Kupffer cell depletion by gadolinium chloride enhances liver regeneration after partial hepatectomy in rats

Rai, R. M.; Yang, Shiqi; McClain, Christopher B.; Karp, Christopher; Klein, Andrew S.; Diehl, Anna Mae

doi:10.1152/ajpgi.1996.270.6.g909

Cited by 82 publications

(109 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…51,6 The production of IL-6 by BECs in vitro is reported to have growth modulating and differentiation inducing effects on intrahepatic BECs 11,32 and is an important factor for liver development and differentiation. 10,52,53 However, it has been shown that IL-6 production of BECs in serum-free medium depended on stimulation with cytokines including IL-1␤ and platelet-derived growth factors, 32 which were not present in our model. In the coculture studies few (if any) inflammatory or stroma cells were present, which could be a source of production.…”

Section: Discussionmentioning

confidence: 64%

“…[5][6][7] In rats, factors including epidermal growth factor (EGF), hepatocyte growth factor (HGF), somatostatin, bile acids, and cytokines have been implicated in the proliferative response 6-10 after bile duct ligation 6,7 or partial hepatectomy. 10 After bile duct ligation in mice, HGF receptors (cmet) are up-regulated and interleukin 6 (IL-6) receptors (gp-80) are induced on the proliferating ductular cells. 11 Studies on isolated intrahepatic BECs from normal rats have also proven productive.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Morphogenesis of primary human biliary epithelial cells: Induction in high-density culture or by coculture with autologous human hepatocytes

et al. 2001

View full text Add to dashboard Cite

Although the control of biliary ductular morphogenesis has received some attention particularly using isolated rat biliary epithelial cell models, the regulation of human bile duct formation is not well defined. In the present study, using a 3-dimensional culture model comprising primary human biliary epithelial cells (BECs) and coculture with primary human hepatocytes, we have sought to define the factors involved. We have shown that primary human BECs can be expanded on collagen gels in the absence of growth factors or serum. When plated in high density in double collagen gels, BECs established 3-dimensional structures that subsequently developed into well differentiated polarized luminal ducts. This morphogenic response occurred in the absence of hepatocyte growth factor (HGF) and epidermal growth factor. Strikingly, the addition of growth factors While the control of liver regeneration has focused on the factors that regulate the initiation of growth in primary hepatocytes (HCs) 1,2 since they are the first cell type in the liver to respond in the regenerative process, 3 less attention has been paid to the biliary epithelial cell (BEC) compartment. We know that in vivo, BECs respond to partial hepatectomy with a delay of approximately 24 hours 4 (together with the sinusoidal cell populations). Although some of the mitogenic signaling molecules have been identified, 1,3 the factors that induce biliary ductular morphogenesis, essential to the efficient regeneration of the bile drainage system, are not well characterized.Many rodent-based biliary epithelial cell studies have focused on the bile duct ligation model, which results in extensive hyperplasia of ductular epithelium and indeed is a chosen means of increasing the yield of BECs that can be isolated from liver tissue. [5][6][7] In rats, factors including epidermal growth factor (EGF), hepatocyte growth factor (HGF), somatostatin, bile acids, and cytokines have been implicated in the proliferative response 6-10 after bile duct ligation 6,7 or partial hepatectomy. 10 After bile duct ligation in mice, HGF receptors (cmet) are up-regulated and interleukin 6 (IL-6) receptors (gp-80) are induced on the proliferating ductular cells. 11 Studies on isolated intrahepatic BECs from normal rats have also proven productive. 8,12,13 Other investigators have used dissected rodent bile duct units to show that interactions of the periductal inflammatory stroma are the source of these factors 11 and to perform functional studies on intrahepatic biliary epithelium. 12,[14][15][16][17][18] Some work on the control of ductular morphogenesis in vitro has also been performed with BECs from bile ductligated rats 5,6,18 and normal rats, 15-17 but the important regulatory factors remain poorly characterized. In other systems, most notably during angiogenesis and mammary gland ductulogenesis, factors such as EGF and HGF have been shown to be the principal morphogenic factors. [19][20][21][22][23][24] Recent evidence from in vitro-based cell proliferation and motility assays has ...

show abstract

Section: Discussionmentioning

confidence: 64%

mentioning

confidence: 99%

Morphogenesis of primary human biliary epithelial cells: Induction in high-density culture or by coculture with autologous human hepatocytes

et al. 2001

View full text Add to dashboard Cite

show abstract

“…These findings were interpreted as being consistent with KC depletion after GD treatment. More recently, Rai et al 22 stained GD-treated KC with the KCR antibody, which recognizes a KC-specific lectin-binding receptor, and Pu-1, which binds to a ubiquitous monocyte gene product. The persistence of Pu-1 staining in the setting of loss of KCR expression after GD treatment indicates that KC undergo phenotypic transformation rather than depletion.…”

Section: Discussionmentioning

confidence: 99%

“…19 More recently, GD has been shown to impair KC antigen presentation, 2 enhance intrahepatic metastases, 20 and alter KC phenotype. 21,22 GD is a member of the trivalent cations of the lanthanide series (La, Ce, Pr, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu) that exhibits properties similar to that of calcium in biological systems, presumably by virtue of its comparable ionic radius. 23 Lathanide cations displace Ca ϩϩ from its binding site on the external surface of the plasma membrane and block Ca ϩϩ influx and efflux from keratinocytes.…”

mentioning

confidence: 99%

Gadolinium Blocks Rat Kupffer Cell Calcium Channels: Relevance to Calcium–Dependent Prostaglandin E2 Synthesis and Septic Mortality

et al. 1999

View full text Add to dashboard Cite

Hepatic Kupffer cells (KC), the major tissue macrophage population, produce the septic response mediators, tumor necrosis factor ␣ (TNF-␣) and prostaglandin E 2 (PGE 2 ), and have been shown to internalize gadolinium chloride (GD), a rare earth metal of the lanthanide series. Because GD pretreatment of rats has been shown to inhibit the mortality of sepsis, we studied the secretory response to lipopolysaccharide (LPS) by KC isolated from rats injected with either saline or GD (7 mg/kg, intravenously) on the 2 days before KC isolation. Using culture conditions modified to reflect the intrasinusoidal milieu of arginine (RPMI-1640 media with 10 or 100 mol/L arginine), KC from GD-treated rats responded to LPS (0.0025 g/mL) with significantly (P F .01) reduced PGE 2 release. In contrast, TNF-␣ release by treated KC was significantly (P F .05) enhanced, consistent with the loss of PGE 2 autocoid inhibition of TNF-␣. Calcium flux is an early signaling event in eicosanoid synthesis, and GD is known to block calcium channels. Therefore, KC were loaded with fura-2-AM to study the effect of GD on KC calcium flux. GD prevented ionomycin and platelet-activating factor (PAF)-mediated [Ca ؉؉ ] i increase and calcium-dependent PGE 2 synthesis, while GD did not affect PGE 2 synthesis when protein kinase C (PKC) was directly activated with tetradecanoylphorbolacetate (TPA). The inhibition of calcium flux and calciumdependent PGE 2 synthesis in the major cell of the monocytic phagocytic system by GD may explain the previously reported ability of this lanthanide to prevent the mortality of endotoxemia. (HEPATOLOGY 1999;29:756-765.)

show abstract

“…Data from several laboratories have suggested that signaling via the JNK (c-Jun NH 2 -terminal kinase)/ stress-activated protein (SAP) kinase cascade plays a role in the transformation and proliferation of several types of cells, including epithelial cells such as hepatocytes (Liu et al, 1994;Rai et al, 1994;Westwick et al, 1995;Boylan et al, 1996;Bruccderi et al, 1997;Michalopoulos and DeFrances, 1997). This is in contrast to other data using transformed and established fibroblast cell lines, which suggests that signaling by the mitogen-activated protein (MAP) kinase cascade plays the dominant role in stimulating cellular proliferation (Williams and Roberts, 1994).…”

Section: Introductionmentioning

confidence: 99%

The Ras/Rac1/Cdc42/SEK/JNK/c-Jun Cascade Is a Key Pathway by Which Agonists Stimulate DNA Synthesis in Primary Cultures of Rat Hepatocytes

Auer¹,

Contessa²,

Brenz-Verca

et al. 1998

MBoC

126

112

View full text Add to dashboard Cite

The ability of signaling via the JNK (c-Jun NH2-terminal kinase)/stress-activated protein kinase cascade to stimulate or inhibit DNA synthesis in primary cultures of adult rat hepatocytes was examined. Treatment of hepatocytes with media containing hyperosmotic glucose (75 mM final), tumor necrosis factor α (TNFα, 1 ng/ml final), and hepatocyte growth factor (HGF, 1 ng/ml final) caused activation of JNK1. Glucose, TNFα, or HGF treatments increased phosphorylation of c-Jun at serine 63 in the transactivation domain and stimulated hepatocyte DNA synthesis. Infection of hepatocytes with poly-l-lysine–coated adenoviruses coupled to constructs to express either dominant negatives Ras N17, Rac1 N17, Cdc42 N17, SEK1−, or JNK1− blunted the abilities of glucose, TNFα, or HGF to increase JNK1 activity, to increase phosphorylation of c-Jun at serine 63, and to stimulate DNA synthesis. Furthermore, infection of hepatocytes by a recombinant adenovirus expressing a dominant-negative c-Jun mutant (TAM67) also blunted the abilities of glucose, TNFα, and HGF to stimulate DNA synthesis. These data demonstrate that multiple agonists stimulate DNA synthesis in primary cultures of hepatocytes via a Ras/Rac1/Cdc42/SEK/JNK/c-Jun pathway. Glucose and HGF treatments reduced glycogen synthase kinase 3 (GSK3) activity and increased c-Jun DNA binding. Co-infection of hepatocytes with recombinant adenoviruses to express dominant- negative forms of PI3 kinase (p110α/p110γ) increased basal GSK3 activity, blocked the abilities of glucose and HGF treatments to inhibit GSK3 activity, and reduced basal c-Jun DNA binding. However, expression of dominant-negative PI3 kinase (p110α/p110γ) neither significantly blunted the abilities of glucose and HGF treatments to increase c-Jun DNA binding, nor inhibited the ability of these agonists to stimulate DNA synthesis. These data suggest that signaling by the JNK/stress-activated protein kinase cascade, rather than by the PI3 kinase cascade, plays the pivotal role in the ability of agonists to stimulate DNA synthesis in primary cultures of rat hepatocytes.

show abstract

Kupffer cell depletion by gadolinium chloride enhances liver regeneration after partial hepatectomy in rats

Cited by 82 publications

References 0 publications

Morphogenesis of primary human biliary epithelial cells: Induction in high-density culture or by coculture with autologous human hepatocytes

Morphogenesis of primary human biliary epithelial cells: Induction in high-density culture or by coculture with autologous human hepatocytes

Gadolinium Blocks Rat Kupffer Cell Calcium Channels: Relevance to Calcium–Dependent Prostaglandin E2 Synthesis and Septic Mortality

The Ras/Rac1/Cdc42/SEK/JNK/c-Jun Cascade Is a Key Pathway by Which Agonists Stimulate DNA Synthesis in Primary Cultures of Rat Hepatocytes

Contact Info

Product

Resources

About