Ventilator-Induced Lung Injury

Li and coworkers  evaluated the mechanisms of ventilator-induced lung injury in a mouse model. High VT ventilation (30 ml/kg) was compared with low VT ventilation (6 ml/kg) for 5 hours. The high VT ventilation induced neutrophil influx into the lung and activation of MIP-2 together with JNK activation. In JNK knockout mice, as well as with pharmacologic inhibition of JNK, the deleterious effects of the large VT were attenuated. Therefore, neutrophils, in part through JNK pathways, caused lung injury in part by this pathway.

Dolinay and colleagues  evaluated the hypothesis that a low concentration of inhaled CO could protect the lungs against ventilator-induced lung injury. The results showed that low concentration of inhaled CO reduced TNF- levels and total inflammatory cell counts in bronchoalveolar lavage (BAL) fluid while also simultaneously elevating the levels of the antiinflammatory IL-10 levels. The CO exerted its antiinflammatory affect by p38 mitogen-activated protein kinase pathways. Although the signaling pathway by which CO exerts its effects is not clearly established, the study does raise the intriguing possibility that low levels of inhaled CO might have therapeutic benefit in patients with acute lung injury.

In pigs with surfactant deactivation, Steinberg and coworkers  determined whether alveolar instability can mechanically injure the lung independent of inflammatory damage and whether positive end-expiratory pressure (PEEP) can be of benefit. Alveolar instability was calculated using in vivo video microscopy by subtracting the alveolar area at end expiration from that at peak inspiration. Alveolar instability was not associated with a significant increase in neutrophil influx or protease activity but did induce a modest increase in tissue and BAL IL-6 levels. PEEP of 15 cm H₂O improved alveolar instability and histologic evidence of lung injury as well as oxygenation and lung mechanics. The authors concluded that alveolar instability causes lung injury without increasing neutrophil recruitment or elevating inflammatory mediators and that PEEP stabilizes the abnormally unstable alveoli, leading to reduced lung damage.

Ventilation with increased pressure or volume (overventilation) as well as LPS challenge activates nuclear translocation of nuclear factor–B (NF-B). Uhlig and coworkers  examined mechanisms affecting NF-B activation and IL-6 mRNA expression in alveolar machophages and alveolar epithelial type II cells under these conditions. Pretreatment with Ly294002, a phosphoinositide 3-OH kinase inhibitor, prevented NF-B activation and the subsequent release of IL-6 and MIP-2 in overventilated but not in endotoxic lungs. Ly294002 also prevented NF-B activation by overventilation but not by endotoxin in vivo. The authors concluded that alveolar macrophages and alveolar epithelial type II cells contribute to the over-ventilation–induced proinflammatory response and that selective inhibition of this process is possible without inhibiting the activation of NF-B by endotoxin.

To determine whether ventilator-induced lung injury is accompanied by stress failure of the plasma membrane, Gajic and coworkers  subjected perfused rat lungs to one of four ventilator strategies. The lungs were perfused with a membrane-impermeable marker, propidium iodide, and the number of marker-positive cells per alveolus (assessed by confocal microscopy) was taken as a measure of stress failure of the plasma membrane. Ventilation with a tidal volume of 40 ml per kg plus zero PEEP caused more plasma membrane wounds than did ventilation with a tidal volume of 6 ml per kg plus PEEP of 3 cm H₂O: 0.35 versus 0.04 marker-positive cells per alveolus. The number of wounded cells was correlated with gain in lung weight, change in dynamic compliance, and histologic injury score. In a second set of experiments, the propidium iodide marker was perfused either during or after ventilation with a high tidal volume for 30 minutes. Injured cells decreased by about 66% in the period immediately after ventilation. The authors conclude that ventilator-induced lung injury is accompanied by plasma membrane stress failure, and that discontinuation of ventilation results in wound healing (restoration of integrity of the plasma membrane). An editorial commentary by McNeil  accompanies this article.

In pigs with surfactant deactivation induced by Tween instillation, Halter and coworkers  determined whether recruited alveoli would again collapse or become unstable if PEEP was not applied after the recruitment maneuver. The number and stability of alveoli was measured by in vivo microscopy. A recruitment maneuver consisting of peak pressure of 45 cm H₂O plus PEEP of 35 cm H₂O for 1 minute opened a significant number of alveoli, which remained stable during the maneuver. After the recruitment maneuver, pigs ventilated with PEEP of 10 cm H₂O showed improved oxygenation and alveolar stability; but pigs ventilated with PEEP of 5 cm H₂O showed significant alveolar instability. The authors conclude that collapsed alveoli opened by a recruitment maneuver collapse again if ventilation is not accompanied by an adequate level of PEEP. An editorial commentary Kavanagh  accompanies this article.

Copland and coworkers  used gene arrays to assess global changes in gene expression after exposing in vivo adult rat lungs to 30 minutes of ventilation at high tidal volume (25 ml per kg). Thirty minutes of high-volume ventilation did not induce discernable change in lung histology or lung mechanics; obvious injury occurred when ventilation was continued for 90 minutes. Thirty minutes of high-volume ventilation, however, did cause significant upregulation of 10 genes and suppression of 12 genes. Among the upregulated genes were transcription factors, stress proteins, and inflammatory mediators. The downregulated genes were exemplified by metabolic regulatory genes. Temporal studies revealed that Egr-1 and c-Jun were increased early and before heat shock protein 70 and interleukin-1ß. All four of the genes were upregulated primarily in the bronchiolar airway epithelium. Ninety minutes of high-volume ventilation caused an increase in intracellular interleukin-1ß protein. The authors conclude that specific patterns of gene activation and suppression precede the lung injury caused by high-volume ventilation. An editorial commentary by Jacobson and Garcia  accompanies this article.

Hypercapnic acidosis protects against lung injury caused by a direct pulmonary insult, but it is not known if it protects against injury originating in a nonpulmonary source. To investigate this issue, Laffey and coworkers  used a splanchnic ischemia-reperfusion injury to produce lung injury in rats. Compared with control conditions, hypercapnia (resulting from the addition of CO₂ to inspired gas) attenuated protein leakage, improved oxygenation, and preserved lung mechanics. Hypercapnia had both therapeutic and prophylactic actions. Protection was dose-dependent, although benefit at inspired CO₂ concentrations above 5% was small. Protection occurred despite pulmonary artery pressure being higher than the pressure during normocapnia. Hypercapnia did not alter the injury to the bowel caused by ischemia and reperfusion. The authors conclude that hypercapnia protects against lung injury in rats caused by bowel injury resulting from ischemia and reperfusion.

To determine the effect of ventilation with and without a recruitment strategy on cardiopulmonary function, Duggan and coworkers  studied rats receiving conventional ventilation. Mortality was lower in rats ventilated with recruitment maneuvers plus PEEP than in rats ventilated without recruitment maneuvers: 59 versus 100%. Ventilation without recruitment maneuvers also resulted in greater hypoxemia, lung stiffness, pulmonary hypertension, microvascular leak, and lactic acidosis. Rats ventilated without recruitment maneuvers exhibited right-ventricular dysfunction on echocardiography and endothelial disruption on electron microscopy. The authors conclude that atelectasis arising from lack of recruitment during mechanical ventilation is accompanied by microvascular leak and right-ventricular dysfunction, which may contribute to systemic abnormalities and increased mortality.

To determine whether ventilator-induced lung injury causes a systemic microvascular leak that is dependent on nitric oxide synthase expression, Choi and coworkers  ventilated rats for 2 hours with tidal volumes of 7 or 20 ml per kg. The larger tidal volume induced a significant microvascular leak in both the lungs and the kidneys, and also increased the serum concentration of vascular endothelial growth factor. The larger tidal volume increased the expression of endothelial nitric oxide synthase in lung and kidney tissue, but not inducible nitric oxide synthase. An inhibitor of nitric oxide synthase, N-nitro-L-arginine methyl ester, attenuated the microvascular leak in the lungs and kidneys. The authors conclude that ventilator-induced lung injury results in a systemic microvascular leak that is mediated by endothelial nitric oxide synthase.

Mechanical ventilation at high tidal volume downregulates the function of alveolar sodium, potassium–ATPase, and impairs clearance of lung liquid. Adir and coworkers  investigated whether the overexpression of sodium, potassium–ATPase in alveolar epithelium increases liquid clearance in rats. Seven days before inducing lung injury with a tidal volume of 40 ml per kg, the rats were infected with a replication-incompetent adenovirus to overexpress sodium, potassium-ATPase ß₁ subunit gene. Compared with sham or animals infected with a null gene, the animals infected with the ß₁ subunit gene exhibited greater lung liquid clearance, greater sodium, potassium-ATPase activity, and more abundant protein. The authors conclude that overexpression of the ß₁ subunit gene for sodium, potassium-ATPase in alveolar epithelium increases activity of sodium, potassium-ATPase and lung liquid clearance in rats with ventilator-induced lung injury. An editorial commentary by Saumon  accompanies this article.

Mechanical distortion of blood vessels is known to activate endothelial cells. To determine whether airway distension with the application of PEEP promotes leukocyte recruitment, Lim and Wagner  used intravital microscopy in rat tracheas. Normal mechanical ventilation produced no change in leukocyte rolling velocity and the number of adherent cells over 2 hours. Ventilation with PEEP of 8 cm H₂O for 1 hour caused a decrease in leukocyte rolling velocity and an increase in adhesion. PEEP did not alter leukocyte recruitment in the mesenteric circulation. Application of PEEP distal to the site of measurement in the airway did not induce leukocyte recruitment. Pretreatment with endothelin receptor and selectin inhibitors blocks the effect of PEEP on leukocyte recruitment. The authors conclude that airway distension induced by PEEP leads to inflammatory leukocyte trafficking in the airways. An editorial commentary by Uhlig  accompanies this article.

In a critical care perspective, Dreyfuss and colleagues  discuss the physiological and clinical relevance of lung-borne cytokines during ventilator-induced lung injury.

Tierney  recalls early studies of ventilator-induced lung injury.

During partial liquid ventilation in the setting of ventilator-induced lung injury in rats, Ricard and coworkers  studied the influence of varying the dose of perfluorocarbon from 0 to 20 ml per kg. A high dose of perfluorocarbon (20 ml per kg) aggravated the lung capillary leak induced by ventilation at a tidal volume of 33 ml per kg. The leak was decreased partially by PEEP of 5 cm H₂O. A low dose of perfluorocarbon (10 ml per kg) decreased the amount of capillary leak induced by ventilation without perfluorocarbon or with a high dose of perfluorocarbon. PEEP had no effect on the capillary leak observed at the low dose of perfluorocarbon. The high dose of perfluorocarbon was accompanied by a 68% increase in functional residual capacity (FRC); this gas trapping was reduced by PEEP of 5 cm H₂O. The authors conclude that the effect of perfluorocarbon on the vulnerability to ventilator-induced lung injury is complex: low doses of perfluorocarbon protect against lung capillary leak whereas high doses aggravate the leak (and the latter can be reduced by the addition of PEEP).

The endothelial responses to circumferential vascular stretch are poorly defined. In two different models of vascular stretch in the intact lung, Kuebler and coworkers  studied the effect of circumferential stretch on lung endothelial production of nitric oxide. In isolated–perfused rat lungs, increases in vascular pressure caused stretch-dependent increases in nitric oxide, which were localized to capillary endothelial cells; the response was inhibited by blockers of nitric oxide synthase. In isolated–perfused mouse lungs, vascular stretch (induced by negative-pressure ventilation) induced phosphorylation of Akt and endothelial nitric oxide synthase in lung endothelial cells; production of nitric oxide was also increased. In both models, the endothelial responses to stretch were abrogated by phosphatidylinositol-3-OH kinase inhibitors. The authors conclude that circumferential vascular stretch activates the production of nitric oxide in the pulmonary endothelial cells by a signaling cascade that involves phosphatidylinositol-3-OH kinase, Akt, and endothelial nitric oxide synthase, and that this response is independent of mechanical factors causing vascular distension.

Citations 1-22 of 22 total displayed.

Inhaled Carbon Monoxide Confers Antiinflammatory Effects against Ventilator-induced Lung Injury

Tamás Dolinay, Mária Szilasi, Mingyao Liu, and Augustine M. K. Choi
Am. J. Respir. Crit. Care Med. 170: 613 -620. First published online as doi:10.1164/rccm.200401-023OC [Abstract] [Full text]  

High Tidal Volume Ventilation Causes Different Inflammatory Responses in Newborn versus Adult Lung

Ian B. Copland, Francisco Martinez, Brian P. Kavanagh, Doreen Engelberts, Colin McKerlie, Jaques Belik, and Martin Post
Am. J. Respir. Crit. Care Med. 169: 739 -748. First published online as doi:10.1164/rccm.200310-1417OC [Abstract] [Full text]  

Ventilation-induced Neutrophil Infiltration Depends on c-Jun N-Terminal Kinase

Li-Fu Li, Lunyin Yu, and Deborah A. Quinn
Am. J. Respir. Crit. Care Med. 169: 518 -524. First published online as doi:10.1164/rccm.200305-660OC [Abstract] [Full text]  

Phosphoinositide 3-OH Kinase Inhibition Prevents Ventilation-induced Lung Cell Activation

Ulrike Uhlig, Heinz Fehrenbach, Robert A. Lachmann, Torsten Goldmann, Burkhard Lachmann, Ekkehard Vollmer, and Stefan Uhlig
Am. J. Respir. Crit. Care Med. 169: 201 -208. First published online as doi:10.1164/rccm.200303-343OC [Abstract] [Full text]  

Alveolar Instability Causes Early Ventilator-induced Lung Injury Independent of Neutrophils

Jay M. Steinberg, Henry J. Schiller, Jeffrey M. Halter, Louis A. Gatto, Hsi-Ming Lee, Lucio A. Pavone, and Gary F. Nieman
Am. J. Respir. Crit. Care Med. 169: 57 -63. First published online as doi:10.1164/rccm.200304-544OC [Abstract] [Full text]  

Pump and Circumstances

Georges Saumon
Am. J. Respir. Crit. Care Med. 168: 1408-1409. [Full text]  

Ventilator-induced Lung Injury Occurs in Rats, but Does It Occur in Humans?

Donald F. Tierney
Am. J. Respir. Crit. Care Med. 168: 1414-1415. [Full text]  

Na,K-ATPase Gene Transfer Increases Liquid Clearance during Ventilation-induced Lung Injury

Yochai Adir, Phillip Factor, Vidas Dumasius, Karen M. Ridge, and Jacob I. Sznajder
Am. J. Respir. Crit. Care Med. 168: 1445 -1448. First published online as doi:10.1164/rccm.200207-702OC [Abstract] [Full text]  

Dose–Response Effect of Perfluorocarbon Administration on Lung Microvascular Permeability in Rats

Jean-Damien Ricard, Didier Dreyfuss, Jean-Pierre Laissy, and Georges Saumon
Am. J. Respir. Crit. Care Med. 168: 1378 -1382. First published online as doi:10.1164/rccm.200206-527OC [Abstract] [Full text]  

Effects of Therapeutic Hypercapnia on Mesenteric Ischemia–Reperfusion Injury

John G. Laffey, Robert P. Jankov, Doreen Engelberts, A. Keith Tanswell, Martin Post, Thomas Lindsay, J. Brendan Mullen, Alex Romaschin, Derek Stephens, Colin McKerlie, and Brian P. Kavanagh
Am. J. Respir. Crit. Care Med. 168: 1383-1390. [Abstract] [Full text]  

Stretch Activates Nitric Oxide Production in Pulmonary Vascular Endothelial Cells In Situ

Wolfgang M. Kuebler, Ulrike Uhlig, Torsten Goldmann, Gregor Schael, Alexander Kerem, Kay Exner, Christian Martin, Ekkehard Vollmer, and Stefan Uhlig
Am. J. Respir. Crit. Care Med. 168: 1391 -1398. First published online as doi:10.1164/rccm.200304-562OC [Abstract] [Full text]  

Genomics Made Functional in Ventilator-associated Lung Injury

Jeffrey R. Jacobson and Joe G. N. Garcia
Am. J. Respir. Crit. Care Med. 168: 1023-1025. [Full text]  

Taking a Peep at the Upper Airways

Stefan Uhlig
Am. J. Respir. Crit. Care Med. 168: 1026-1027. [Full text]  

Early Changes in Lung Gene Expression due to High Tidal Volume

Ian B. Copland, Brian P. Kavanagh, Doreen Engelberts, Colin McKerlie, Jaques Belik, and Martin Post
Am. J. Respir. Crit. Care Med. 168: 1051 -1059. First published online as doi:10.1164/rccm.200208-964OC [Abstract] [Full text]  

Airway Distension Promotes Leukocyte Recruitment in Rat Tracheal Circulation

Lina H. K. Lim and Elizabeth M. Wagner
Am. J. Respir. Crit. Care Med. 168: 1068 -1074. First published online as doi:10.1164/rccm.200207-690OC [Abstract] [Full text]  

Lung Recruitment in Real Time: Learning Was Never So Easy

Brian P. Kavanagh
Am. J. Respir. Crit. Care Med. 167: 1585-1586. [Full text]  

Positive End-Expiratory Pressure after a Recruitment Maneuver Prevents Both Alveolar Collapse and Recruitment/Derecruitment

Jeffrey M. Halter, Jay M. Steinberg, Henry J. Schiller, Monica DaSilva, Louis A. Gatto, Steve Landas, and Gary F. Nieman
Am. J. Respir. Crit. Care Med. 167: 1620 -1626. First published online as doi:10.1164/rccm.200205-435OC [Abstract] [Full text]  

Systemic Microvascular Leak in an In Vivo Rat Model of Ventilator-induced Lung Injury

Won-Il Choi, Deborah A. Quinn, Kwon Moo Park, Ramzi K. Moufarrej, Behrouz Jafari, Olga Syrkina, Joseph V. Bonventre, and Charles A. Hales
Am. J. Respir. Crit. Care Med. 167: 1627 -1632. First published online as doi:10.1164/rccm.200210-1216OC [Abstract] [Full text]  

Atelectasis Causes Vascular Leak and Lethal Right Ventricular Failure in Uninjured Rat Lungs

Michelle Duggan, Conán L. McCaul, Patrick J. McNamara, Doreen Engelberts, Cameron Ackerley, and Brian P. Kavanagh
Am. J. Respir. Crit. Care Med. 167: 1633 -1640. First published online as doi:10.1164/rccm.200210-1215OC [Abstract] [Full text]  

On the Physiologic and Clinical Relevance of Lung-borne Cytokines during Ventilator-induced Lung Injury

Didier Dreyfuss, Jean-Damien Ricard, and Georges Saumon
Am. J. Respir. Crit. Care Med. 167: 1467-1471. [Full text]  

Cell Suffering and Its Prevention in Lung

Paul L. McNeil
Am. J. Respir. Crit. Care Med. 167: 1046-1047. [Full text]  

Ventilator-induced Cell Wounding and Repair in the Intact Lung

Ognjen Gajic, Jaeho Lee, Clinton H. Doerr, Jorge C. Berrios, Jeffrey L. Myers, and Rolf D. Hubmayr
Am. J. Respir. Crit. Care Med. 167: 1057 -1063. First published online as doi:10.1164/rccm.200208-889OC [Abstract] [Full text]