Effect of Local Tidal Lung Strain on Inflammation in Normal and Lipopolysaccharide-Exposed Sheep*

Objectives:Regional tidal lung strain may trigger local inflammation during mechanical ventilation, particularly when additional inflammatory stimuli are present. However, it is unclear whether inflammation develops proportionally to tidal strain or only above a threshold. We aimed to 1) assess the relationship between regional tidal strain and local inflammation in vivo during the early stages of lung injury in lungs with regional aeration heterogeneity comparable to that of humans and 2) determine how this strain-inflammation relationship is affected by endotoxemia. Design:Interventional animal study. Setting:Experimental laboratory and PET facility. Subjects:Eighteen 2- to 4-month-old sheep. Interventions:Three groups of sheep (n = 6) were mechanically ventilated to the same plateau pressure (30–32 cm H2O) with high-strain (VT = 18.2 ± 6.5 mL/kg, positive end-expiratory pressure = 0), high-strain plus IV lipopolysaccharide (VT = 18.4 ± 4.2 mL/kg, positive end-expiratory pressure = 0), or low-strain plus lipopolysaccharide (VT = 8.1 ± 0.2 mL/kg, positive end-expiratory pressure = 17 ± 3 cm H2O). At baseline, we acquired respiratory-gated PET scans of inhaled 13NN to measure tidal strain from end-expiratory and end-inspiratory images in six regions of interest. After 3 hours of mechanical ventilation, dynamic [18F]fluoro-2-deoxy-D-glucose scans were acquired to quantify metabolic activation, indicating local neutrophilic inflammation, in the same regions of interest. Measurements and Main Results:Baseline regional tidal strain had a significant effect on [18F]fluoro-2-deoxy-D-glucose net uptake rate Ki in high-strain lipopolysaccharide (p = 0.036) and on phosphorylation rate k3 in high-strain (p = 0.027) and high-strain lipopolysaccharide (p = 0.004). Lipopolysaccharide exposure increased the k3-tidal strain slope three-fold (p = 0.009), without significant lung edema. The low-strain lipopolysaccharide group showed lower baseline regional tidal strain (0.33 ± 0.17) than high-strain (1.21 ± 0.62; p < 0.001) or high-strain lipopolysaccharide (1.26 ± 0.44; p < 0.001) and lower k3 (p < 0.001) and Ki (p < 0.05) than high-strain lipopolysaccharide. Conclusions:Local inflammation develops proportionally to regional tidal strain during early lung injury. The regional inflammatory effect of strain is greatly amplified by IV lipopolysaccharide. Tidal strain enhances local [18F]fluoro-2-deoxy-D-glucose uptake primarily by increasing the rate of intracellular [18F]fluoro-2-deoxy-D-glucose phosphorylation.

[1]  Alessandro Santini,et al.  Lung stress and strain during mechanical ventilation: any safe threshold? , 2011, American journal of respiratory and critical care medicine.

[2]  R. Pagano,et al.  Deformation-induced lipid trafficking in alveolar epithelial cells. , 2001, American journal of physiology. Lung cellular and molecular physiology.

[3]  J. Korevaar,et al.  Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial , 2010, Critical care.

[4]  L. Guerra,et al.  Lung regional metabolic activity and gas volume changes induced by tidal ventilation in patients with acute lung injury. , 2011, American journal of respiratory and critical care medicine.

[5]  Eric A. Hoffman,et al.  Registration-based estimates of local lung tissue expansion compared to xenon CT measures of specific ventilation , 2008, Medical Image Anal..

[6]  B. Chetaille,et al.  Mechanical Ventilation Affects Lung Function and Cytokine Production in an Experimental Model of Endotoxemia , 2005, Anesthesiology.

[7]  G. Musch,et al.  Modeling pulmonary kinetics of 2-deoxy-2-[18F]fluoro-D-glucose during acute lung injury. , 2008, Academic radiology.

[8]  C. Haslett,et al.  In vivo measurement of neutrophil activity in experimental lung inflammation. , 1994, American journal of respiratory and critical care medicine.

[9]  Tyler J. Wellman,et al.  Effects of ventilation strategy on distribution of lung inflammatory cell activity , 2013, Critical Care.

[10]  S. Jaber,et al.  Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. , 2008, JAMA.

[11]  M. Reivich,et al.  THE [14C]DEOXYGLUCOSE METHOD FOR THE MEASUREMENT OF LOCAL CEREBRAL GLUCOSE UTILIZATION: THEORY, PROCEDURE, AND NORMAL VALUES IN THE CONSCIOUS AND ANESTHETIZED ALBINO RAT 1 , 1977, Journal of neurochemistry.

[12]  S. Russo,et al.  Lung opening and closing during ventilation of acute respiratory distress syndrome. , 2010, American journal of respiratory and critical care medicine.

[13]  Gaetano Perchiazzi,et al.  Lung regional stress and strain as a function of posture and ventilatory mode. , 2011, Journal of applied physiology.

[14]  N. Carboni,et al.  Prone position delays the progression of ventilator-induced lung injury in rats: Does lung strain distribution play a role?* , 2005, Critical care medicine.

[15]  A. Serpa Neto,et al.  Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: a meta-analysis. , 2012, JAMA.

[16]  L. Gattinoni,et al.  Stress and strain within the lung , 2012, Current opinion in critical care.

[17]  R. Hubmayr,et al.  Biophysical determinants of alveolar epithelial plasma membrane wounding associated with mechanical ventilation. , 2013, American journal of physiology. Lung cellular and molecular physiology.

[18]  Gary E. Christensen,et al.  Analysis of Regional Mechanics in Canine Lung Injury Using Forced Oscillations and 3D Image Registration , 2010, Annals of Biomedical Engineering.

[19]  T. van der Poll,et al.  Mechanical Ventilation with Lower Tidal Volumes and Positive End-expiratory Pressure Prevents Pulmonary Inflammation in Patients without Preexisting Lung Injury , 2008, Anesthesiology.

[20]  Tyler J. Wellman,et al.  Effect of regional lung inflation on ventilation heterogeneity at different length scales during mechanical ventilation of normal sheep lungs. , 2012, Journal of applied physiology.

[21]  J. Chevrolet,et al.  Activation of human macrophages by mechanical ventilation in vitro. , 1998, American journal of physiology. Lung cellular and molecular physiology.

[22]  F. Fazio,et al.  Lungs of patients with acute respiratory distress syndrome show diffuse inflammation in normally aerated regions: A [18F]-fluoro-2-deoxy-D-glucose PET/CT study , 2009, Critical care medicine.

[23]  Eric A Hoffman,et al.  CT-measured regional specific volume change reflects regional ventilation in supine sheep. , 2008, Journal of applied physiology.

[24]  G. Musch,et al.  Regional Gas Exchange and Cellular Metabolic Activity in Ventilator-induced Lung Injury , 2007, Anesthesiology.

[25]  J. S. St. Sauver,et al.  Ventilator-associated lung injury in patients without acute lung injury at the onset of mechanical ventilation* , 2004, Critical care medicine.

[26]  G. Musch,et al.  Measurement of Regional Specific Lung Volume Change Using Respiratory-Gated PET of Inhaled 13N-Nitrogen , 2010, Journal of Nuclear Medicine.

[27]  M. Mintun,et al.  FDG-PET imaging of pulmonary inflammation in healthy volunteers after airway instillation of endotoxin. , 2006, Journal of applied physiology.

[28]  D J Mooney,et al.  Control of microtubule assembly by extracellular matrix and externally applied strain. , 2001, American journal of physiology. Cell physiology.

[29]  A R Boobis,et al.  Dissociation of neutrophil emigration and metabolic activity in lobar pneumonia and bronchiectasis. , 1997, The European respiratory journal.

[30]  Q. Ning,et al.  Response of Alveolar Type II Epithelial Cells to Mechanical Stretch and Lipopolysaccharide , 2007, Respiration.

[31]  G. Friedman,et al.  Mechanical ventilation with high tidal volume induces inflammation in patients without lung disease , 2010, Critical care.

[32]  Massimo Cressoni,et al.  Lung stress and strain during mechanical ventilation for acute respiratory distress syndrome. , 2008, American journal of respiratory and critical care medicine.

[33]  G. Musch,et al.  Modeling 18F-FDG Kinetics during Acute Lung Injury: Experimental Data and Estimation Errors , 2012, PloS one.

[34]  E. Ingenito,et al.  Mechanisms of surfactant dysfunction in early acute lung injury. , 1997, Experimental lung research.

[35]  Tilo Winkler,et al.  Image-Derived Input Function for Assessment of 18F-FDG Uptake by the Inflamed Lung , 2007, Journal of Nuclear Medicine.

[36]  R. Baron,et al.  Micro-Autoradiographic Assessment of Cell Types Contributing to 2-Deoxy-2-[18F]Fluoro-d-Glucose Uptake During Ventilator-Induced and Endotoxemic Lung Injury , 2013, Molecular Imaging and Biology.

[37]  W. Altemeier,et al.  Noninjurious mechanical ventilation activates a proinflammatory transcriptional program in the lung. , 2009, Physiological genomics.

[38]  C. Carvalho,et al.  Effect of a protective-ventilation strategy on mortality in the acute respiratory distress syndrome. , 1998, The New England journal of medicine.

[39]  R. Hubmayr,et al.  Cell wounding and repair in ventilator injured lungs , 2008, Respiratory Physiology & Neurobiology.

[40]  Thomas Guerrero,et al.  Quantification of regional ventilation from treatment planning CT. , 2005, International journal of radiation oncology, biology, physics.

[41]  A. Fischman,et al.  Neutrophil metabolic activity but not neutrophil sequestration reflects the development of pancreatitis-associated lung injury* , 2002, Critical care medicine.

[42]  B. Simon,et al.  Regional pulmonary inflammation in an endotoxemic ovine acute lung injury model , 2012, Respiratory Physiology & Neurobiology.

[43]  D. Schoenfeld,et al.  Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. , 2000, The New England journal of medicine.

[44]  M. Schultz,et al.  Mechanical ventilation using non-injurious ventilation settings causes lung injury in the absence of pre-existing lung injury in healthy mice , 2009, Critical care.

[45]  R. Glenny,et al.  Mechanical Ventilation with Moderate Tidal Volumes Synergistically Increases Lung Cytokine Response to Systemic Endotoxin Running Title: Mechanical Ventilation and Lps , 2022 .

[46]  L. Blanch,et al.  Lung strain and biological response in mechanically ventilated patients , 2012, Intensive Care Medicine.

[47]  G. Musch,et al.  Mild Endotoxemia during Mechanical Ventilation Produces Spatially Heterogeneous Pulmonary Neutrophilic Inflammation in Sheep , 2010, Anesthesiology.

[48]  M. Plataki,et al.  The physical basis of ventilator-induced lung injury , 2010, Expert review of respiratory medicine.

[49]  David W. Kaczka,et al.  Regional lung strain and inflammation. , 2012, American Journal of Respiratory and Critical Care Medicine.