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1 Department of Surgery, Beth Israel Hospital Deaconess Medical Center, Harvard Medical School; 3 Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and Divisions of 2 Gastroenterology, 4 Oncology, and 5 Clinical Pathology, Geneva University Hospitals, 1211 Geneva 14, Switzerland
Severe pancreatitis is frequently
associated with acute lung injury (ALI) and the respiratory distress
syndrome. The role of granulocyte-macrophage colony-stimulating factor
(GM-CSF) in mediating the ALI associated with secretagogue-induced
experimental pancreatitis was evaluated with GM-CSF knockout mice
(GM-CSF
/
). Pancreatitis was induced by hourly (12×)
intraperitoneal injection of a supramaximally stimulating dose of the
cholecystokinin analog caerulein. The resulting pancreatitis was
similar in GM-CSF-sufficient (GM-CSF +/+) control animals and GM-CSF
/
mice. Lung injury, quantitated by measuring lung myeloperoxidase
activity (an indicator of neutrophil sequestration), alveolar-capillary
permeability, and alveolar membrane thickness was less severe in GM-CSF
/
than in GM-CSF +/+ mice. In GM-CSF +/+ mice, pancreas, lung and serum GM-CSF levels increase during pancreatitis. Lung levels of
macrophage inflammatory protein (MIP)-2 are also increased during
pancreatitis, but, in this case, the rise is less profound in GM-CSF
/
mice than in GM-CSF +/+ controls. Administration of anti-MIP-2
antibodies was found to reduce the severity of pancreatitis-associated ALI. Our findings indicate that GM-CSF plays a critical role in coupling pancreatitis to ALI and suggest that GM-CSF may act indirectly by regulating the release of other proinflammatory factors including MIP-2.
granulocyte-macrophage colony-stimulating factor; caerulein; inflammation; adult respiratory distress syndrome; adhesion molecules; neutrophils
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