Clodronate-nintedanib-loaded exosome–liposome hybridization enhances the liver fibrosis therapy by inhibiting Kupffer cell activity

Biomaterials Science ◽

10.1039/d1bm01663f ◽

2022 ◽

Author(s):

Keqin Ji ◽

Mingrui Fan ◽

Dong Huang ◽

Lingna Sun ◽

Bingqin Li ◽

...

Keyword(s):

Liver Fibrosis ◽

Inflammatory Cytokines ◽

Kupffer Cell ◽

Kupffer Cells ◽

Cell Activity ◽

Therapeutic Effects

CLD/NIN@LIEV decreases the nonspecific phagocytosis of nanoparticles and suppresses the inflammatory cytokines secreted by Kupffer cells, thus enhancing the therapeutic effects against liver fibrosis.

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Monocyte aryl hydrocarbon hydroxylase (AHH) activity mimics Kupffer cell and hepatocyte AHH activity in an animal model of liver disease

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y91-265 ◽

1991 ◽

Vol 69 (12) ◽

pp. 1797-1803 ◽

Cited By ~ 5

Author(s):

T. C. Peterson ◽

C. N. Williams ◽

D. A. Malatjalian

Keyword(s):

Animal Model ◽

Liver Disease ◽

Liver Fibrosis ◽

Kupffer Cell ◽

Kupffer Cells ◽

Early Stage ◽

Enzyme Function ◽

Aryl Hydrocarbon Hydroxylase ◽

Aryl Hydrocarbon ◽

Yellow Phosphorus

We have previously reported that monocyte aryl hydrocarbon hydroxylase (AHH) activity is depressed in patients with liver disease and is decreased more in cirrhosis than in early stage liver disease. To determine if monocyte AHH activity reflects liver AHH activity, we studied an animal model of cirrhosis, i.e., yellow phosphorus induced cirrhosis in the pig. AHH activity was detectable in monocytes isolated from peripheral blood of normal pigs (0.32 ± 0.13 nmol∙mg−1 P∙h−1, n = 11) and was comparable to the level of AHH activity in hepatic Kupffer cells isolated from wedge or needle biopsies of livers of normal pigs (0.38 ± 0.21, n = 7). The AHH level in pig Kupffer cells was approximately 10% of the AHH level in hepatocytes and microsomes. To induce liver disease, pigs were administered yellow phosphorus (0.6 mg/kg) 5 days per week for 16 weeks. At 4 weeks of treatment, monocyte AHH activity was not different from control and liver histology was normal. Depression of monocyte AHH activity was evident at 8 weeks of treatment when liver fibrosis was seen histologically. At 12 weeks of treatment when histology revealed extensive liver fibrosis and collagen levels were elevated, the level of monocyte AHH activity was decreased 67% compared with controls. Similar changes were observed at 12 weeks in Kupffer cell AHH activity (86% decrease) and hepatocyte AHH activity (70% decrease) compared with controls. These results suggest that monocyte AHH activity reflects liver AHH activity and may be a good indicator of change in liver enzyme function in liver disease in the pig model of cirrhosis.Key words: aryl hydrocarbon hydroxylase, animal model of liver disease, monocyte, hepatocyte, Kupffer cells.

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Cangju Qinggan Jiangzhi Decoction Reduces the Development of NonAlcoholic Steatohepatitis and Activation of Kupffer Cells

Cellular Physiology and Biochemistry ◽

10.1159/000491965 ◽

2018 ◽

Vol 48 (3) ◽

pp. 971-982 ◽

Cited By ~ 2

Author(s):

Yang Cheng ◽

Tianyang Chen ◽

Jian Ping ◽

Jianjie Chen

Keyword(s):

Treatment Group ◽

Palmitic Acid ◽

Inflammatory Cytokines ◽

Kupffer Cells ◽

Nonalcoholic Steatohepatitis ◽

Lipid Accumulation ◽

Hepatic Injury ◽

High Dose ◽

Therapeutic Effects ◽

Dependent Manner

Background/Aims: Nonalcoholic steatohepatitis (NASH) is defined as lipid accumulation with hepatic injury, inflammation and early to moderate fibrosis. Kupffer cells play a crucial role in promoting hepatic inflammation, which further facilitates the development of NASH. Here we investigated the effects of Cangju Qinggan Jiangzhi decoction (CQJD) on high fat diet (HFD) and methionine-choline deficient (MCD) induced mouse NASH pathogenesis. Methods: Mouse NASH models were developed by HFD and MCD diet. The treated mice were divided into three groups: the control group (n = 10), the low-dose CQJD treatment group (n = 10) and the high-dose CQJD treatment group (n = 10). The hepatic injury, inflammation, and apoptotic molecules were evaluated by H&E staining, immunohistochemistry and real-time PCR. Kupffer cells were isolated from control mice and CQJD-treated mice after stimulation by lipopolysaccharide (LPS) and/or palmitic acid. The level of the inflammatory cytokines TNFα, IL1β, and CCL2 was measured by ELISA. Results: The HFD-fed mice displayed significant metabolic, inflammatory, and oxidative stress-related alterations due to hepatic lipid accumulation. CQJD treatment largely normalized the hepatic injury, lowered the ALT/AST level, and reduced the severity of liver inflammation, as revealed by the decreased inflammatory cytokines levels. In vitro, CQJD blocked the activation of LPS- or palmitic acid-primed Kupffer cells in a dose-dependent manner. In the MCD diet-induced NASH mice, similar therapeutic effects of CQJD were also observed. Conclusion: CQJD ameliorates mouse nonalcoholic steatohepatitis. The reduction in liver injury and inflammation induced by CQJD is associated with reduced activation of Kupffer cells. Our results suggest that CQJD is a promising therapeutic strategy in clinical steatohepatitis.

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Macrophage activation and leukocyte adhesion after liver transplantation

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1993.265.1.g172 ◽

1993 ◽

Vol 265 (1) ◽

pp. G172-G177 ◽

Cited By ~ 1

Author(s):

I. Marzi ◽

F. Walcher ◽

V. Buhren

Keyword(s):

Liver Transplantation ◽

Calcium Channel ◽

Calcium Channel Blocker ◽

Kupffer Cell ◽

Kupffer Cells ◽

Cell Activation ◽

Channel Blocker ◽

Leukocyte Adhesion ◽

Cell Activity ◽

Phagocytic Cells

Reperfusion injury involving oxygen radicals, leukocyte adhesion, and Kupffer cell activation has been suggested to contribute to the failure of transplanted livers. The aim of this study was to evaluate Kupffer cell activity, leukocyte adhesion, and the effect of the calcium channel blocker nisoldipine after rat liver transplantation by means of in vivo fluorescence microscopy to further investigate the mechanism of graft failure. Inclusion of 1.4 microM nisoldipine to the University of Wisconsin cold storage solution (UW) did not improve sinusoidal perfusion and vasoconstriction after transplantation compared with UW alone (82.7 +/- 1.0% vs. 79.2 +/- 1.7% perfused sinusoids; 7.3 +/- 0.1 vs. 8.0 +/- 0.2 microns diam of sinusoids; means +/- SE). Permanent as well as temporary adhesion of leukocytes rose from 9.4 +/- 0.8 and 10.2 +/- 0.5% in sham-operated controls to 19.1 +/- 2.2 and 19.2 +/- 0.5% after liver transplantation, respectively. Inclusion of the calcium channel blocker reduced permanent (9.1 +/- 0.8%; P < 0.05) and temporary adherent leukocytes (11.3 +/- 1.0%; P < 0.05). Phagocytosis of latex beads by Kupffer cells or other phagocytic cells as a function of activity rose after transplantation (e.g., periportal area: 509 +/- 44/mm2) compared with controls (316 +/- 22/mm2). This was significantly reduced by inclusion of nisoldipine to UW (322 +/- 32/mm2). The results of this study demonstrate activation of Kupffer cells and increase of leukocyte adhesion to the sinusoidal endothelial wall during reperfusion of transplanted livers. A calcium-dependent release of mediators by Kupffer cells that promote leukocyte adhesion is suggested as an underlying mechanism.

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Human umbilical cord mesenchymal stem cell-derived extracellular vesicles attenuate experimental autoimmune encephalomyelitis via regulating pro and anti-inflammatory cytokines

Scientific Reports ◽

10.1038/s41598-021-91291-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Samira Ahmadvand Koohsari ◽

Abdorrahim Absalan ◽

Davood Azadi

Keyword(s):

Spinal Cord ◽

Body Weight ◽

Extracellular Vesicles ◽

Inflammatory Cytokines ◽

Clinical Score ◽

Human Umbilical Cord ◽

Therapeutic Effects ◽

Leukocyte Infiltration ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

AbstractThe therapeutic effects of mesenchymal stem cells-extracellular vesicles have been proved in many inflammatory animal models. In the current study, we aimed to investigate the effect of extracellular vesicles (EVs) derived from human umbilical cord-MSC (hUCSC-EV) on the clinical score and inflammatory/anti-inflammatory cytokines on the EAE mouse model. After induction of EAE in C57Bl/6 mice, they were treated intravenously with hUCSC-EV or vehicle. The clinical score and body weight of all mice was registered every day. On day 30, mice were sacrificed and splenocytes were isolated for cytokine assay by ELISA. Cytokine expression of pro-/anti-inflammatory cytokine by real-time PCR, leukocyte infiltration by hematoxylin and eosin (H&E) staining, and the percent of glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) positive cells by immunohistochemistry were assessed in the spinal cord. Our results showed that hUCSC-EV-treated mice have lower maximum mean clinical score (MMCS), pro-inflammatory cytokines, and inflammatory score in comparison to the control mice. We also showed that hUCSC-EV administration significantly improved body weight and increased the anti-inflammatory cytokines and the frequency of Treg cells in the spleen. There was no significant difference in the percent of GFAP and MBP positive cells in the spinal cord of experimental groups. Finally, we suggest that intravenous administration of hUCSC-EV alleviate induce-EAE by reducing the pro-inflammatory cytokines, such as IL-17a, TNF-α, and IFN-γ, and increasing the anti-inflammatory cytokines, IL-4 and IL-10, and also decrease the leukocyte infiltration in a model of MS. It seems that EVs from hUC-MSCs have the same therapeutic effects similar to EVs from other sources of MSCs, such as adipose or bone marrow MSCs.

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Th2-Associated Alternative Kupffer Cell Activation Promotes Liver Fibrosis without Inducing Local Inflammation

International Journal of Biological Sciences ◽

10.7150/ijbs.7.1273 ◽

2011 ◽

Vol 7 (9) ◽

pp. 1273-1286 ◽

Cited By ~ 22

Author(s):

Giuliana López-Navarrete ◽

Espiridión Ramos-Martínez ◽

Karina Suárez-Álvarez ◽

Jesús Aguirre-García ◽

Yadira Ledezma-Soto ◽

...

Keyword(s):

Liver Fibrosis ◽

Kupffer Cell ◽

Cell Activation ◽

Local Inflammation

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The anti-inflammatory and anti-fibrotic effects of tadalafil in thioacetamide-induced liver fibrosis in rats

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2018-0338 ◽

2018 ◽

Vol 96 (12) ◽

pp. 1308-1317 ◽

Cited By ~ 9

Author(s):

Heba M. Mansour ◽

Abeer A.A. Salama ◽

Rania M. Abdel-Salam ◽

Naglaa A. Ahmed ◽

Noha N. Yassen ◽

...

Keyword(s):

Liver Fibrosis ◽

Inflammatory Cytokines ◽

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Smooth Muscle Actin ◽

Interleukin 1 ◽

Health Concern ◽

Dependent Manner ◽

Serum Transaminases ◽

Anti Inflammatory

Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. This study aimed to explore the protective effect of tadalafil, a phosphodiesterase-5 inhibitor, against thioacetamide (TAA)-induced liver fibrosis. Fibrosis was induced by administration of TAA (200 mg/kg, i.p.) twice weekly for 6 weeks. Serum transaminases activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA induced marked histopathological changes in liver tissues coupled with elevations in serum transaminases activities. Furthermore, hepatic content of nitric oxide and tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta were elevated, together with a reduction of interleukin-10 in the liver. In addition, TAA increased hepatic contents of transforming growth factor-beta, hydroxyproline, alpha-smooth muscle actin, and gene expression of collagen-1. Pretreatment with tadalafil protected against TAA-induced liver fibrosis, in a dose-dependent manner, as proved by the alleviation of inflammatory and fibrotic biomarkers. The effects of tadalafil were comparable with that of silymarin, a natural antioxidant, and could be assigned to its anti-inflammatory and anti-fibrotic properties.

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