Characterization of the Kupffer cell response to exogenous endotoxin in a rodent model of obstructive jaundice

Kennedy, J. A.; Clements, W. D. B.; Kirk, Stephen; McCaigue, M. D.; Campbell, Gareth; Erwin, P. J.; Halliday, M. I.; Rowlands, B. J.

doi:10.1046/j.1365-2168.1999.01114.x

Cited by 47 publications

(24 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our model differs from other models of bile duct obstruction in the literature (2,9,10,19,22,23). These models have focused on late time points (1 to 3 weeks) after bile duct obstruction.…”

Section: Discussionmentioning

confidence: 99%

Infection by Gram-Negative Organisms via the Biliary Route Results in Greater Mortality than Portal Venous Infection

Jeyarajah

Kielar

Frantz

et al. 2003

Clin Vaccine Immunol

View full text Add to dashboard Cite

Cholangitis requires bile duct obstruction and infection. Patients with cholangitis are often more affected than those with infections that reach the liver through the portal vein. We will attempt to study the influences of (i) route of entry and (ii) presence of bile duct obstruction on hepatic infection. C57BL/6 mice received injections of Escherichia coli or lipopolysaccharide into the obstructed bile duct or portal vein and were monitored for survival. Livers were assayed for bacteria, and cytokine mRNA was measured. In order to examine the effect of biliary obstruction on hepatic infection, animals were subjected to bile duct ligation 1 day prior to portal vein injection and were monitored for survival. The 50% lethal dose (LD 50 ) for E. coli injected into the bile duct was 50 CFU/animal; the LD 50 for E. coli injected into the portal vein was 5 ؋ 10 7 CFU/animal. Initial hepatic delivery of bacteria was equivalent 1 h after injection into the bile duct or portal vein. However, by 24 h, a significantly greater amount of bacteria was recovered from the livers of the bile duct-injected group. Interleukin 10 (IL-10) and IL-1RA mRNA was expressed at greater levels in the bile duct-injected group. Prior bile duct ligation followed by portal vein injection resulted in a higher incidence of death than when sham operation was performed prior to portal vein injection. Our data suggest that the increased mortality from cholangitis, compared with that from other hepatic infections, is related to the different route of delivery of pathogen and the maladaptive response (possibly involving IL-10 and IL-1RA) to biliary obstruction itself.Despite antibiotics and biliary drainage, either surgically or endoscopically, patients with ascending cholangitis have greater mortality and morbidity than patients with other appropriately treated intra-abdominal infections. In contrast to portal vein entry of bacteria into the liver, for example, after appendicitis or diverticulitis, entry via the biliary ducts has higher morbidity and mortality (4, 7). Indeed, small numbers of bacteria from the gastrointestinal tract may continually shower the liver via the portal vein without ill effect (11). This study reports a murine model that compares infection via the biliary and portal venous routes. This model reproduces the extraordinary mortality seen in patients after the former. Our model differs from others (9, 19). It focuses on early events within days of biliary infection, as opposed to late events after biliary obstruction has resulted in chronic liver injury.Our model suggests that the host response to infection via the bile duct is fundamentally different from the response to infection via the portal vein. We will show that one manifestation of this difference is the pattern of cytokines elicited by the infection. These cytokines affect the outcome in models of infection and injury and are supported by the literature. For example, levels of interleukin 6 (IL-6) in serum correlate with survival in critically ill patients; manipulat...

show abstract

“…Our model differs from other models of bile duct obstruction in the literature (2,9,10,19,22,23). These models have focused on late time points (1 to 3 weeks) after bile duct obstruction.…”

Section: Discussionmentioning

confidence: 99%

Infection by Gram-Negative Organisms via the Biliary Route Results in Greater Mortality than Portal Venous Infection

Jeyarajah

Kielar

Frantz

et al. 2003

Clin Vaccine Immunol

View full text Add to dashboard Cite

show abstract

“…18,23 After endotoxin administration to cholestatic rats, Kennedy et al demonstrated that blockade of Kuppfer cells with gadolinium chloride leads to a lower systemic TNF activity and subsequently resulted in an improved survival. 17 On the other hand, the enhanced IL-6 release, as found in jaundiced mice exposed to endotoxin, might actually play an important role in protecting the cholestatic host against hypersensitivity to endotoxin and was found to abrogate cholestatic liver injury. 22,24 In the perspective of these results found in animal models of biliary obstruction, it appears that the generalized inflammatory state in patients with obstructive jaundice was profoundly different.…”

Section: Experimental Studiesmentioning

confidence: 99%

“…[17][18][19][20][21][22] Increased concentrations of TNF, mainly produced by liver Kuppfer cells, or rather, the imbalance with its soluble receptors, as antagonists and released from the cell membrane by endotoxemia, are suggested to contribute to development of complications. 18,23 After endotoxin administration to cholestatic rats, Kennedy et al demonstrated that blockade of Kuppfer cells with gadolinium chloride leads to a lower systemic TNF activity and subsequently resulted in an improved survival.…”

Section: Experimental Studiesmentioning

confidence: 99%

Preoperative Biliary Drainage in Patients with Obstructive Jaundice: History and Current Status

Gaag

Kloek

Castro

et al. 2009

Journal of Gastrointestinal Surgery

157

114

View full text Add to dashboard Cite

Rationale Preoperative biliary drainage (PBD) has been introduced to improve outcome after surgery in patients suffering from obstructive jaundice due to a potentially resectable proximal or distal bile duct/pancreatic head lesion. In experimental models, PBD is almost exclusively associated with beneficial results: improved liver function and nutritional status; reduction of systemic endotoxemia; cytokine release; and, as a result, an improved immune response. Mortality was significantly reduced in these animal models. Human studies show conflicting results. Findings For distal obstruction, currently the "best-evidence" available clearly shows that routine PBD does not yield the appreciated improvement in postoperative morbidity and mortality in patients undergoing resection. Moreover, PBD harbors its own complications. However, most of the available data are outdated or suffer from methodological deficits. Conclusion The highest level of evidence for PBD to be performed in proximal obstruction, as well as over the preferred mode, is lacking but, nevertheless, assimilated in the treatment algorithm for many centers. Logistics and waiting lists, although sometimes inevitable, could be factors that might influence the decision to opt for PBD, as well as an extended diagnostic workup with laparoscopy (on indication) or scheduled preoperative chemotherapy.

show abstract

“…Numerous experimental studies have demonstrated a profound proinflammatory response following endotoxin challenge, which is marked by an increased production of tumor necrosis factor (TNF)-␣, interleukin (IL)-1, and IL-6 in animals with biliary obstruction (9,14,17,18,28). This proinflammatory milieu is associated with increased markers of end organ injury [aspartate aminotransferase (AST) and creatinine] and death (14), and blockade of this response through the administration of gadolinium chloride has been shown to suppress the systemic proinflammatory response leading to improved survival (18,24).…”

mentioning

confidence: 99%

LPS-binding protein mediates LPS-induced liver injury and mortality in the setting of biliary obstruction

Minter¹,

Bi²,

Ben-Josef³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

View full text Add to dashboard Cite

GL. LPS-binding protein mediates LPS-induced liver injury and mortality in the setting of biliary obstruction. Am J Physiol Gastrointest Liver Physiol 296: G45-G54, 2009. First published October 23, 2008 doi:10.1152/ajpgi.00041.2008.-It is generally accepted that low levels of lipopolysaccharide (LPS)-binding protein (LBP) augment the cell's response to LPS, whereas high levels of LBP have been shown to inhibit cell responses to LPS. Clinical studies and in vitro work by our group have demonstrated that, in the setting of liver disease, increased or acute-phase levels of LBP may actually potentiate rather than inhibit an overwhelming proinflammatory response. Therefore, in the present studies we sought to determine the role of acute-phase LBP in mediating morbidity and mortality in animals challenged with LPS in the setting of biliary obstruction. Using LBP-deficient mice and LBP blockade in wild-type mice, we demonstrate that high levels of LBP are deleterious in the setting of cholestasis. Following biliary obstruction and intraperitoneal LPS challenge, hepatic injury, hepatic neutrophil infiltration, and mortality were significantly increased in animals with an intact LBP acute-phase response. Kupffer cell responses from these animals demonstrated a significant increase in several inflammatory mediators, and Kupffer cell-associated LBP appears to be responsible for these differences, at least in part. Our results indicate that the role of LBP signaling in inflammatory conditions is complex and heterogeneous, and elevated levels of LBP are not always protective. Increased LBP production in the setting of cholestatic liver disease appears to be deleterious and may represent a potential therapeutic target for preventing overwhelming inflammatory responses to LPS in this setting.

show abstract

Characterization of the Kupffer cell response to exogenous endotoxin in a rodent model of obstructive jaundice

Abstract: These data demonstrate simultaneous impairment of Kupffer cell clearance of endotoxin and increased secretion of proinflammatory cytokines in experimental obstructive jaundice. These diverse responses may contribute to the development of sepsis-related complications in biliary obstruction.

Cited by 47 publications

References 37 publications

Infection by Gram-Negative Organisms via the Biliary Route Results in Greater Mortality than Portal Venous Infection

Infection by Gram-Negative Organisms via the Biliary Route Results in Greater Mortality than Portal Venous Infection

Preoperative Biliary Drainage in Patients with Obstructive Jaundice: History and Current Status

LPS-binding protein mediates LPS-induced liver injury and mortality in the setting of biliary obstruction

Contact Info

Product

Resources

About