Bile ducts and portal and central veins are major producers of tumor necrosis factor alpha in regenerating rat liver

Loffreda, S.; Rai, Rudra; Yang, Shi Qi; Lin, Hui-Kuan; Diehl, Anna Mae

doi:10.1053/gast.1997.v112.pm9178702

Cited by 52 publications

(25 citation statements)

References 6 publications

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“…ment of nonclassical T and NK cells (12,14,16,29). We will attempt to characterize the cellular response to hepatic infection via the bile duct and portal vein.…”

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

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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...

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“…ment of nonclassical T and NK cells (12,14,16,29). We will attempt to characterize the cellular response to hepatic infection via the bile duct and portal vein.…”

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

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“…Thus, NO also may prevent caspase 3 activation via a cGMP-dependent mechanism (17). Given growing evidence that caspase 3 plays a critical role in TNFmediated hepatocyte death (46,47), caspase 3 seems to be a logical target for NO in the regenerating liver, where hepatocytes are exposed to increased levels of TNF␣ (22,23,48). Consistent with this possibility, we found that caspase 3 activity is increased in transgenic mice with targeted disruption of the iNOS gene compared with control mice, which presumably exhibit induction of iNOS during their normal regenerative response.…”

Section: Discussionmentioning

confidence: 99%

Impaired liver regeneration in inducible nitric oxide synthasedeficient mice

Rudra

Lee

Rosen

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

225

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The mechanisms that permit adult tissues to regenerate when injured are not well understood. Initiation of liver regeneration requires the injury-related cytokines, tumor necrosis factor (TNF) ␣ and interleukin (IL) 6, and involves the activation of cytokine-regulated transcription factors such as NF-␤ and STAT3. During regeneration, TNF␣ and IL-6 promote hepatocyte viability, as well as proliferation, because interventions that inhibit either cytokine not only block hepatocyte DNA synthesis, but also increase liver cell death. These observations suggest that the cytokines induce hepatoprotective factors in the regenerating liver. Given evidence that nitric oxide can prevent TNF-mediated activation of the pro-apoptotic protease caspase 3 and protect hepatocytes from cytokine-mediated death, cytokine-inducible nitric oxide synthase (iNOS) may be an important hepatoprotective factor in the regenerating liver. In support of this hypothesis we report that the hepatocyte proliferative response to partial liver resection is severely inhibited in transgenic mice with targeted disruption of the iNOS gene. Instead, partial hepatectomy is followed by increased caspase 3 activity, hepatocyte death, and liver failure, despite preserved induction of TNF␣, IL-6, NF-␤, and STAT3. These results suggest that during successful tissue regeneration, injury-related cytokines induce factors, such as iNOS and its product, NO, that protect surviving cells from cytokine-mediated death.

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“…6). To investigate whether sustained Ntcp repression despite efficient Kupffer cell depletion was due to proinflammatory cytokines excreted by other cells (e.g., bile duct epithelial cells, endothelial cells), 36 we compared hepatic TNF-␣ and IL-1␤ mRNA expression-both known to be involved in Ntcp regulation 9,16,37 -in Kupffer cell-depleted and naive CBDL animals. CL 2 MBP liposome administration before CBDL attenuated upregulation of TNF-␣ mRNA (229% Ϯ 123% in Kupffer cell-depleted CBDL vs. 552% Ϯ 64% in naive CBDL mice) (Fig.…”

Section: Kupffer Cell Depletion Does Not Prevent Ntcpmentioning

confidence: 99%