Toll-like receptor 4 deficiency and acute pancreatitis act similarly in reducing host defense during murine Escherichia coli peritonitis

Objective. Acute pancreatitis is frequently complicated by Gram-negative sepsis. Mammalian cells recognize lipopolysaccharide from Gram-negative bacteria via Toll-like receptor (TLR) 4. The objective of this study was to determine the role of TLR4 in the defense against Gram-negative sepsis in previously healthy mice and in animals with preexisting pancreatitis. Design: A controlled, in vivo laboratory study. Setting: Research laboratory of a health sciences university. Subjects: Female C3H/HeJ (nonfunctional TLR4 mutant) and C3H/HeN (wild-type) mice. Interventions. Abdominal sepsis was induced by the intraperitoneal injection of Escherichia coli. Pancreatitis was induced by 12 hourly intraperitoneal injections of cerulein. Measurements and Main Results: The following experiments were performed. First, healthy TLR4 mutant mice demonstrated an enhanced bacterial load and dissemination of the infection relative to wild-type mice after intraperitoneal injection with E coli, associated with a reduced early release of proinflammatory cytokines and an attenuated influx of neutrophils into the peritoneal fluid. Second, wild-type mice in which acute pancreatitis was induced by repeated cerulein injections showed an increased bacterial load and dissemination of E coli relative to wild-type mice without pancreatitis, which was accompanied by a blunted proinflammatory cytokine response by peritoneal macrophages ex vivo and a diminished early cytokine and neutrophil response in vivo. Third, whereas the severity of cerulein-induced pancreatitis was similar in TLR4 mutant and wild-type mice, the important contribution of TLR4 to an effective host defense against E coli sepsis observed in previously healthy mice was no longer present in mice with preexisting pancreatitis. Conclusions. These data suggest that TLR4 deficiency and acute pancreatitis act similarly in reducing host defense against E coli peritonitis and that the role of TLR4 in severe Gram-negative infection depends, at least in part, on the presence of preexisting critical illness