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Am J Physiol Lung Cell Mol Physiol 295: L718-L724, 2008. First published August 15, 2008; doi:10.1152/ajplung.90298.2008
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INNOVATIVE METHODOLOGY

Usefulness of pressure-controlled ventilation at high inspiratory pressures to induce acute lung injury in mice

Tobias Eckle,1,2,* Lars Füllbier,1,* Almut Grenz,2,3 and Holger K. Eltzschig1,2

Departments of 1Anesthesiology and Intensive Care Medicine, and 3Pharmacology and Toxicology, Tübingen University Hospital, Tübingen, Germany; and 2Mucosal Inflammation Program, Department of Anesthesiology and Perioperative Medicine, University of Colorado Health Sciences Center, Denver, Colorado

Submitted 3 May 2008 ; accepted in final form 14 August 2008

ABSTRACT

Acute lung injury (ALI), as occurs with prolonged mechanical ventilation, contributes to morbidity and mortality of critical illness, and studies on novel genetic or pharmacological targets are areas of intense investigation. Here, we systematically tested a murine model of ALI by using pressure-controlled ventilation to induce ventilator-induced lung injury. For this purpose, C57BL/6 or Sv129 mice were anesthetized and underwent tracheotomy followed by induction of ALI via mechanical ventilation. Mice were ventilated in a pressure-controlled setting at different inspiratory pressure levels (15–45 mbar) and over different times (0–90 min, 100% oxygen). As outcome parameters, we assessed pulmonary edema (wet-to-dry ratios), bronchoalveolar fluid albumin content, pulmonary myeloperoxidase activity, macrophage inflammatory protein-2, and pulmonary gas exchange. These studies revealed maximal differences in severity of lung injury between different mouse strains after 90 min of ventilation time at 45 mbar. Use of lower concentrations of inspired oxygen did not alter disease severity. Increases of CD73 transcript (5'-ectonucleotidase, pacemaker of extracellular adenosine production) or total pulmonary adenosine levels with mechanical ventilation were less pronounced in C57BL/6 mice, suggesting attenuated adenosine protection in C57BL/6 mice. Together, these studies demonstrate feasibility of this model to induce murine ALI.

ventilator-induced lung injury

STUDIES OF TISSUE PROTECTION utilizing murine models of acute injury are areas of intense investigation (7–9, 11–16, 18–21, 24, 27, 31, 38, 39, 41). For example, previous studies have used intratracheal bleomycin (46), inhalation of cigarette smoke (43), hyperoxia (34), acute ischemia-reperfusion injury (47), oleic acid (6), endotoxin (32, 36, 41), or different murine pathogens (30, 41) to induce acute lung injury (ALI). In addition, several studies have used cyclic mechanical ventilation with increased tidal volumes (22, 33, 45) for the induction of ventilator-induced lung injury (VILI). As such, VILI closely resembles many aspects of ALI (acute setting, attenuated gas exchange, bilateral lung disease) and allows the study gene-targeted mice (2, 8, 26).

Previous studies have used volume-controlled mechanical ventilation to induce VILI. When using volume-controlled ventilation, relatively small tidal volumes specifically adjusted to the animals’ weight have to be delivered (between 5 and 20 ml/kg body wt). While murine ventilators can be used in a volume-controlled setting to ventilate mice over prolonged periods without injury (e.g., up to 8 h), an alternative ventilatory strategy to induce ALI resembles pressure-controlled ventilation. Here, we hypothesized that pressure-controlled ventilation can be utilized to induce a highly reproducible degree of injury. Based on previous studies showing differences in pulmonary mechanics between different inbred mouse strains (40) or different susceptibility to lung injury (25), we exposed two different inbred mouse strains (C57BL/6 or Sv129) to pressure-controlled mechanical ventilation. Different levels of inspiratory pressure and ventilation times revealed more differences between murine strains utilizing high inspiratory pressure levels (45 mbar) over a time period of 90 min in conjunction with a highly reproducible degree of ALI.

METHODS

Murine mechanical ventilation. All animal protocols were in accordance with the German guidelines for use of living animals and were approved by the Institutional Animal Care and Use Committee of the Tübingen University Hospital, the Regierungspräsidium Tübingen, or the University of Colorado Health Sciences Center, Denver. Mice on the C57BL/6 (C57BL/6NCrl) or the Sv129 (129S2/SvPasCrlf) strain were purchased from Charles River Laboratory. Mice were selected and allocated according to age, sex, and weight in a prospective manner. Animals were anesthetized with pentobarbital (70 mg/kg ip for induction; 20 mg·kg–1·h–1 for maintenance) and placed on a temperature-controlled heated table (RT; Effenberg, Munich, Germany) with a rectal thermometer probe attached to a thermal feedback controller to maintain body temperature at 37°C. In addition, all animals were monitored with an electrocardiogram (Hewlett Packard, Böblingen, Germany). Fluid replacement was performed with normal saline, 0.05 ml/h ip. Tracheotomy was performed in a supine position (8). The tracheal tube was connected to a mechanical ventilator (Servo 900C; Siemens, Germany, with pediatric tubing). Mice were ventilated in a pressure-controlled ventilation mode at different inspiratory pressure levels (15, 35, and 45 mbar) for different time periods (30–90 min). Respiratory rate and inspiratory to expiratory time (I:E) ratios were adjusted based on arterial blood gas sampling obtained by cardiac puncture in control animals to maintain a carbon dioxide partial pressure between 35 and 40 mmHg and a pH between 7.35 and 7.40 (Supplemental Table). All animals were ventilated with an inspired oxygen concentration of 100% (FIO2 of 1), except in studies on the influence of FIO2 on VILI. In a subset of experiments, animals were ventilated under deep anesthesia at 45 mbar until a cardiac standstill was observed in the surface electrocardiogram (8), and mice were subsequently euthanized.

Bronchoalveolar lavage. To obtain bronchoalveolar lavage (BAL) fluid, the lungs were lavaged three times with 0.5 ml of PBS. (Supplemental data for this article is available online at the AJP-Lung web site.)

Measurement of albumin and MIP-2 in BAL fluid. Albumin or MIP-2 concentrations were measured by ELISA. Values below the limit of the assay were considered "zero" (for details, see data supplement).

Myeloperoxidase assay. Pulmonary neutrophil sequestration was quantified using a myeloperoxidase (MPO) (for details, see data supplement).

Wet-to-dry ratios. Following ventilation with indicated settings, lungs were excised en bloc, and wet-to-dry ratios were determined (for details, see data supplement).

Transcriptional analysis and measurements of pulmonary adenosine levels. Measurements of pulmonary CD73 transcript and adenosine levels are detailed in the supplementary data.

Blood gas analysis. To assess pulmonary gas exchange, blood gas analyses were preformed in subsets of experiments by obtaining arterial blood via cardiac puncture(for details, see data supplement).

Histopathological evaluation of ALI. Following ventilation at indicated settings, the mice were euthanized, and lungs were fixed by instillation of 10% formaldehyde solution, followed by histopathological elevation (for details, see data supplement).

Data analysis. Lung injury score and survival data are given as median (range); all other data are presented as means ± SD from four to six animals per condition. We performed statistical analysis using Student's t-test (2-sided, P < 0.05) or ANOVA to determine group differences. Lung injury score was analyzed with Kruskal-Wallis rank test. Kaplan Maier curves were compared using log rank test (Mantel-Haenszel) test. P < 0.05 was considered statistically significant.

RESULTS

Pressure-controlled ventilation to induce ALI. C57BL/6 mice matched according to sex, age, and weight were ventilated at indicated settings using pressure-controlled ventilation (15, 35, and 45 mbar) over different time periods (0–90 min). In these studies, all animals were ventilated with an inspired oxygen concentration of 100% (FIO2 of 1) without positive end-expiratory pressure (PEEP). Outcome parameters of ALI included albumin leakage into the BAL, lung water content as assessed by wet-to-dry ratios, pulmonary neutrophil accumulation as measured by tissue MPO levels, and functional parameters of gas-exchange [ratio of arterial partial pressure of oxygen (PaO2) and fraction of inspired oxygen (FIO2)]. These studies revealed a highly reproducible degree of ALI in all examined parameters at 45 mbar inspiratory pressure (Fig. 1). Lung injury consistent with the definition of ALI (ratio of partial pressure of oxygen to the inspired oxygen concentration) (3) was achieved with ventilation times between 60 and 90 min at a pressure level of 45 mbar.


Figure 1
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  		Fig. 1. Induction of acute lung injury (ALI) by pressure-controlled ventilation. C57BL/6 mice were prospectively allocated based on age, gender, and weight, followed by mechanical ventilation at indicated settings. A: albumin concentration in the bronchoalveolar (BAL) fluid. B: lung water content. Neutrophil accumulation (myeloperoxidase assay) (C) and gas exchange (D) assessed by the ratio of arterial partial pressure of oxygen (PaO2) over the fraction of inspired oxygen (FIO2). E: albumin concentration in the BAL. F: lung water content. G: neutrophil accumulation (myeloperoxidase assay). H: gas exchange (PaO2/FIO2). All results are presented as means ± SD and derived from 6 animals in each condition. In control groups with similar conditions, the same set of data/animals was analyzed.

 
VILI is enhanced in C57BL/6 mice compared with Sv129 mice. Previous studies had shown differences between inbred mouse strains with regard to their pulmonary mechanics (40). To test the usefulness of this model to determine such differences in the setting of ALI, we compared BAL albumin leakage and lung water content in C57BL/6 or Sv129 mice. As shown in Fig. 2A, Sv129 and C57BL/6 mice both showed increases in albumin leakage into the BAL fluid and in lung water content. However, these increases were more pronounced in C57BL/6 mice compared with Sv129 mice. Similarly, pressure-dependent increases in lung water were significantly enhanced in C57BL/6 mice (Fig. 2B). We next compared the levels of the pulmonary neutrophil accumulation by measuring MPO (Fig. 2C) or the proinflammatory cytokine MIP-2 (Fig. 2D) in C57BL/6 or Sv129 mice. In fact, PMN infiltration and MIP-2 levels were significantly more elevated in C57BL/6 compared with Sv129 mice. Similar findings were obtained when measuring pulmonary gas exchange (Fig. 2E). Based on previous studies showing a protective role of extracellular adenosine generation during VILI (8), we pursued the hypothesis that endogenous production of adenosine via the ecto-5'-nucleotidase (CD73) is attenuated in C57BL/6 mice compared with Sv129. As shown in Fig. 2, F and G, induction of CD73 transcript levels and increases of pulmonary adenosine levels were attenuated in C57BL/6 mice compared with Sv129, respectively. These studies suggest that ALI induced by mechanical ventilation is more severe in C57BL/6 compared with Sv129 mice and reveals differences in the generation of extracellular adenosine between both mouse strains. The latter could explain the differences in susceptibility to VILI.


Figure 2
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  		Fig. 2. Ventilator-induced lung injury in Sv129 or C57BL/6 mice. Sv129 or C57BL/6 mice were prospectively allocated based on age, gender, and weight, followed by mechanical ventilation at indicated settings. A: albumin concentration in the BAL. B: lung water content. Neutrophil accumulation (myeloperoxidase assay) (C) and macrophage inflammatory protein (MIP)-2 (D) in the BAL fluid. E: Gas exchange [ratio of arterial oxygen partial pressure (PaO2) over inspired oxygen fraction (FIO2)]. All results are presented as means ± SD and derived from 6 animals in each condition. Pulmonary transcript levels of 5'-ectonucleotidase (CD73) were determined by quantitative real-time reverse transcriptase PCR relative to the housekeeping gene β-action (n = 3). Pulmonary adenosine levels were determined by HPLC.

 
Histological characteristics of pulmonary injury and gas-exchange in C57BL/6 or Sv129 mice. As shown in Fig. 3, the differences between both mouse strains could be confirmed on a histological level. To investigate differences in pulmonary gas exchange during VILI as a surrogate parameter of function, blood gas analyses were performed. Together, these studies suggest that histological tissue injury is more severely impaired in C57BL/6 compared with Sv129 mice.


Figure 3
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  		Fig. 3. Macroscopic and microscopic images of lungs from Sv129 or C57BL/6 mice exposed to ventilator-induced lung injury (VILI). A: Sv129 or C57BL/6 mice were mechanically ventilated (pressure-controlled ventilation, 100% inspired oxygen) for 0 or 90 min at an inspiratory pressure of 45 mbar. One of four representative images are displayed. B: quantitative histological assessment of tissue damage (median ± range, n = 4).

 
Influence of the inspired oxygen concentration on VILI in C57BL/6 or Sv129 mice. Sv129 or C57BL/6 mice were ventilated with pressure-controlled ventilation at an inspiratory pressure of 45 mbar over indicated time periods (0 or 90 min) using different concentrations of inspired oxygen (20% or 100% oxygen). These studies confirmed differences between Sv129 and C57BL/6 mice with regard to pulmonary edema and lung inflammation during VILI (Fig. 4, A–D). However, different inspired oxygen concentrations did not alter these results, suggesting that differences between Sv129 and C57BL/6 mice during VILI occur independently of the inspired oxygen concentration in this model.


Figure 4
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  		Fig. 4. A–D: Sv129 or C57BL/6 mice were prospectively allocated based on age, gender, and weight, followed by mechanical ventilation at indicated settings. A: albumin concentration in the BAL fluid. B: lung water content. Neutrophil accumulation (myeloperoxidase assay) (C) and MIP-2 (D) in the BAL fluid. All results are presented as means ± SD and derived from 6 animals in each condition. E and F: survival during VILI. Sv129 or C57BL/6 mice matched in age, gender, and weight were mechanically ventilated, and survival times were determined during VILI. E: inspiratory pressure of 35 mbar, 0 PEEP. F: inspiratory pressure of 45 mbar, 0 PEEP. G: inspiratory pressure of 45 mbar in addition to 5 mbar PEEP.

 
Different survival times of C57BL/6 or Sv129 mice during VILI. Next, we exposed mice from both strains to VILI at an inspiratory pressure level of 35 (Fig. 4E) or 45 mbar (Fig. 4F). These studies confirmed the above differences between Sv129 and C57BL/6. To test the influence of PEEP on survival time in this model, we repeated these studies with the addition of 5 mbar of PEEP (Fig. 4G). Here we found optimal, better resolution of different susceptibility between both mouse strains. Together, these studies demonstrate suitability of pressure-controlled ventilation at high inspiratory pressure levels (45 mbar) to study survival times during VILI under deep anesthesia.

DISCUSSION

ALI significantly contributes to critical illness, as it occurs frequently (37) and carries a high mortality rate (44). Moreover, the only therapeutic interventions currently available are elimination of causative agents and supportive therapy (44). Therefore, murine studies of ALI to discover the contribution of specific gene products or novel pharmacological targets are areas of intense investigation. Such studies require models of ALI that are associated with highly reproducible outcome parameters, such as pulmonary edema, lung inflammation, histology, and functional parameters including gas-exchange or survival time. Here, we hypothesized that induction of ALI utilizing pressure-controlled ventilation may be associated with highly reproducible degrees of ALI in mice. Consistent with this hypothesis, we demonstrate here that pressure-controlled ventilation at high inspiratory pressure levels (45 mbar) over a time period of 60–90 min is associated with the induction of ALI, including bilateral pulmonary edema and attenuated gas exchange (3). Extension of these studies utilizing different inbred mouse strains (C57BL/6 or Sv129 mice) revealed that this model is reliable in resolving the influence of genetic factors on outcome parameters of ALI, including studies of survival. In addition, these studies revealed differences in CD73 induction and pulmonary adenosine generation as response to VILI. This could be an explanation for the increased susceptibility of C57BL/6 compared with Sv129 mice in this model.

Consistent with the present findings, previous studies have found different degrees of injury in mouse strains in models of acute injury. As such, previous studies described differences in pulmonary mechanics between different inbred mouse strains (40). Similarly, studies of murine myocardial resistance to ischemia revealed different degrees of susceptibility between inbred mouse strains to myocardial infarction induced by coronary artery occlusion. When exposed to similar ischemia time periods, myocardial infarction in CD1 mice was significantly larger than in C57BL/6 mice (9). Similarly, it is well established that differences in responses to renal ischemia have been observed when exposing mice with different genetic backgrounds to renal artery occlusion (1, 4). For example, a recent study searched for an in vivo model of intrinsic resistance to renal ischemia, as this would provide an invaluable tool to investigate putative protectors from renal injury. This study showed that Brown Norway rats are virtually resistant to renal ischemic injury, thus providing a novel model for studying mechanisms of renal protection from acute renal failure (1). Moreover, recent studies of hepatic ischemia revealed different susceptibility between inbred mouse strains to liver ischemia (23). Together, these studies reveal dramatic differences in different models of acute injury between inbred mouse strains.

Our studies of pulmonary adenosine production suggest an inverse correlation between the degree of lung injury and the capability to produce extracellular adenosine. These data suggest a protective role of extracellular adenosine production and signaling in lung protection during VILI. This is consistent with other studies using genetic and pharmacological approaches to study extracellular adenosine in lung protection. For example, studies in mice with genetic defects in extracellular adenosine production (cd39–/– or cd73–/– mice) show enhanced susceptibility to ALI induced by mechanical ventilation (8). Moreover, studies comparing gene-targeted mice for individual adenosine receptors (ARs) found a selective role of the A2BAR in attenuating injury during high-pressure mechanical ventilation (10). Consistent with other studies on adenosine in enhancing alveolar fluid clearance (17, 28), these studies revealed a role of A2BAR signaling in enhancing alveolar fluid clearance during VILI, suggesting that A2BAR signaling protects during VILI by drying out the lungs (10).

The present studies suggest the usefulness of pressure-controlled ventilation to induce ALI. In fact, the present data show rapid and reproducible lung injury within hours of mechanical ventilation. However, some limitations should be pointed out. First, previous studies have shown that ventilating animals with inspiratory pressures and zero PEEP results in very rapid massive injury, which is associated with mechanical disruption of lung structures (29). This is somewhat different from the modulation of innate immune responses without mechanical disruption seen at lower inspiratory pressures (5). However, the model used in the present studies allows the investigation of additional parameters, such as survival time, and more closely resembles the severe degree of impaired lung function seen in patients with ARDS. For studies to address more subtle innate immune responses (independently of disruption of lung structures), pressure-controlled ventilation at lower inspiratory pressure levels (e.g., 20 or 25 mbar) could be considered. Second, the ventilatory parameters required for the high-pressure model are only rarely applied in patients. However, particularly in European countries, pressure-controlled ventilation remains a common treatment form of ARDS in many patients (35) or is clinically applied during short-term recruitment maneuvers (42).

Together, the present studies demonstrate feasibility of pressure-controlled high-pressure ventilation to induce ALI as assessed by pulmonary edema, lung inflammation, gas exchange, and survival time. In addition, the present findings of significant differences between mouse strains during VILI underscore the role of genetic factors in susceptibility to ALI and suggest that it is critical for murine studies of ALI to carefully choose appropriate control groups (e.g., matched littermate control mice).

GRANTS

This work was supported by Fortune Grant 1416-0-0, IZKF Verbundprojekt 1597-0-0, DFG Grant EL274/2-2, a DFG Fellowship to A. Grenz, and a Foundation of Anesthesia Education and Research grant to H. K. Eltzschig and IZKF Nachwuchsgruppe 1605-0-0 to T. Eckle.

ACKNOWLEDGMENTS

We acknowledge Marion Faigle and Stephanie Zug for technical assistance and Dr. Michel Mittelbron for histological analysis of tissue sections.

FOOTNOTES


Address for reprint requests and other correspondence: H. K. Eltzschig, Mucosal Inflammation Program, University of Colorado Denver Dept. of Anesthesiology and Perioperative Medicine, 12700 E. 19th Ave., Mailstop B112, RC-2, Aurora, CO 80045 (e-mail: holger.eltzschig{at}uchsc.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.

* T. Eckle and L. Füllbier contributed equally to this work. Back

REFERENCES

  1. Basile DP, Donohoe D, Cao X, Van Why SK. Resistance to ischemic acute renal failure in the Brown Norway rat: a new model to study cytoprotection. Kidney Int 65: 2201–2211, 2004.[CrossRef][Web of Science][Medline]
  2. Belperio JA, Keane MP, Burdick MD, Londhe V, Xue YY, Li K, Phillips RJ, Strieter RM. Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury. J Clin Invest 110: 1703–1716, 2002.[CrossRef][Web of Science][Medline]
  3. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, Legall JR, Morris A, Spragg R. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149: 818–824, 1994.[Abstract]
  4. Burne MJ, Haq M, Matsuse H, Mohapatra S, Rabb H. Genetic susceptibility to renal ischemia reperfusion injury revealed in a murine model. Transplantation 69: 1023–1025, 2000.[CrossRef][Web of Science][Medline]
  5. Choudhury S, Wilson MR, Goddard ME, O'Dea KP, Takata M. Mechanisms of early pulmonary neutrophil sequestration in ventilator-induced lung injury in mice. Am J Physiol Lung Cell Mol Physiol 287: L902–L910, 2004.[Abstract/Free Full Text]
  6. Davidson KG, Bersten AD, Barr HA, Dowling KD, Nicholas TE, Doyle IR. Lung function, permeability, and surfactant composition in oleic acid-induced acute lung injury in rats. Am J Physiol Lung Cell Mol Physiol 279: L1091–L1102, 2000.[Abstract/Free Full Text]
  7. Eckle T, Faigle M, Grenz A, Laucher S, Thompson LF, Eltzschig HK. A2B adenosine receptor dampens hypoxia-induced vascular leak. Blood 111: 2024–2035, 2008.[Abstract/Free Full Text]
  8. Eckle T, Fullbier L, Wehrmann M, Khoury J, Mittelbronn M, Ibla J, Rosenberger P, Eltzschig HK. Identification of ectonucleotidases CD39 and CD73 in innate protection during acute lung injury. J Immunol 178: 8127–8137, 2007.[Abstract/Free Full Text]
  9. Eckle T, Grenz A, Kohler D, Redel A, Falk M, Rolauffs B, Osswald H, Kehl F, Eltzschig HK. Systematic evaluation of a novel model for cardiac ischemic preconditioning in mice. Am J Physiol Heart Circ Physiol 291: H2533–H2540, 2006.[Abstract/Free Full Text]
  10. Eckle T, Grenz A, Laucher S, Eltzschig HK. A2B adenosine receptor attenuates ventilator induced lung injury by enhancing alveolar fluid clearance. J Clin Invest. In press.
  11. Eckle T, Krahn T, Grenz A, Kohler D, Mittelbronn M, Ledent C, Jacobson MA, Osswald H, Thompson LF, Unertl K, Eltzschig HK. Cardioprotection by ecto-5'-nucleotidase (CD73) and A2B adenosine receptors. Circulation 115: 1581–1590, 2007.[Abstract/Free Full Text]
  12. Eltzschig HK, Abdulla P, Hoffman E, Hamilton KE, Daniels D, Schonfeld C, Loffler M, Reyes G, Duszenko M, Karhausen J, Robinson A, Westerman KA, Coe IR, Colgan SP. HIF-1-dependent repression of equilibrative nucleoside transporter (ENT) in hypoxia. J Exp Med 202: 1493–1505, 2005.[Abstract/Free Full Text]
  13. Eltzschig HK, Eckle T, Mager A, Kuper N, Karcher C, Weissmuller T, Boengler K, Schulz R, Robson SC, Colgan SP. ATP release from activated neutrophils occurs via connexin 43 and modulates adenosine-dependent endothelial cell function. Circ Res 99: 1100–1108, 2006.[Abstract/Free Full Text]
  14. Eltzschig HK, Faigle M, Knapp S, Karhausen J, Ibla J, Rosenberger P, Odegard KC, Laussen PC, Thompson LF, Colgan SP. Endothelial catabolism of extracellular adenosine during hypoxia: the role of surface adenosine deaminase and CD26. Blood 108: 1602–1610, 2006.[Abstract/Free Full Text]
  15. Eltzschig HK, Ibla JC, Furuta GT, Leonard MO, Jacobson KA, Enjyoji K, Robson SC, Colgan SP. Coordinated adenine nucleotide phosphohydrolysis and nucleoside signaling in posthypoxic endothelium: role of ectonucleotidases and adenosine A2B receptors. J Exp Med 198: 783–796, 2003.[Abstract/Free Full Text]
  16. Eltzschig HK, Thompson LF, Karhausen J, Cotta RJ, Ibla JC, Robson SC, Colgan SP. Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism. Blood 104: 3986–3992, 2004.[Abstract/Free Full Text]
  17. Factor P, Mutlu GM, Chen L, Mohameed J, Akhmedov AT, Meng FJ, Jilling T, Lewis ER, Johnson MD, Xu A, Kass D, Martino JM, Bellmeyer A, Albazi JS, Emala C, Lee HT, Dobbs LG, Matalon S. Adenosine regulation of alveolar fluid clearance. Proc Natl Acad Sci USA 104: 4083–4088, 2007.[Abstract/Free Full Text]
  18. Fredholm BB. Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 14: 1315–1323, 2007.[CrossRef][Medline]
  19. Grenz A, Eckle T, Zhang H, Huang DY, Wehrmann M, Kohle C, Unertl K, Osswald H, Eltzschig HK. Use of a hanging-weight system for isolated renal artery occlusion during ischemic preconditioning in mice. Am J Physiol Renal Physiol 292: F475–F485, 2007.[Abstract/Free Full Text]
  20. Grenz A, Zhang H, Eckle T, Mittelbronn M, Wehrmann M, Kohle C, Kloor D, Thompson LF, Osswald H, Eltzschig HK. Protective role of ecto-5'-nucleotidase (CD73) in renal ischemia. J Am Soc Nephrol 18: 833–845, 2007.[Abstract/Free Full Text]
  21. Grenz A, Zhang H, Hermes M, Eckle T, Klingel K, Huang DY, Muller CE, Robson SC, Osswald H, Eltzschig HK. Contribution of E-NTPDase1 (CD39) to renal protection from ischemia-reperfusion injury. FASEB J 21: 2863–2873, 2007.[Abstract/Free Full Text]
  22. Hamanaka K, Jian MY, Weber DS, Alvarez DF, Townsley MI, Al-Mehdi AB, King JA, Liedtke W, Parker JC. TRPV4 initiates the acute calcium-dependent permeability increase during ventilator-induced lung injury in isolated mouse lungs. Am J Physiol Lung Cell Mol Physiol 293: L923–L932, 2007.[Abstract/Free Full Text]
  23. Hart ML, Much C, Kohler D, Schittenhelm J, Gorzolla IC, Stahl GL, Eltzschig HK. Use of a hanging-weight system for liver ischemic preconditioning in mice. Am J Physiol Gastrointest Liver Physiol 294: G1431–G1440, 2008.[Abstract/Free Full Text]
  24. Hartmann H, Eltzschig HK, Wurz H, Hantke K, Rakin A, Yazdi AS, Matteoli G, Bohn E, Autenrieth IB, Karhausen J, Neumann D, Colgan SP, Kempf VA. Hypoxia-independent activation of HIF-1 by enterobacteriaceae and their siderophores. Gastroenterology 134: 756–767, 2008.[Medline]
  25. Held HD, Boettcher S, Hamann L, Uhlig S. Ventilation-induced chemokine and cytokine release is associated with activation of nuclear factor-kappaB and is blocked by steroids. Am J Respir Crit Care Med 163: 711–716, 2001.[Abstract/Free Full Text]
  26. Imanaka H, Shimaoka M, Matsuura N, Nishimura M, Ohta N, Kiyono H. Ventilator-induced lung injury is associated with neutrophil infiltration, macrophage activation, and TGF-β1 mRNA upregulation in rat lungs. Anesth Analg 92: 428–436, 2001.[Abstract/Free Full Text]
  27. Kohler D, Eckle T, Faigle M, Grenz A, Mittelbronn M, Laucher S, Hart ML, Robson SC, Muller CE, Eltzschig HK. CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury. Circulation 116: 1784–1794, 2007.[Abstract/Free Full Text]
  28. Kreindler JL, Shapiro SD. Lung turns to AA (adenosine analogues) to dry out. Nat Med 13: 406–408, 2007.[CrossRef][Web of Science][Medline]
  29. Lesur O, Hermans C, Chalifour JF, Picotte J, Levy B, Bernard A, Lane D. Mechanical ventilation-induced pneumoprotein CC-16 vascular transfer in rats: effect of KGF pretreatment. Am J Physiol Lung Cell Mol Physiol 284: L410–L419, 2003.[Abstract/Free Full Text]
  30. Mizgerd JP, Skerrett SJ. Animal models of human pneumonia. Am J Physiol Lung Cell Mol Physiol 294: L387–L398, 2008.[Abstract/Free Full Text]
  31. Morote-Garcia JC, Rosenberger P, Kuhlicke J, Eltzschig HK. HIF-1-dependent repression of adenosine kinase attenuates hypoxia-induced vascular leak. Blood 111: 5571–5580, 2008.[Abstract/Free Full Text]
  32. Ohta A, Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature 414: 916–920, 2001.[CrossRef][Web of Science][Medline]
  33. Okutani D, Han B, Mura M, Waddell TK, Keshavjee S, Liu M. High-volume ventilation induces pentraxin 3 expression in multiple acute lung injury models in rats. Am J Physiol Lung Cell Mol Physiol 292: L144–L153, 2007.[Abstract/Free Full Text]
  34. Perkowski S, Scherpereel A, Murciano JC, Arguiri E, Solomides CC, Albelda SM, Muzykantov V, Christofidou-Solomidou M. Dissociation between alveolar transmigration of neutrophils and lung injury in hyperoxia. Am J Physiol Lung Cell Mol Physiol 291: L1050–L1058, 2006.[Abstract/Free Full Text]
  35. Prella M, Feihl F, Domenighetti G. Effects of short-term pressure-controlled ventilation on gas exchange, airway pressures, and gas distribution in patients with acute lung injury/ARDS: comparison with volume-controlled ventilation. Chest 122: 1382–1388, 2002.[CrossRef][Web of Science][Medline]
  36. Reutershan J, Basit A, Galkina EV, Ley K. Sequential recruitment of neutrophils into lung and bronchoalveolar lavage fluid in LPS-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 289: L807–L815, 2005.[Abstract/Free Full Text]
  37. Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD. Incidence and outcomes of acute lung injury. N Engl J Med 353: 1685–1693, 2005.[Abstract/Free Full Text]
  38. Sitkovsky M, Lukashev D. Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat Rev Immunol 5: 712–721, 2005.[CrossRef][Web of Science][Medline]
  39. Sitkovsky MV, Lukashev D, Apasov S, Kojima H, Koshiba M, Caldwell C, Ohta A, Thiel M. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol 22: 657–682, 2004.[CrossRef][Web of Science][Medline]
  40. Tankersley CG, Rabold R, Mitzner W. Differential lung mechanics are genetically determined in inbred murine strains. J Appl Physiol 86: 1764–1769, 1999.[Abstract/Free Full Text]
  41. Thiel M, Chouker A, Ohta A, Jackson E, Caldwell C, Smith P, Lukashev D, Bittmann I, Sitkovsky MV. Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury. PLoS Biol 3: e174, 2005.[CrossRef][Medline]
  42. Villagra A, Ochagavia A, Vatua S, Murias G, Del Mar Fernandez M, Lopez Aguilar J, Fernandez R, Blanch L. Recruitment maneuvers during lung protective ventilation in acute respiratory distress syndrome. Am J Respir Crit Care Med 165: 165–170, 2002.[Abstract/Free Full Text]
  43. Vlahos R, Bozinovski S, Jones JE, Powell J, Gras J, Lilja A, Hansen MJ, Gualano RC, Irving L, Anderson GP. Differential protease, innate immunity, and NF-kappaB induction profiles during lung inflammation induced by subchronic cigarette smoke exposure in mice. Am J Physiol Lung Cell Mol Physiol 290: L931–L945, 2006.[Abstract/Free Full Text]
  44. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 342: 1334–1349, 2000.[Free Full Text]
  45. Wilson MR, Goddard ME, O'Dea KP, Choudhury S, Takata M. Differential roles of p55 and p75 tumor necrosis factor receptors on stretch-induced pulmonary edema in mice. Am J Physiol Lung Cell Mol Physiol 293: L60–L68, 2007.[Abstract/Free Full Text]
  46. Xu J, Mora AL, LaVoy J, Brigham KL, Rojas M. Increased bleomycin-induced lung injury in mice deficient in the transcription factor T-bet. Am J Physiol Lung Cell Mol Physiol 291: L658–L667, 2006.[Abstract/Free Full Text]
  47. Zhao M, Fernandez LG, Doctor A, Sharma AK, Zarbock A, Tribble CG, Kron IL, Laubach VE. Alveolar macrophage activation is a key initiation signal for acute lung ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol 291: L1018–L1026, 2006.[Abstract/Free Full Text]



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