kg is partly accounted for by greater protection of the alveolar epithelium.
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Keywords: acute respiratory distress syndrome; alveolar type I cell antigen; von Willebrand factor antigen; respiration; artificial adverse effects; alveolar fluid clearance
In recent studies, clinical investigators have reported improved outcomes for patients with acute lung injury and the acute respiratory distress syndrome (ARDS) who were ventilated with reduced tidal volumes (1, 2). The most convincing trial showed that a ventilation strategy incorporating a reduced tidal volume of 6 ml/kg and a 30 cm H2O plateau pressure limit resulted in a 22% reduction in mortality compared with a conventional tidal volume of 12 ml/kg and similar levels of positive end-expiratory pressure (PEEP) (1). The mechanisms that account for the protective effect are not fully understood. Animal studies have demonstrated that ventilation of normal lungs with high tidal volumes causes pulmonary edema and diffuse alveolar damage (3, 4). Proposed mechanisms of this ventilator-induced lung injury (VILI) include physical damage to cells caused by alveolar overdistention, sheer stress, and capillary stress failure (4, 5). In addition to mechanical disruption of the alveolar barrier, stretch-induced changes in cell function, including release of proinflammatory cytokines, altered ion transport, and decreased surfactant secretion, may contribute to lung injury (5- 9). Previous animal studies of acute lung injury have demonstrated a reduction in the degree of lung edema with lower tidal volume ventilation (10); however, no report has correlated the degree of pulmonary edema with specific functional and biochemical markers of alveolar epithelial and lung endothelial injury in a clinically relevant model of mechanical ventilation after acute lung injury. Such a model tests the degree of lung injury attributable to the ventilator, or what is termed ventilator-associated lung injury (VALI).
Therefore, the first objective of this study was to test the hypothesis that a reduction in tidal volume from 12 to 6 ml/kg would diminish the degree of pulmonary edema after intratracheal acid instillation by decreasing both alveolar epithelial and lung endothelial cell injury. The second objective was to determine whether a further reduction in tidal volume to 3 ml/kg would further attenuate lung injury. The third objective was to test the hypothesis that lower tidal volumes provide a differential protection to the alveolar epithelial and lung endothelial barriers of the lung.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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See online data supplement for detailed Methods.
Sprague-Dawley rats weighing 300 to 350 g were anesthetized with pentobarbital (50 mg/kg intraperitoneally followed by 500 µg/kg/h intravenously). Muscle relaxation was maintained with intravenously administered pancuronium (2 mg/kg/h). Rats were ventilated with a tidal volume of 6 ml/kg, PEEP 10 cm H2O, and 100% oxygen (Model 683; Harvard Apparatus Co., South Natik, MA). Respiratory rate was adjusted to maintain arterial pH between 7.30 and 7.45. Airway, systemic arterial, and central venous pressures were monitored continuously. Arterial blood gases, plateau airway pressure, and total PEEP were measured every 30 min. To induce lung injury, an HCl solution (pH, 1.25) was instilled into the trachea (4 ml/kg). After 2 h, rats were randomized to receive one of three tidal volumes for an additional 4 h: 12 ml/kg (n = 10), 6 ml/kg (n = 31), or 3 ml/kg (n = 31). PEEP and initial minute volume were maintained at similar levels in all groups. A fourth group of rats ventilated with a tidal volume of 12 ml/kg and lower PEEP such that plateau airway pressures were comparable to the 6 ml/kg PEEP 10 cm H2O group was also included (n = 17). If pH was below 7.30 and the respiratory rate could not be increased because of intrinsic PEEP, NaHCO3 was administered to maintain pH above 7.30. At the end of the 6-h experiment, end-expiratory lung volume above functional residual capacity was measured using a Fleisch tube pneumotachometer (Model 4-0; A. Fleisch, Lausanne, Switzerland).
Pulmonary Edema, Endothelial Permeability, and Endothelial Cell Injury
Pulmonary edema (excess extravascular lung water) was measured using the gravimetric method (11). Endothelial permeability to albumin was determined by measuring extravasated intravenous 125I-labeled albumin (11). Plasma von Willebrand factor antigen, a biochemical marker of endothelial cell injury (12, 13), was measured using an ELISA (American Bioproducts, Parssipany, NJ).
Alveolar Fluid Clearance and Epithelial Cell Injury
Alveolar fluid clearance was measured in the absence of ventilation or blood flow using our previously described in situ model (14). Plasma epinephrine levels were measured using an ELISA (IBL, Hamburg, Germany). The type I alveolar epithelial cell specific protein RTI40 (a biochemical marker of type I cell injury (15)) was measured in plasma and edema fluid using a previously described dot blot assay (15). Surfactant protein-C mRNA was quantified using Northern blot analysis as previously described (16).
Histology and Ultrastructure
Lungs for histologic examination were inflated to 30 cm H2O twice and then to 10 cm H2O and fixed in formalin (17). Ten fields at each of three levels were examined in each lung at ×200 and scored 0 to 5 using the following criteria: septal thickening, alveolar and interstitial edema, hyaline membranes, inflammatory cell infiltration, and small airway epithelial injury (with 0 meaning normal and 5 indicating the most severe injury) (18). Specimens were scored for injury severity by a pulmonary pathologist blinded to the treatment group. In addition, 10 fields were examined at ×40 and scored for the distribution of the inflated volume as previously described (18). Additional tissue samples were prepared for examination of ultrastructural differences as previously described (15).
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RESULTS |
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METHODS
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Pulmonary Edema
Pulmonary edema, measured as excess extravascular lung water, decreased by 55% when tidal volume was decreased from 12 to 6 ml/kg (Figure 1) (p < 0.05 by ANOVA with Student-Newmann-Keuls (SNK) correction for multiple comparisons). A further reduction in tidal volume to 3 ml/kg resulted in an additional 30% decrease in pulmonary edema (p < 0.05) (Figure 1). Extravascular lung water in ventilated control rats treated with saline instead of acid was not different from unventilated, uninjured control rats (data not shown).
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p < 0.05 compared with the 6 ml/kg group, 
p < 0.05 compared with the
12 ml/kg PEEP 5 cm H2O group). All acid-injured rats (black bars) had
a significantly more extravascular lung water than did ventilated control rats instilled with saline instead of acid (white bars) (p < 0.001 by
ANOVA with SNK correction for multiple comparisons). Excess lung
water did not differ among the control groups (p > 0.05). Sample
sizes: 12 ml/kg PEEP 10 cm H2O, n = 4; 12 ml/kg PEEP 5 cm H2O, n = 8; 6 ml/kg PEEP 10 cm H2O, n = 13; 3 ml/kg PEEP 10 cm H2O, n = 12. Data are means ± SD.
Histology
Histologic examination of the lungs demonstrated differences in edema and in lung injury among the groups (Figure 2). For each group, 240 fields were scored by a pulmonary pathologist (KDJ) blinded to the treatment groups using a previously described scoring system (18). The mean histologic lung injury scores were 3.9 ± 0.1 for the 12 ml/kg PEEP 10 cm H2O group, 3.5 ± 0.2 for the 12 ml/kg PEEP 5 group, 3.5 ± 0.2 for the 6 ml/kg group, and 3.0 ± 0.1 for the 3 ml/kg group (mean ± SEM, p = 0.01 for the 12 ml/kg PEEP 10 cm H2O group compared with the 3 ml/kg group by one-way ANOVA with SNK correction for multiple comparisons, n = 4 in each group). Although lung injury was patchy in all groups, there were fewer areas of normal lung in the high tidal volume groups. Lung inflation was more uneven in the lungs of rats ventilated with the highest tidal volume. On histologic examination, the proportion of atelectatic alveolar units in the 12 ml/kg PEEP 5 cm H2O group was 37 ± 10%, which was significantly higher than in the 12 ml/kg PEEP 10 cm H2O group (22.5 ± 9%) and the 3 ml/kg PEEP 10 cm H2O group (14.5 ± 9.4%). The proportion of atelectatic alveolar units in the 12 ml/kg PEEP 10 cm H2O group was also significantly higher than in the 6 ml/kg PEEP 10 cm H2O group (p < 0.05 by ANOVA with SNK post test), and there was significantly more overdistention in the 12 ml/kg PEEP 10 cm H2O compared with the other groups (data not shown).
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Lung Injury
To determine how low tidal volume ventilation diminished the quantity of pulmonary edema and the severity of histologic lung injury, biochemical and functional markers were used to quantify lung endothelial and alveolar epithelial injury.
Endothelial injury. Plasma vWf:Ag, a biochemical marker of endothelial injury (12, 13), increased to similar levels in all groups prior to randomization (data not shown). After randomization, plasma vWf:Ag was higher in both groups ventilated with 12 ml/kg compared with the 6 and 3 ml/kg groups. In the 6 and 3 ml/kg groups, vWf:Ag increased to comparable levels, which were 25% of the levels in the high tidal volume groups (Figure 3A). Ventilation with any of the strategies in the absence of acid injury did not result in an increase in plasma vWf:Ag levels (data not shown).
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Epithelial injury. Plasma levels of RTI40, a biochemical marker of type I cell injury (15), were highest in the 12 ml/kg PEEP 10 cm H2O group and were significantly lower with lower tidal volume ventilation (Figure 4A). To further substantiate the differences in alveolar epithelial injury between the two low tidal volume groups, RTI40 levels were measured in undiluted edema fluid. Edema fluid RTI40 levels in the 6 ml/kg group were 2.7 times higher than in the 3 ml/kg group (18,881 ± 5,519 relative light units compared with 7,027 ± 825) (p < 0.05 by unpaired, two-tailed t test). Comparison of ultrastructure further demonstrated differences in alveolar epithelial injury among the groups (Figure 5).
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Alveolar fluid clearance. Alveolar fluid clearance is a functional marker of epithelial injury. After acid injury, alveolar fluid clearance rates were reduced in all groups. Among the acid-injured groups, alveolar fluid clearance rates were lowest in the rats that were ventilated with the highest tidal volume and significantly increased with tidal volume reduction (Figure 4B). Because increases in endogenous epinephrine can upregulate alveolar fluid clearance, plasma epinephrine levels were measured. Plasma epinephrine levels were normal and similar in all groups prior to injury (data not shown). At the end of the experiments, plasma epinephrine was minimally elevated to a comparable level in all groups. Mean plasma epinephrine was 676 ± 442 pg/ml in the 12 ml/kg PEEP 10 cm H2O group, 667 ± 412 pg/ml in the 12 ml/kg PEEP 5 cm H2O group, 695 ± 377 pg/ml in the 6 ml/kg group, and 642 ± 450 pg/ml in the 3 ml/kg group (p = 0.9 by ANOVA).
Surfactant protein C expression. After normalization to 18S RNA, surfactant protein C expression, a type II cell-specific protein, was decreased by 50% after ventilation with either 6 or 12 ml/kg compared with 3 ml/kg (Figure 6).
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Airway Pressures and Respiratory Mechanics
Peak, plateau, and mean airway pressures were similar at baseline and increased after acid instillation. Plateau pressures were significantly different among the groups ventilated with a PEEP of 10 cm H2O after randomization (Table 1). Plateau airway pressure was comparable between the 6 ml/kg PEEP 10 cm H2O group and the 12 ml/kg PEEP 5 cm H2O group. Mean airway pressures were comparable in all groups except the 12 ml/kg PEEP 10 cm H2O group (Table 1). There were no significant differences in total PEEP (PEEPt) among the groups ventilated with a set PEEP of 10 cm H2O. Inspiratory capacity (IC) and end-expiratory lung volume (EELV) above functional residual capacity were lower after higher tidal volume ventilation (Table 2). Although there was a trend toward lower chord compliance of the respiratory system (Crs) with higher tidal volume ventilation, quasi-static compliance (Cqs) during tidal ventilation was similar among the groups (Table 2).
Arterial Blood Gases and Hemodynamics
The alveolar-arterial oxygen pressure was not different among
the groups at the time of randomization, but significantly increased with 12 ml/kg tidal volume ventilation (Table 3). As
expected, the PaCO2 increased when tidal volume was reduced,
but because sodium bicarbonate was used to buffer acidosis,
pH was similar among the groups (Table 3). Mean arterial
blood pressure (
) decreased minimally in the 12 ml/kg
PEEP 5 cm H2O group after randomization, but was not different among the other groups. At 6 h, was 68 ± 30 mm Hg
in the 12 ml/kg PEEP 10 cm H2O group, 62 ± 20 mm Hg in the
12 ml/kg PEEP 5 cm H2O group, 79 ± 22 in the 6 ml/kg group,
and 76 ± 19 in the 3 ml/kg group (p > 0.05). Central venous
pressure was not different among the groups at any time point.
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DISCUSSION |
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DISCUSSION
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Although previous experimental studies have demonstrated that high tidal volume ventilation of injured lungs increases pulmonary edema formation and may result in the increased release of pro-inflammatory cytokines (4, 10, 19), the effect of low tidal volume ventilation on specific markers of alveolar epithelial and lung endothelial injury has not been previously reported. The overall objective of this study was to determine if tidal volume reduction at similar levels of PEEP reduces pulmonary edema by decreasing alveolar epithelial and lung endothelial cell injury in a rat model of acid-induced lung injury. Using biochemical, functional, histologic, and ultrastructural markers of injury, we found that ventilation with 6 ml/kg compared with 12 ml/kg reduces both alveolar epithelial and lung endothelial injury. A further reduction in tidal volume to 3 ml/kg resulted in a further decrease in alveolar epithelial injury (Figures 3 and 4).
Before discussing the results of this study in detail, an explanation of the study design is warranted. Unlike most studies of ventilator-induced lung injury, the ventilator strategies used in this study were intended to be clinically applicable; none of the tested strategies alone caused lung injury (Figures 1, 3, and 4). The range of tidal volumes tested was selected based on the finding that, during spontaneous ventilation, Sprague-Dawley rats breathe at a tidal volume of 7.0 ± 0.4 ml/kg (23) and on tidal volumes used clinically (1). In our own preliminary studies, the lowest tidal volume feasible with conventional positive pressure ventilation was 3 ml/kg. A PEEP level of 10 cm H2O was selected because it produced an end-expiratory lung volume near the inflection point of the deflation limb of the pressure-volume curve determined in our own preliminary experiments and in other rat studies of acid-induced lung injury (21). This PEEP level corresponds to an end-expiratory lung volume that is approximately 40% of total lung capacity in normal rats. To minimize the number of variables tested, this protocol did not include the use of recruitment maneuvers or determination of pressure-volume curves, issues that have been explored in other studies (24, 25).
Ventilation with a tidal volume of 6 ml/kg resulted in significantly less pulmonary edema compared with 12 ml/kg when either PEEP or plateau airway pressures were comparable (Figure 1). This may have been the result of a reduction in the severity of lung endothelial (Figure 3) and alveolar epithelial injury, including the preservation of alveolar epithelial sodium and fluid transport (Figure 4). It is important to note that the rate of edema formation can also be affected by differences in variables other than lung injury. For example, transmural vascular pressure and pulmonary blood flow, variables that are influenced by mean airway pressure and lung volume (5, 26- 28), affect edema formation rates. However, our data indicate that differences in both endothelial and alveolar epithelial injury account for much of the observed difference in pulmonary edema. This conclusion is further supported by the finding that mean airway pressures and central venous pressures were comparable among the groups in this study.
One of the most important findings of this study is that a reduction in tidal volume from 6 to 3 ml/kg resulted in significantly less pulmonary edema and lung injury. Interestingly, the additional decrease in pulmonary edema with 3 ml/kg was primarily explained by additional protection to the alveolar epithelium. Functional and biochemical markers of endothelial injury were not significantly different between the 6 and 3 ml/kg groups (Figures 3 and 4); however, plasma and edema fluid levels of RTI40 were lower and the rate of alveolar epithelial fluid transport (a functional marker of epithelial injury) was significantly higher in rats ventilated with 3 ml/kg compared with 6 ml/kg.
The loss of normal alveolar fluid transport capacity could be both a marker of injury and a mechanism by which lung injury is amplified because air-space edema reduces lung volume and may inactivate surfactant. Previous studies in isolated rat lungs have shown that high tidal volume ventilation is associated with downregulation of sodium-potassium ATPase and reduced alveolar fluid clearance (6, 29). Therefore, the difference in alveolar epithelial fluid transport among the groups in this study could be due to stretch-induced changes in ion transport (6, 8, 9); however, the finding of higher plasma and edema fluid levels of RTI40 (Figure 4), as well as the histologic and ultrastructural differences among the groups, supports differences in injury to alveolar epithelial cells as an important mechanism. Similarly, the lower levels of surfactant protein C expression in rats ventilated with higher tidal volumes (Figure 6) may have been the result of more severe type II cell injury although previous in vitro studies have found that mechanical distention decreases surfactant protein C transcription (30). We selected surfactant protein C because it is a potential functional marker of type II cell injury and may have implications about the pathophysiology of VALI. For example, loss of surfactant protein C may result in a less stable surfactant (31) and may have contributed to lung injury.
As expected, alveolar ventilation was lower in the 3 ml/kg group resulting in a higher PaCO2. Difficulty maintaining adequate alveolar ventilation is a potential limitation to the use of low tidal volume ventilation clinically; however, there are discordant data on the potential advantages or deleterious effects of hypercapnia and acidosis on lung injury (32). Arterial pH was buffered in our studies and there was no significant difference in pH among the groups (Table 2). We do not believe the protection in our 3 ml/kg studies can be explained by the modest hypercapnia since there was no significant acidosis.
Although we found differences in pulmonary edema and lung injury, oxygenation was similar in the 6 ml/kg and 3 ml/kg groups. Arterial oxygenation can be influenced by many factors, including pulmonary blood flow distribution and lung volume. In the clinical setting, low tidal volume ventilation does not necessarily improve oxygenation despite the reduction in mortality (1).
There are important clinical implications to this experimental study. Previous clinical studies have shown that preserved alveolar fluid clearance correlates with improved outcome, including lower mortality in patients with acute lung injury (33, 34). Other clinical studies have reported that differences in plasma vWf:Ag and a human analogue of RTI40 correlate with the severity of lung injury (35). Therefore, the reduced injury to the lung endothelial and alveolar epithelial barriers and particularly the preservation of epithelial fluid transport capacity in this study may help to explain the mortality benefit observed in clinical trials of low tidal volume ventilation. Furthermore, the additional protection provided to the alveolar epithelium by the lowest tidal volume strategy suggests that there may be ongoing, preventable ventilator-associated lung injury even with a tidal volume of 6 ml/kg.
We have found that the continued reduction in tidal volume to the lower limit compatible with conventional mechanical ventilation results in the progressive reduction of alveolar epithelial injury, including preservation of alveolar epithelial fluid transport in this experimental model of acid-induced acute lung injury. Because preserved alveolar barrier function and fluid transport correlate with improved clinical outcomes (33, 34), a protective ventilation strategy incorporating a tidal volume as low as 3 ml/kg may further improve outcomes in patients with acute lung injury and the acute respiratory distress syndrome.
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Footnotes |
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Correspondence and requests for reprints should be addressed to James A. Frank, M.D., Cardiovascular Research Institute, University of California, San Francisco, 505 Parnassus Ave., Campus Box 0130, San Francisco, CA 94143-0130. Email: frankja{at}itsa.ucsf.edu
(Received in original form August 20, 2001 and accepted in revised form October 29, 2001).
Dr. Frank is recipient of a Glaxo Wellcome Pulmonary Fellowship Research Grant.This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org
Acknowledgments: The writers wish to thank Dr. John Clements for helpful comments regarding this study.
Supported by Grants HL 51854, HL 04372 from the National Heart, Lung, and Blood Institute.
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METHODS
RESULTS
DISCUSSION
REFERENCES
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J. Hirsch, K. C. Hansen, A. Sapru, J. A. Frank, R. J. Chalkley, X. Fang, J. C. Trinidad, P. Baker, A. L. Burlingame, and M. A. Matthay Impact of Low and High Tidal Volumes on the Rat Alveolar Epithelial Type II Cell Proteome Am. J. Respir. Crit. Care Med., May 15, 2007; 175(10): 1006 - 1013. [Abstract] [Full Text] [PDF]
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D. Okutani, B. Han, M. Mura, T. K. Waddell, S. Keshavjee, and M. Liu High-volume ventilation induces pentraxin 3 expression in multiple acute lung injury models in rats Am J Physiol Lung Cell Mol Physiol, January 1, 2007; 292(1): L144 - L153. [Abstract] [Full Text] [PDF]
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 J. A. Frank, P. E. Parsons, and M. A. Matthay Pathogenetic Significance of Biological Markers of Ventilator-Associated Lung Injury in Experimental and Clinical Studies Chest, December 1, 2006; 130(6): 1906 - 1914. [Abstract] [Full Text] [PDF]
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J. A. Frank, C. M. Wray, D. F. McAuley, R. Schwendener, and M. A. Matthay Alveolar macrophages contribute to alveolar barrier dysfunction in ventilator-induced lung injury Am J Physiol Lung Cell Mol Physiol, December 1, 2006; 291(6): L1191 - L1198. [Abstract] [Full Text] [PDF]
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E. N. Ogawa, A. Ishizaka, S. Tasaka, H. Koh, H. Ueno, F. Amaya, M. Ebina, S. Yamada, Y. Funakoshi, J. Soejima, et al. Contribution of High-Mobility Group Box-1 to the Development of Ventilator-induced Lung Injury Am. J. Respir. Crit. Care Med., August 15, 2006; 174(4): 400 - 407. [Abstract] [Full Text] [PDF]
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D. N. Hager, J. A. Krishnan, D. L. Hayden, R. G. Brower, and for the ARDS Clinical Trials Network Tidal Volume Reduction in Patients with Acute Lung Injury When Plateau Pressures Are Not High Am. J. Respir. Crit. Care Med., November 15, 2005; 172(10): 1241 - 1245. [Abstract] [Full Text] [PDF]
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G. M. Mutlu and J. I. Sznajder Mechanisms of pulmonary edema clearance Am J Physiol Lung Cell Mol Physiol, November 1, 2005; 289(5): L685 - L695. [Abstract] [Full Text] [PDF]
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K. E. Chapman, S. E. Sinclair, D. Zhuang, A. Hassid, L. P. Desai, and C. M. Waters Cyclic mechanical strain increases reactive oxygen species production in pulmonary epithelial cells Am J Physiol Lung Cell Mol Physiol, November 1, 2005; 289(5): L834 - L841. [Abstract] [Full Text] [PDF]
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 M. A. Matthay, L. Robriquet, and X. Fang Alveolar Epithelium: Role in Lung Fluid Balance and Acute Lung Injury Proceedings of the ATS, October 1, 2005; 2(3): 206 - 213. [Abstract] [Full Text] [PDF]
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J. A. Frank and M. A. Matthay Leukotrienes in Acute Lung Injury: A Potential Therapeutic Target? Am. J. Respir. Crit. Care Med., August 1, 2005; 172(3): 261 - 262. [Full Text] [PDF]
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P. E. Parsons, M. A. Matthay, L. B. Ware, M. D. Eisner, and and the National Heart, Lung, Blood Institute Acut Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury Am J Physiol Lung Cell Mol Physiol, March 1, 2005; 288(3): L426 - L431. [Abstract] [Full Text] [PDF]
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S. Q. Ye, B. A. Simon, J. P. Maloney, A. Zambelli-Weiner, L. Gao, A. Grant, R. B. Easley, B. J. McVerry, R. M. Tuder, T. Standiford, et al. Pre-B-Cell Colony-enhancing Factor as a Potential Novel Biomarker in Acute Lung Injury Am. J. Respir. Crit. Care Med., February 15, 2005; 171(4): 361 - 370. [Abstract] [Full Text] [PDF]
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M. T. Pawlik, A. G. Schreyer, K. P. Ittner, C. Selig, M. Gruber, S. Feuerbach, and K. Taeger Early Treatment With Pentoxifylline Reduces Lung Injury Induced by Acid Aspiration in Rats Chest, February 1, 2005; 127(2): 613 - 621. [Abstract] [Full Text] [PDF]
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D. Mehta, J. Bhattacharya, M. A. Matthay, and A. B. Malik Integrated control of lung fluid balance Am J Physiol Lung Cell Mol Physiol, December 1, 2004; 287(6): L1081 - L1090. [Abstract] [Full Text] [PDF]
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L. B. Ware, M. D. Eisner, B. T. Thompson, P. E. Parsons, and M. A. Matthay Significance of Von Willebrand Factor in Septic and Nonseptic Patients with Acute Lung Injury Am. J. Respir. Crit. Care Med., October 1, 2004; 170(7): 766 - 772. [Abstract] [Full Text] [PDF]
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W. A. Altemeier, G. Matute-Bello, C. W. Frevert, Y. Kawata, O. Kajikawa, T. R. Martin, and R. W. Glenny Mechanical ventilation with moderate tidal volumes synergistically increases lung cytokine response to systemic endotoxin Am J Physiol Lung Cell Mol Physiol, September 1, 2004; 287(3): L533 - L542. [Abstract] [Full Text] [PDF]
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