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Am J Physiol Lung Cell Mol Physiol 283: L541-L548, 2002. First published May 3, 2002; doi:10.1152/ajplung.00413.2001
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Vol. 283, Issue 3, L541-L548, September 2002

In vivo evidence for the role of GM-CSF as a mediator in acute pancreatitis-associated lung injury

Jean Louis Frossard1,2, Ashok K. Saluja1, Nicolas Mach3,4, Hong Sik Lee1, Lakshmi Bhagat1, Antoine Hadenque2, Laura Rubbia-Brandt5, Glenn Dranoff3, and Michael L. Steer1

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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