Background: Lung derecruitment is common during general anesthesia. Mechanical ventilation with physiological tidal volumes could magnify derecruitment, and produce lung dysfunction and inflammation. The authors used positron emission tomography to study the process of derecruitment in normal lungs ventilated for 16 h and the corresponding changes in regional lung perfusion and inflammation. Methods: Six anesthetized supine sheep were ventilated with VT = 8 ml/kg and positive end-expiratory pressure = 0. Transmission scans were performed at 2-h intervals to assess regional aeration. Emission scans were acquired at baseline and after 16 h for the following tracers: (1) 18F-fluorodeoxyglucose to evaluate lung inflammation and (2) 13NN to calculate regional perfusion and shunt fraction. Results: Gas fraction decreased from baseline to 16 h in dorsal (0.31 ± 0.13 to 0.14 ± 0.12, P < 0.01), but not in ventral regions (0.61 ± 0.03 to 0.63 ± 0.07, P = nonsignificant), with time constants of 1.5-44.6 h. Although the vertical distribution of relative perfusion did not change from baseline to 16 h, shunt increased in dorsal regions (0.34 ± 0.23 to 0.63 ± 0.35, P < 0.01). The average pulmonary net 18F-fluorodeoxyglucose uptake rate in six regions of interest along the ventral-dorsal direction increased from 3.4 ± 1.4 at baseline to 4.1 ± 1.5·10-3/min after 16 h (P < 0.01), and the corresponding average regions of interest 18F-fluorodeoxyglucose phosphorylation rate increased from 2.0 ± 0.2 to 2.5 ± 0.2·10-2/min (P < 0.01). Conclusions: When normal lungs are mechanically ventilated without positive end-expiratory pressure, loss of aeration occurs continuously for several hours and is preferentially localized to dorsal regions. Progressive lung derecruitment was associated with increased regional shunt, implying an insufficient hypoxic pulmonary vasoconstriction. The increased pulmonary net uptake and phosphorylation rates of 18F-fluorodeoxyglucose suggest an incipient inflammation in these initially normal lungs.