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Objective: In acute lung injury (ALI) activated protein C (APC) may reopen occluded lung vessels and minimize lung inflammation. We aimed at assessing the effect of APC on regional lung perfusion, aerated lung volume, cytokine production and oxygenation in experimental ALI., Design and Setting: Prospective, controlled study in an imaging facility., Participants: Pigs tracheotomized and mechanically ventilated., Intervention: Pigs were randomly given intravenously APC (n = 8) or saline (n = 8). Thirty minutes later, ALI was induced by injecting oleic acid., Measurements and Results: Lung perfusion and aerated lung volume measured with positron emission tomography, plasma cytokines and arterial blood gas were determined just before ALI and 110 and 290 min thereafter. Lung cytokines were measured at the end of the experiment. PaO2 under F I O2 1 was significantly lower in the APC group before lung injury (473+/-129 vs. 578+/-54 mmHg) and 110 min (342+/-138 vs. 446+/-103 mmHg) and 290 min (303+/-171 vs. 547+/-54 mmHg) thereafter (p < 0.05). Lung perfusion nonsignificantly tended to redistribute towards dorsal lung regions with APC. Total aerated lung volume was not different between APC and control before ALI (10.0+/-1.5 vs. 11.0+/-2.5 ml/kg) (p > 0.05) or thereafter. Plasma IL-6 and IL-8 at 110 min were greater with APC (p < 0.05)., Conclusions: In contrast to studies using other models, pretreatment with APC was associated with worsening oxygenation in the present investigation. This might be due to ventilation-perfusion mismatch, with more perfusion to dependent nonaerated areas.