Role of Toll-like receptor 4 on pancreatic and pulmonary injury in a mice model of acute pancreatitis associated with endotoxemia.
OBJECTIVE
Infection of pancreatic necrosis is a severe complication of acute pancreatitis. Because Toll-like receptor 4 (TLR4) has been identified as a receptor necessary to transduct the signal of bacteria-derived lipopolysaccharide into cells, we investigated the role of TLR4 on pancreatic and pulmonary injury in acute pancreatitis and acute pancreatitis associated with endotoxemia in wild-type and TLR4-deficient mice.


METHODS
Laboratory investigation.


METHODS
University laboratory.


METHODS
Heterozygous TLR4 mice.


METHODS
Mice were injected intraperitoneally with a supramaximal dose of cerulein each hour for 10 hrs. To mimic infection, additional groups of mice were injected with lipopolysaccharide in the presence or absence of cerulein injections.


RESULTS
The severity of acute pancreatitis was assessed by serum amylase activity, pancreatic edema, acinar cell necrosis, and pancreas myeloperoxidase activity. Lung injury was quantitated by lung microvascular permeability and lung myeloperoxidase activity. Injections of cerulein induced an edematous pancreatitis that was of similar severity in wild-type and TLR4-deficient mice. Lipopolysaccharide alone had no toxic effect on pancreas and lungs and did not worsen the pancreatic injury induced by cerulein in wild-type and TRL4-deficient mice. In contrast, lipopolysaccharide worsened pancreatitis-associated lung injury, and the deficiency in TLR4 fully prevented this aggravation.


CONCLUSIONS
TLR4 may not play a role in the pancreatitis-associated lung injury but participates in the pulmonary injury mediated by endotoxemia.
Division of Gastroenterology and Hepatology, Department of Pediatrics (MC), Geneva University Hospitals, Geneva, Switzerland.
Catherine M
CM
Pastor
Jérôme
J
Pugin
Brenda
B
Kwak
Marc
M
Chanson
François
F
Mach
Antoine
A
Hadengue
Jean Louis
JL
Frossard
D000208:Acute Disease; D000681:Amylases / Q000097:blood / Q000378:metabolism; D000818:Animals; D002108:Ceruletide; D004195:Disease Models, Animal; D008070:Lipopolysaccharides; D008171:Lung Diseases / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D010179:Pancreas / Q000201:enzymology; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
D008070:Lipopolysaccharides; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D002108:Ceruletide; D000681:Amylases