This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (148)  • Contact me when this article is cited  Related Content  • Related letter  • Related article  • Similar articles in JAMA  Topic Collections  • Critical Care/ Intensive Care Medicine  • Adult Critical Care  • Pulmonary Diseases  • Pulmonary Diseases, Other  • Alert me on articles by topic  Social Bookmarking   What's this?

Yumiko Imai, MD, PhD; Jean Parodo, BSc; Osamu Kajikawa, PhD; Marc de Perrot, MD; Stefan Fischer, MD; Vern Edwards; Ernest Cutz, MD; Mingyao Liu, MD, PhD; Shaf Keshavjee, MD; Thomas R. Martin, MD; John C. Marshall, MD; V. Marco Ranieri, MD; Arthur S. Slutsky, MD

JAMA. 2003;289:2104-2112.

Context  Recent clinical trials have demonstrated a decrease in multiple organ dysfunction syndrome (MODS) and mortality in patients with acute respiratory distress syndrome (ARDS) treated with a protective ventilatory strategy.

Objective  To examine the hypothesis that an injurious ventilatory strategy may lead to end-organ epithelial cell apoptosis and organ dysfunction.

Design and Setting  In vivo animals: 24 rabbits with acid-aspiration lung injury were ventilated with injurious or noninjurious ventilatory strategies. In vitro: rabbit epithelial cells were exposed to plasma from in vivo rabbit studies. In vivo human: plasma samples from patients included in a previous randomized controlled trial examining a lung protective strategy were analyzed (lung protection group, n = 9 and controls, n = 11).

Main Outcome Measures  In vivo animals: biochemical markers of liver and renal dysfunction; apoptosis in end organs. In vitro: induction of apoptosis in LLC-RK1 renal tubular epithelial cells. In vivo human: correlation of plasma creatinine and soluble Fas ligand.

Results  The injurious ventilatory strategy led to increased rates of epithelial cell apoptosis in the kidney (mean [SE]: injurious, 10.9% [0.88%]; noninjurious, 1.86% [0.17%]; P<.001) and small intestine villi (injurious, 6.7% [0.66%]; noninjurious, 0.97% [0.14%]; P<.001), and led to the elevation of biochemical markers indicating renal dysfunction in vivo. Induction of apoptosis was increased in LLC-RK1 cells incubated with plasma from rabbits ventilated with injurious ventilatory strategy at 4 hours (P = .03) and 8 hours (P = .002). The Fas:Ig, a fusion protein that blocks soluble Fas ligand, attenuated induction of apoptosis in vitro. There was a significant correlation between changes in soluble Fas ligand and changes in creatinine in patients with ARDS (R = 0.64, P = .002).

Conclusions  Mechanical ventilation can lead to epithelial cell apoptosis in the kidney and small intestine, accompanied by biochemical evidence of organ dysfunction. This may partially explain the high rate of MODS observed in patients with ARDS and the decrease in morbidity and mortality in patients treated with a lung protective strategy.

Author Affiliations: Department of Critical Care, St Michael's Hospital, University of Toronto, Toronto, Ontario (Drs Imai and Slutsky); General Surgery (Dr Marshall and Ms Parodo) and Thoracic Surgery (Drs de Perrot, Fischer, Liu, and Keshavjee), Research Laboratory, University Health Network, Toronto, Ontario; Seattle Veterans Administration Medical Center, Seattle, Wash (Drs Kajikawa and Martin); Department of Pediatric Laboratory Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario (Dr Cutz and Mr Edwards); and Division of the Dipartimento di discipline Medico-Chirurgiche, Sezione di Anestesiologia e Rianimazione, Università di Torino, Ospedale S. Giovanni Battista, Torino, Italy (Dr Ranieri).

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

RELATED LETTER

Apoptosis and Renal Function in Patients With Acute Respiratory Distress Syndrome
Yen-Hong Kuo
JAMA. 2003;290(4):461.
EXTRACT | FULL TEXT  

RELATED ARTICLE

Translational Medical Research
Phil B. Fontanarosa and Catherine D. DeAngelis
JAMA. 2003;289(16):2133.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Kidney calling lung and call back: how organs talk to each other
Floege and Uhlig
Nephrol Dial Transplant 2009;0:gfp464v1-gfp464.
FULL TEXT  

Low Tidal Volume Ventilation in a Porcine Model of Acute Lung Injury Improves Cerebral Tissue Oxygenation
Bickenbach et al.
Anesth. Analg. 2009;109:847-855.
ABSTRACT | FULL TEXT  

Titration and Implementation of Neurally Adjusted Ventilatory Assist in Critically Ill Patients
Brander et al.
Chest 2009;135:695-703.
ABSTRACT | FULL TEXT  

Impact of acute kidney injury on lung injury
Liu
Am. J. Physiol. Lung Cell. Mol. Physiol. 2009;296:L1-L2.
FULL TEXT  

Mechanical ventilation enhances lung inflammation and caspase activity in a model of mouse pneumovirus infection
Bem et al.
Am. J. Physiol. Lung Cell. Mol. Physiol. 2009;296:L46-L56.
ABSTRACT | FULL TEXT  

Mechanical Ventilation Guided by Esophageal Pressure in Acute Lung Injury
Talmor et al.
NEJM 2008;359:2095-2104.
ABSTRACT | FULL TEXT  

Alveolar cell apoptosis is dependent on p38 MAP kinase-mediated activation of xanthine oxidoreductase in ventilator-induced lung injury
Le et al.
J. Appl. Physiol. 2008;105:1282-1290.
ABSTRACT | FULL TEXT  

Production of Endothelin-1 and Reduced Blood Flow in the Rat Kidney During Lung-Injurious Mechanical Ventilation
Kuiper et al.
Anesth. Analg. 2008;107:1276-1283.
ABSTRACT | FULL TEXT  

Neutrophil Elastase Is Needed for Neutrophil Emigration into Lungs in Ventilator-Induced Lung Injury
Kaynar et al.
Am. J. Respir. Cell Mol. Bio. 2008;39:53-60.
ABSTRACT | FULL TEXT  

Interactions between Mechanical and Biological Processes in Acute Lung Injury
Martin
Proc Am Thorac Soc 2008;5:291-296.
ABSTRACT | FULL TEXT  

Effects of acid aspiration-induced acute lung injury on kidney function
Hoag et al.
Am. J. Physiol. Renal Physiol. 2008;294:F900-F908.
ABSTRACT | FULL TEXT  

Sepsis: rethinking the approach to clinical research
Marshall
J. Leukoc. Biol. 2008;83:471-482.
ABSTRACT | FULL TEXT  

Sepsis: A Clinical Update
Ventetuolo and Levy
CJASN 2008;3:571-577.
FULL TEXT  

Advances in Critical Care for the Nephrologist: Acute Lung Injury/ARDS
Liu and Matthay
CJASN 2008;3:578-586.
ABSTRACT | FULL TEXT  

Potential Interventions in Sepsis-Related Acute Kidney Injury
Ronco et al.
CJASN 2008;3:531-544.
ABSTRACT | FULL TEXT  

Mechanical Ventilation and Lung-Kidney Interactions
Koyner and Murray
CJASN 2008;3:562-570.
FULL TEXT  

Lack of matrix metalloproteinase-9 worsens ventilator-induced lung injury
Albaiceta et al.
Am. J. Physiol. Lung Cell. Mol. Physiol. 2008;294:L535-L543.
ABSTRACT | FULL TEXT  

Mechanisms of Fibrogenesis
Kisseleva and Brenner
Exp. Biol. Med. 2008;233:109-122.
ABSTRACT | FULL TEXT  

ACE mediates ventilator-induced lung injury in rats via angiotensin II but not bradykinin
Wosten-van Asperen et al.
Eur Respir J 2008;31:363-371.
ABSTRACT | FULL TEXT  

Nonventilatory Interventions in ALI/ARDS: Recent Work
Tidswell
J Intensive Care Med 2008;23:70-72.
 

Cytokine Release Following Recruitment Maneuvers
Talmor et al.
Chest 2007;132:1434-1439.
ABSTRACT | FULL TEXT  

Low-Tidal-Volume Ventilation in the Acute Respiratory Distress Syndrome
Malhotra
NEJM 2007;357:1113-1120.
FULL TEXT  

Acute Lung Injury Edema Fluid Decreases Net Fluid Transport across Human Alveolar Epithelial Type II Cells
Lee et al.
J. Biol. Chem. 2007;282:24109-24119.
ABSTRACT | FULL TEXT  

Door-to-Dialysis Time and Daily Hemodialysis in Patients with Leptospirosis: Impact on Mortality
Andrade et al.
CJASN 2007;2:739-744.
ABSTRACT | FULL TEXT  

Leptospirosis leads to dysregulation of sodium transporters in the kidney and lung
Andrade et al.
Am. J. Physiol. Renal Physiol. 2007;292:F586-F592.
ABSTRACT | FULL TEXT  

High-volume ventilation induces pentraxin 3 expression in multiple acute lung injury models in rats
Okutani et al.
Am. J. Physiol. Lung Cell. Mol. Physiol. 2007;292:L144-L153.
ABSTRACT | FULL TEXT  

Pathogenetic Significance of Biological Markers of Ventilator-Associated Lung Injury in Experimental and Clinical Studies
Frank et al.
Chest 2006;130:1906-1914.
ABSTRACT | FULL TEXT  

Gene expression profiling of target genes in ventilator-induced lung injury
Dolinay et al.
Physiol. Genomics 2006;26:68-75.
ABSTRACT | FULL TEXT  

The contribution of arterio-venous extracorporeal lung assist to gas exchange in a porcine model of lavage-induced acute lung injury
Brederlau et al.
Perfusion 2006;21:277-284.
ABSTRACT  

Mechanotransduction of stretch-induced prostanoid release by fetal lung epithelial cells
Copland et al.
Am. J. Physiol. Lung Cell. Mol. Physiol. 2006;291:L487-L495.
ABSTRACT | FULL TEXT  

Ischemia and Reperfusion Increases Susceptibility to Ventilator-induced Lung Injury in Rats
Crimi et al.
Am. J. Respir. Crit. Care Med. 2006;174:178-186.
ABSTRACT | FULL TEXT  

Bridge to lung transplantation with the novel pumpless interventional lung assist device NovaLung.
J. Thorac. Cardiovasc. Surg. 2006;131:719-723.
 

Apoptosis and Epithelial Injury in the Lungs
Martin et al.
Proc Am Thorac Soc 2005;2:214-220.
ABSTRACT | FULL TEXT  

Fas-Mediated Acute Lung Injury Requires Fas Expression on Nonmyeloid Cells of the Lung
Matute-Bello et al.
J. Immunol. 2005;175:4069-4075.
ABSTRACT | FULL TEXT  

Mechanical ventilation affects inflammatory mediators in patients undergoing cardiopulmonary bypass for cardiac surgery: A randomized clinical trial
Zupancich et al.
J. Thorac. Cardiovasc. Surg. 2005;130:378-383.
ABSTRACT | FULL TEXT  

Cellular Stress Failure in Ventilator-injured Lungs
Vlahakis and Hubmayr
Am. J. Respir. Crit. Care Med. 2005;171:1328-1342.
ABSTRACT | FULL TEXT  

Hypercapnic Acidosis Impairs Plasma Membrane Wound Resealing in Ventilator-injured Lungs
Doerr et al.
Am. J. Respir. Crit. Care Med. 2005;171:1371-1377.
ABSTRACT | FULL TEXT  

Mechanical Ventilation Alters Airway Nucleotides and Purinoceptors in Lung and Extrapulmonary Organs
Douillet et al.
Am. J. Respir. Cell Mol. Bio. 2005;32:52-58.
ABSTRACT | FULL TEXT  

Sphingosine 1-Phosphate Reduces Vascular Leak in Murine and Canine Models of Acute Lung Injury
McVerry et al.
Am. J. Respir. Crit. Care Med. 2004;170:987-993.
ABSTRACT | FULL TEXT  

Phosphoinositide 3-OH Kinase Inhibition Prevents Ventilation-induced Lung Cell Activation
Uhlig et al.
Am. J. Respir. Crit. Care Med. 2004;169:201-208.
ABSTRACT | FULL TEXT  

Apoptosis and Renal Function in Patients With Acute Respiratory Distress Syndrome
Kuo
JAMA 2003;290:461-461.
FULL TEXT  

Mechanical ventilation may damage organs other than the lungs
Johnson
Thorax 2003;58:612-612.
FULL TEXT  

Identification of Severe Acute Respiratory Syndrome in Canada
Poutanen et al.
NEJM 2003;348:1995-2005.
ABSTRACT | FULL TEXT  

Translational Medical Research
Fontanarosa and DeAngelis
JAMA 2003;289:2133-2133.
FULL TEXT