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 (V-T = 18.2 6.5 mL/kg, positive end-expiratory pressure = 0), high-strain plus IV lipopolysaccharide (V-T = 18.4 4.2 mL/kg, positive end-expiratory pressure = 0), or low-strain plus lipopolysaccharide (V-T = 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)-N-13 to measure tidal strain from end-expiratory and end-inspiratory images in six regions of interest. After 3 hours of mechanical ventilation, dynamic [F-18]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 [F-18]fluoro-2-deoxy-d-glucose net uptake rate K-i in high-strain lipopolysaccharide (p = 0.036) and on phosphorylation rate k(3) in high-strain (p = 0.027) and high-strain lipopolysaccharide (p = 0.004). Lipopolysaccharide exposure increased the k(3)-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 k(3) (p < 0.001) and K-i (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-18]fluoro-2-deoxy-d-glucose uptake primarily by increasing the rate of intracellular [F-18]fluoro-2-deoxy-d-glucose phosphorylation.