Neutrophil metabolic activity but not neutrophil sequestration reflects the development of pancreatitis-associated lung injury*

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Abstract
Objective Activated neutrophils are presumed to injure pulmonary endothelium by releasing oxygen radicals, proteases, and proinflammatory cytokines. Standard counting methods do not distinguish between leukocytosis, neutrophil sequestration, and activation. We used leukocyte uptake of the glucose analog [18F]fluorodeoxyglucose (18FDG), which indicates postmigrational neutrophil activity, to identify and quantify the relationship between acute respiratory distress syndrome and neutrophil activation in experimental pancreatitis in rats. Design Prospective, experimental study. Setting Research laboratory at a university hospital. Subjects Mild and severe pancreatitis models in the rat. Interventions Pulmonary (with muscle as control) leukocyte accumulation was assessed by uptake of technetium-99m-labeled chemotactic peptide (fMLFK) and confirmed by measurement of myeloperoxidase activity. Neutrophil activity was assessed by 18FDG uptake. Tissue-to-blood ratios for fMLFK, 18FDG, and leukocytes were calculated to control for background. Neutrophils were counted in histologic sections of saline-perfused lungs. Bronchoalveolar lavage fluid was assessed for neutrophil migration and autoradiographed for intracellular 18FDG localization. Measurements and Main Results Lung myeloperoxidase activity, 18FDG, and peripheral white blood cells all significantly increased in both mild and severe pancreatitis, but lung fMLFK only increased in severe pancreatitis. After correction for blood background, only 18FDG in lung (but not muscle) was significantly increased in pancreatitis (severe > mild > normal, p < .001). Histologic analysis showed significant increase in extravascular (migrated) neutrophils only in severe pancreatitis. Autoradiography of bronchoalveolar lavage fluid confirmed the 18FDG within intra-alveolar neutrophils. Conclusions In this pancreatitis model of acute respiratory distress syndrome, there was nonspecific and noninjurious increase of neutrophils in the lung, attributable in part to background leukocytosis and to intravascular sequestration. However, 18FDG uptake uniquely showed that interstitial and intra-alveolar neutrophil migration and activation occurred in severe but not in mild pancreatitis, consistent with clinical correlations between acute respiratory distress syndrome and severity of underlying systemic disease. 18FDG uptake, which is also accessible by positron emission tomography scanning, better quantitates the contribution of activated neutrophils to tissue injury than other measurements of neutrophil accumulation or sequestration.