A new method to monitor Kupffer-cell function continuously in the perfused rat liver. Dissociation of glycogenolysis from particle phagocytosis

Cowper, Katherine; Currin, Robert T.; Dawson, Thomas L.; Lindert, Kelly; Lemasters, John J.; Thurman, Ronald G.

doi:10.1042/bj2660141

Cited by 67 publications

(48 citation statements)

References 18 publications

(18 reference statements)

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“…During this time, perfusate samples were collected every 5 min to determine uptake of CC by comparing the absorbance at 623 nm of the perfusate going into the liver to the perfusate leaving the liver. The rate of CC uptake was expressed as micrograms per minute times grams liver tissue (11,27).…”

Section: Methodsmentioning

confidence: 99%

Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype

Lindell¹,

Klahn²,

Piazza³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

114

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. Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype. Am J Physiol Gastrointest Liver Physiol 288: G473-G480, 2005; doi:10.1152/ajpgi.00223.2004.-The success of liver grafts is currently limited by the length of time organs are cold preserved before transplant. Novel insights to improve viability of cold-stored organs may emerge from studies with animals that naturally experience low body temperatures (T b) for extended periods. In this study, we tested whether livers from hibernating ground squirrels tolerate cold ischemia-warm reperfusion (cold I/R) for longer times and with better quality than livers from rats or summer squirrels. Hibernators were used when torpid (T b Ͻ 10°C) or aroused (Tb ϭ 37°C). Livers were stored at 4°C in University of Wisconsin solution for 0 -72 h and then reperfused with 37°C buffer in vitro. Lactate dehydrogenase (LDH) release after 60 min was increased 37-fold in rat livers after 72 h cold I/R but only 10-fold in summer livers and approximately three-to sixfold in torpid and aroused hibernator livers, despite twofold higher total LDH content in livers from hibernators compared with rats or summer squirrels. Reperfusion for up to 240 min had the least effect on LDH release in livers from hibernators and the greatest effect in rats. Compared with rats or summer squirrels, livers from hibernators after 72 h cold I/R showed better maintenance of mitochondrial respiration, bile production, and sinusoidal lining cell viability, as well as lower vascular resistance and Kupffer cell phagocytosis. These results demonstrate that the hibernation phenotype in ground squirrels confers superior resistance to liver cold I/R injury compared with rats and summer squirrels. Because hibernation-induced protection is not dependent on animals being in the torpid state, the mechanisms responsible for this effect may provide new strategies for liver preservation in humans. transplantation; cold storage; Kupffer cells; sinusoidal lining cells DESPITE MAJOR ADVANCES IN hypothermic preservation of organs before transplant, problems associated with extended cold ischemia-reperfusion (cold I/R) injury still limit the optimal use of transplantation as a therapeutic intervention for organ failure. For example, human livers can be successfully stored at 4°C for up to 12 h in University of Wisconsin (UW) solution, but graft failure is greatly increased after extended storage periods (14,33,34). In the rat liver transplant model, when livers are cold stored in UW for up to 24 h, 100% of the recipients survive (42); in contrast, without nutritional manipulation, none survive after receiving livers stored for 48 h (39).The damaging effects of cold I/R are evident on organ reperfusion with warmed, oxygenated blood, with damage increasing with the length of the cold ischemia period (10,35,40).A variety of pharmacological strategies has been explored to improve graft function after cold I/R to extend cold storage times and provide more flexibility in organ distribut...

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Section: Methodsmentioning

confidence: 99%

Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype

Lindell¹,

Klahn²,

Piazza³

et al. 2005

American Journal of Physiology-Gastrointestinal and Liver Physi

114

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“…The liver was flushed with 10 ml of Krebs-Henseliet bicarbonate buffer from a height of 30 cm to remove blood cells before excision and weighing. To relax postoperative vasoconstriction, perfusion was held at a constant flow rate of 3 ml͞g͞min with Krebs-Henseliet bicarbonate buffer, at an O 2 concentration of 95% and a CO 2 concentration of 5%, with a constant temperature of 25°C for 10 min (22). After isolated perfusion, the liver was flushed with 10 ml of colloidal carbon (Pelican Ink), which was prepared by extensive dialysis (48 h), and filtered through an 8-m mesh (22).…”

Section: Methodsmentioning

confidence: 99%

Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice

Lahvis

Lindell

Thomas

et al. 2000

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

339

267

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A physiological examination of mice harboring a null allele at the aryl hydrocarbon (Ah) locus revealed that the encoded aryl hydrocarbon receptor plays a role in the resolution of fetal vascular structures during development. Although the aryl hydrocarbon receptor is more commonly studied for its role in regulating xenobiotic metabolism and dioxin toxicity, a developmental role of this protein is supported by the observation that Ah null mice display smaller livers, reduced fecundity, and decreased body weights. Upon investigating the liver phenotype, we found that the decrease in liver size is directly related to a reduction in hepatocyte size. We also found that smaller hepatocyte size is the result of massive portosystemic shunting in null animals. Colloidal carbon uptake and microsphere perfusion studies indicated that 56% of portal blood flow bypasses the liver sinusoids. Latex corrosion casts and angiography demonstrated that shunting is consistent with the existence of a patent ductus venosus in adult animals. Importantly, fetal vascular structures were also observed at other sites. Intravital microscopy demonstrated an immature sinusoidal architecture in the liver and persistent hyaloid arteries in the eyes of adult Ah null mice, whereas corrosion casting experiments described aberrations in kidney vascular patterns.T he aryl hydrocarbon receptor (AHR) is a member of the per-arnt-sim (PAS) superfamily of proteins. The AHR regulates biological responses to a variety of environmental contaminants, such as the polycyclic aromatic hydrocarbons found in cigarette smoke, the polychlorinated dioxins that contaminate industrial chemicals, and the wartime defoliant Agent Orange (1-5). These chemical ligands bind to the AHR, leading to receptor dimerization with another PAS protein known as the aryl hydrocarbon nuclear translocator (ARNT). This heterocomplex interacts with genomic enhancer elements upstream of a battery of target genes that encode xenobiotic metabolizing enzymes (1, 6, 7). The observation that the up-regulated enzymes often have metabolic activity toward AHR agonists has led to the idea that this pathway represents an adaptive metabolic response that protects an organism from exposure to certain classes of toxic environmental contaminants. Although this adaptive role has considerable experimental support, this pathway is not always protective. Exposure to high-affinity AHR agonists, like the chlorinated dioxins, can result in cancer (8), immunosuppression (9), liver damage (10), and birth defects (11). The mechanisms underlying these toxic effects are unknown but appear to be AHR mediated.Because of its role in mediating responses to environmental contaminants, the biology of the AHR has been extensively characterized from a toxicological viewpoint. However, several observations suggest an additional role for the AHR in vertebrate development. First, a phylogenetic survey indicates that the AHR arose over 450 million years ago, with functional orthologs found in species that have evolved in vario...

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“…KC (Cowper et al 1990;Bojes and Thurman 1996). Activated KC release a variety of pharmacologically active mediators, i.e.…”

Section: Treatmentmentioning

confidence: 99%

Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague–Dawley rats and B₆C₃F₁/N mice when administered by oral gavage for 28 days

Frawley

Smith

Cesta

et al. 2018

Journal of Immunotoxicology

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Poly-and perfluoroalkyl substances (PFAS) are chemically and thermally stable, hydrophobic, lipophobic compounds used in stain repellants and water and oil surfactants, and associated with immunosuppression and peroxisome proliferator activity. Perfluoro-n-decanoic acid (PFDA, (CF 3 (CF 2 ) 8 COOH), a fluorinated straight chain fatty acid compound, is reported to induce thymic atrophy and reversible bone marrow hypocellularity in rodent models. The objective of this study was to assess potential immunotoxicity of PFDA, due to its structural similarity to other immunosuppressive PFASs. Female Harlan Sprague-Dawley rats were exposed to 0-2.0 mg PFDA/kg by oral gavage daily for 28 d. Female B 6 C 3 F 1 /N mice were exposed once/week to 0-5.0 mg PFDA/kg by gavage for 4 weeks. Animals were evaluated for effects on immune cell populations in spleen and bone marrow, and innate, humoral-, and cell-mediated immunity. Mice were also evaluated for resistance to Influenza virus. Treatment-related hepatocyte necrosis and hepatomegaly were observed in rats treated with 0.5 mg PFDA/kg/d. In mice, hepatomegaly (26-89%) was observed following exposure to !0.625 mg PFDA/kg/week, while splenic atrophy (20%) was observed at 5.0 mg PFDA/kg/week. At 5.0 mg PFDA/kg/week, total spleen cells, and Ig þ and NK þ cells were decreased (17.6-27%). At ! 1.25 mg PFDA/kg/week the numbers of splenic CD3 þ , CD4 þ , CD8 þ , and Mac3 þ cells were decreased (10.5-39%). No changes were observed in leukocyte subpopulations in PFDA-exposed rats. Phagocytosis by fixed-tissue macrophages was decreased in liver (specific activity, 24-39%) at !0.25 mg PFDA/kg/d in rats. PFDA-induced effects on humoral-and cell-mediated immunity, host resistance, and bone marrow progenitor cells were limited. These data suggest that exposure to PFDA may induce adverse effects in rat liver in a manner consistent with the PFAS class, and may also alter the balance of immune cell populations in lymphoid tissues in mice.ARTICLE HISTORY

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A new method to monitor Kupffer-cell function continuously in the perfused rat liver. Dissociation of glycogenolysis from particle phagocytosis

Cited by 67 publications

References 18 publications

Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype

Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype

Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice

Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague–Dawley rats and B₆C₃F₁/N mice when administered by oral gavage for 28 days

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A new method to monitor Kupffer-cell function continuously in the perfused rat liver. Dissociation of glycogenolysis from particle phagocytosis

Cited by 67 publications

References 18 publications

Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype

Natural resistance to liver cold ischemia-reperfusion injury associated with the hibernation phenotype

Portosystemic shunting and persistent fetal vascular structures in aryl hydrocarbon receptor-deficient mice

Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague–Dawley rats and B6C3F1/N mice when administered by oral gavage for 28 days

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Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague–Dawley rats and B₆C₃F₁/N mice when administered by oral gavage for 28 days