Effect of local tidal lung strain on inflammation in normal and lipopolysaccharide-exposed sheep*.
OBJECTIVE
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.


METHODS
Interventional animal study.


METHODS
Experimental laboratory and PET facility.


METHODS
Eighteen 2- to 4-month-old sheep.


METHODS
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 NN to measure tidal strain from end-expiratory and end-inspiratory images in six regions of interest. After 3 hours of mechanical ventilation, dynamic [F]fluoro-2-deoxy-D-glucose scans were acquired to quantify metabolic activation, indicating local neutrophilic inflammation, in the same regions of interest.


RESULTS
Baseline regional tidal strain had a significant effect on [F]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 [F]fluoro-2-deoxy-D-glucose uptake primarily by increasing the rate of intracellular [F]fluoro-2-deoxy-D-glucose phosphorylation.
1Department of Biomedical Engineering, Boston University, Boston, MA. 2Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA. 3Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA. 4Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA.
Tyler J
TJ
Wellman
Tilo
T
Winkler
Eduardo L V
EL
Costa
Guido
G
Musch
R Scott
RS
Harris
Hui
H
Zheng
Jose G
JG
Venegas
Marcos F
MF
Vidal Melo
D055371:Acute Lung Injury / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D019788:Fluorodeoxyglucose F18; D007249:Inflammation / Q000503:physiopathology*; D008070:Lipopolysaccharides; D011014:Pneumonia / Q000503:physiopathology*; D011175:Positive-Pressure Respiration; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D012121:Respiration, Artificial; D012129:Respiratory Function Tests; D012756:Sheep; D013990:Tidal Volume
D008070:Lipopolysaccharides; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18