Augmentation of the early phase of liver regeneration after 70% partial hepatectomy in rats following selective Kupffer cell depletion

doi:10.1016/S0168-8278(98)80013-5

Journal of Hepatology

Volume 29, Issue 2, August 1998, Pages 271-280

https://doi.org/10.1016/S0168-8278(98)80013-5 Get rights and content

Abstract

Background/Aims: Kupffer cells are located in liver sinusoids adjacent to hepatocytes and elaborate a range of growth regulatory molecules involved in regulating hepatocyte proliferation. In vitro observations imply the potential for Kupffer cells to exert both stimulatory and inhibitory influences on hepatocyte DNA synthesis. We aimed to determine the overall effect of Kupffer cell activity during the early regenerative processes after partial hepatectomy.

Methods: We investigated hepatocyte DNA synthesis, induced by partial hepatectomy in rats, following selective elimination of Kupffer cells by liposome encapsulated dichlormethylene bisphosphonate (Cl₂MBP).

Results: We demonstrate that the early phase of liver regeneration was enhanced following Kupffer depletion, as indicated by a greater proportion of hepatocytes undergoing DNA synthesis, and a higher mitotic index. This was associated with an alteration in the balance of growth factors in the liver; HGF and TGFβ mRNA were reduced in Kupffer cell-depleted animals, and IL-1β mRNA was absent. In addition, in the absence of partial hepatectomy, the selective depletion of Kupffer cells leads to an increase in the proliferation of hepatocytes in resting liver undergoing DNA synthesis.

Conclusion: The overall effect of depleting the liver of Kupffer cells is to enhance the proliferation rate of hepatocytes, both after partial hepatectomy and in the resting state.

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Interleukin-17A plays a pivotal role after partial hepatectomy in mice
2013, Journal of Surgical Research
Citation Excerpt :
Because insufficient liver regeneration is potentially fatal for these patients, investigation of the physiological mechanism of liver regeneration could lead to decreased morbidity and mortality, leading to increased opportunities for therapy against critical liver disease. The hepatic macrophage, the Kupffer cell, is known to produce a variety of growth and immunomodulating mediators that have stimulatory and inhibitory effects on liver regeneration [6]. It was reported that hepatic macrophages are the major source of tumor necrosis factor (TNF)-α and interleukin (IL)-6 and depletion of hepatic macrophages impaired liver regeneration after PH [7].
Liver regeneration after partial hepatectomy (PH) is regulated by tumor necrosis factor (TNF)-α derived from the Kupffer cell. Furthermore, it was reported from our laboratory that interleukin (IL)-17A enhances the production of TNF-α by the Kupffer cell, suggesting that IL-17A may play a role in liver regeneration.
The purpose was to determine the role of IL-17A and the spleen in liver regeneration after PH.
Two mouse models including the wild-type (WT) mice or the IL-17A knockout (KO) mice underwent PH. Animals were killed at the designated time points; liver tissues were harvested for further investigation. Proliferation of hepatocytes was evaluated. Furthermore, the messenger RNA and protein expression of TNF-α and IL-6 were measured in the liver. In another set of experiments, the two animal models underwent splenectomy before PH. In an in vitro study, CD4-positive lymphocytes in the spleen were isolated from mice, and the number of IL-17A–positive cells was investigated.
Liver regeneration was significantly impaired in the KO mice compared with the WT mice. This was associated with suppression of cell proliferation assessed by cell proliferation markers in the KO mice. In the WT mice that underwent splenectomy, liver regeneration was significantly delayed compared with animals without splenectomy. In contrast, splenectomy did not affect liver regeneration in the KO mice. IL-17A–positive lymphocytes increased significantly in the spleen in the WT mice after PH.
These results indicate that IL-17A derived from CD4-positive lymphocytes in the spleen is a key regulator in liver regeneration after PH.
The Kupffer cell inhibition exacerbates but splenectomy prevents mortality in a rat septic peritonitis model
2012, Journal of Surgical Research
Citation Excerpt :
Rats were given food and water ad libitum throughout the study. Animals received intravenous administration of 1 mL of lipo-MDP 24 h before CLP to eliminate the Kupffer cell but not the splenic macrophage [13]. Non-entrapped liposome (lipo; 1 mL/animal) was administered as a control.
The purpose of this study was to investigate whether inhibition of Kupffer cells (KCs) affects the expression of high mobility group box 1 (HMGB1) and mortality in septic peritonitis. The role of the spleen in septic peritonitis was also investigated.
Rats were given liposome-entrapped dichloromethylene diphosphonate (lipo-MDP) to eliminate KCs or non-entrapped liposome (lipo) before cecal ligation and puncture (CLP), and serum HMGB1 levels and mortality were assessed after CLP. Furthermore, KCs and tissue macrophages were isolated, and production of HMGB1 was investigated. Effects of splenectomy on serum HMGB1 levels and mortality were also investigated after CLP.
Elimination of the Kupffer cells by lipo-MDP increased serum HMGB1 concentrations and mortality significantly. Furthermore, HMGB1 expression in both the periportal area of the liver and the spleen was greater in the lipo-MDP group than the lipo group. On the other hand, splenectomy blunted serum HMGB1 levels and improved mortality after CLP. The HMGB1 expression was greater in the spleen compared with the liver after CLP. Furthermore, production of HMGB1 was greatest in splenic macrophages in vitro. The number of ED3-positive cells increased significantly in non-splenectomized animals but not in splenectomized animals after CLP. In the lipo-MDP treated groups, the number of ED3-positive macrophages also increased in the liver from non-splenectomized animals but not in the splenectomized animals after CLP.
The liver and the spleen play key roles in host defense during septic peritonitis. Migrating macrophages into the liver are, in part, derived from the spleen after CLP.
Liver regeneration is impaired in macrophage colony stimulating factor deficient mice after partial hepatectomy: The role of M-CSF-induced macrophages
2011, Journal of Surgical Research
Citation Excerpt :
However, their function in liver regeneration after partial hepatectomy (PH) and the underlying mechanisms are not fully understood [12]. There are only a limited number of studies available using this Kupffer cell-depleting approach to clarify their role in liver regeneration [13–16]. Although Boulton et al. noted an augmentation of the early phase of liver regeneration following Kupffer cell depletion [16], it has also been reported that Kupffer cell depletion exerts an inhibitory effect on liver regeneration by altering hepatic cytokine expression patterns [4, 14].
Macrophage colony stimulating factor (M-CSF), which induces maturation of macrophages, is notably expressed in the liver. Thus, the specific purpose of this study was to investigate the role of M-CSF in liver regeneration after partial hepatectomy (PH). Osteopetrotic (op/op) mice, genetically lacking functional M-CSF, or their littermate mice underwent 70% PH. Animals were sacrificed at the designated time points after PH, and remnant liver tissues were harvested for further investigations. Proliferation of hepatocytes was evaluated by the expression of BrdU and the liver-body weight ratio. The mRNA expression levels of TNF-α and IL-6 and protein expression levels of phosphorylated (p) STAT3 were measured. The number of Kupffer cells (KCs) was determined by immunohistochemistry. Furthermore, KCs were isolated from op/op mice or littermate mice, and mRNA expression levels of TNF- α and IL-6 were assessed after stimulation with LPS. In littermate mice, steady liver regeneration was observed. The number of KCs reduced markedly by about 60% in the op/op mice compared with littermates as reported previously. Furthermore, these cells were morphologically small and immature. In littermate mice, the peak expression levels of TNF-α and IL-6 in the liver was observed 1h after PH, which was consistent with data in previous reports. In contrast, in op/op mice, the peak expression levels were observed 3 h after PH and were significantly lower compared with littermate mice. As a result, the proliferation of hepatocytes was significantly impaired in op/op mice. The mRNA expression level of IL-6, but not TNF-α,was significantly reduced in isolated KCs from op/op mice compared with the littermates after stimulation with LPS, suggesting that the function of KCs is different between op/op mice and littermate mice. To clarify the role of M-CSF in liver regeneration, op/op mice received intraperitoneally, mouse recombinant M-CSF 2 d before PH, and liver regeneration was also assessed. As a result, the numbers of Kupffer cells and liver regeneration were recovered in the op/op mice treated with M-CSF to a similar extent to those in their littermates. Thus, M-CSF-induced hepatic macrophages play an important role in liver regeneration after PH.
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Augmentation of the early phase of liver regeneration after 70% partial hepatectomy in rats following selective Kupffer cell depletion

Abstract

FEBS Lett

Hepatology

J Immunol Methods

FEBS Lett

J Immunol Methods

J Immunol Methods

Anal Biochem

Anal Biochem

Exp Cell Res

Hepatology

J Surg Res

J Surg Res

J Hepatol

Experimental pathology of the liver I: restoration of the liver of the white rat following partial surgical removal

Arch Pathol

Hepatic regeneration: current concepts and clinical implications

Semin Liver Dis.

Liver regeneration

FASEB J

Expression of transforming growth factor-alpha in regenerating liver and during hepatic differentiation

Mol Carcinog

Intrahepatic distribution of transforming growth factor-alpha (TGF alpha) during liver regeneration following carbon tetrachloride-induced necrosis

J Pathol

Hepatocyte growth factor/hepatopoietin A is expressed in fat-storing cells from rat liver, but not myofibroblast-like cells derived from fat-storing cells

Hepatology

Activation of hepatocyte growth factor by the plasminogen activators uPA and tPA

Am J Pathol

Hepatocyte growth factor, blood clearance, organ uptake, and biliary excretion in normal and partially hepatectomised rats

Lab Invest

Transforming growth factor beta mRNA increases during liver regeneration; a possible paracrine mechanism of growth regulation

Proc Natl Acad Sci USA