Role of toll-like receptor 4 in the pathophysiology of severe acute pancreatitis in mice.
OBJECTIVE
Multiple organ dysfunction and infection are major contributors to the high mortality associated with severe acute pancreatitis (SAP). Toll-like receptor 4 (TLR4) recognizes the lipopolysaccharide of gram-negative bacilli and is involved in inflammatory response and host defense. We examined the effects of TLR4-deficiency in SAP in mice.


METHODS
Closed duodenal loop-induced pancreatitis was induced in C3H/HeN (wild-type) and C3H/HeJ (TLR4-deficient) mice. We compared the severity of pancreatitis, liver and kidney dysfunction, and bacterial translocation to the pancreas between the two types of mice 12 h after the induction of SAP.


RESULTS
The severity of pancreatitis was similar in the two types of mice. The TLR4-deficient mice had significantly lower serum levels of aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, and creatinine; significantly lower serum levels of interleukin-1 and tumor necrosis factor; reduced apoptosis of the liver and kidney; and a significantly higher rate of positive gram-negative bacterial cultures of the pancreas. TLR4 protein expression in the liver, kidney, and small intestine was increased 4 h after the induction of SAP, and decreased 12 h after the induction of SAP.


CONCLUSIONS
TLR4 is implicated in the mechanism of organ dysfunction and bacterial translocation in SAP, and TLR4 may trigger the inflammatory response and function defensively against infection.
Sawa
Hidehiro
H
Department of Gastroenterological Surgery, Kobe University Graduate School of Medical Sciences, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Ueda
Takashi
T
Takeyama
Yoshifumi
Y
Yasuda
Takeo
T
Shinzeki
Makoto
M
Nakajima
Takahiro
T
Kuroda
Yoshikazu
Y
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis; D018988:Bacterial Translocation; D005260:Female; D051379:Mice; D008809:Mice, Inbred C3H; D009102:Multiple Organ Failure / Q000503:physiopathology*; D010195:Pancreatitis / Q000503:physiopathology*; D012307:Risk Factors; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000502:physiology*
D051197:Toll-Like Receptor 4