In vivo evidence for the role of GM-CSF as a mediator in acute pancreatitis-associated lung injury.
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 (12x) 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.
Frossard
Jean Louis
JL
Department of Surgery, Beth Israel Hospital Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Saluja
Ashok K
AK
Mach
Nicolas
N
Lee
Hong Sik
HS
Bhagat
Lakshmi
L
Hadenque
Antoine
A
Rubbia-Brandt
Laura
L
Dranoff
Glenn
G
Steer
Michael L
ML
D000208:Acute Disease; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002108:Ceruletide; D054426:Chemokine CXCL2; D018925:Chemokines / Q000276:immunology / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism*; D007958:Leukocyte Count; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D010179:Pancreas / Q000378:metabolism; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D012016:Reference Values; D012720:Severity of Illness Index
D000906:Antibodies; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002108:Ceruletide