scholarly journals Smad7 Deficiency in Myeloid Cells Does Not Affect Liver Injury, Inflammation or Fibrosis after Chronic CCl4 Exposure in Mice

2021 ◽  
Vol 22 (21) ◽  
pp. 11575
Author(s):  
Ludmilla Unrau ◽  
Jessica Endig ◽  
Diane Goltz ◽  
Paulina Sprezyna ◽  
Hanna Ulrich ◽  
...  
Keyword(s):  
Liver Injury ◽  
Transforming Growth Factor ◽  
Elevated Serum ◽  
Myeloid Cells ◽  
Chronic Liver ◽  
Signalling Pathway ◽  
Liver Inflammation ◽  
Knock Down ◽  
Smad Protein ◽  
Smad7 Expression

Myeloid cells play an essential role in the maintenance of liver homeostasis, as well as the initiation and termination of innate and adaptive immune responses. In chronic hepatic inflammation, the production of transforming growth factor beta (TGF-β) is pivotal for scarring and fibrosis induction and progression. TGF-β signalling is tightly regulated via the Smad protein family. Smad7 acts as an inhibitor of the TGF-β-signalling pathway, rendering cells that express high levels of it resistant to TGF-β-dependent signal transduction. In hepatocytes, the absence of Smad7 promotes liver fibrosis. Here, we examine whether Smad7 expression in myeloid cells affects the extent of liver inflammation, injury and fibrosis induction during chronic liver inflammation. Using the well-established model of chronic carbon tetrachloride (CCl4)-mediated liver injury, we investigated the role of Smad7 in myeloid cells in LysM-Cre Smadfl/fl mice that harbour a myeloid-specific knock-down of Smad7. We found that the chronic application of CCl4 induces severe liver injury, with elevated serum alanine transaminase (ALT)/aspartate transaminase (AST) levels, centrilobular and periportal necrosis and immune-cell infiltration. However, the myeloid-specific knock-down of Smad7 did not influence these and other parameters in the CCl4-treated animals. In summary, our results suggest that, during long-term application of CCl4, Smad7 expression in myeloid cells and its potential effects on the TGF-β-signalling pathway are dispensable for regulating the extent of chronic liver injury and inflammation.

scholarly journals Acute Liver Injury after CCl4 Administration Is Independent of Smad7 Expression in Myeloid Cells

2019 ◽  
Vol 20 (22) ◽  
pp. 5528 ◽  
Author(s):  
Jessica Endig ◽  
Ludmilla Unrau ◽  
Paulina Sprezyna ◽  
Sebasting Rading ◽  
Meliha Karsak ◽  
...  
Keyword(s):  
Liver Injury ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Elevated Serum ◽  
Myeloid Cells ◽  
Transforming Growth Factor Β ◽  
Cellular Processes ◽  
Ccl4 Administration ◽  
Smad7 Expression ◽  
The Impact

Myeloid cells are essential for the initiation and termination of innate and adaptive immunity that create homeostasis in the liver. Smad7 is an inhibitor of the transforming growth factor β (TGF-β) signaling pathway, which regulates inflammatory cellular processes. Knockdown of Smad7 in hepatocytes has been shown to promote liver fibrosis, but little is known about the effects of Smad7 in myeloid cells during inflammatory responses in the liver. Using mice with a myeloid-specific knockdown of Smad7 (LysM-Cre Smad7fl/fl), we investigated the impact of Smad7 deficiency in myeloid cells on liver inflammation and regeneration using the well-established model of CCl4-mediated liver injury. Early (24/48 h) and late (7 d) time points were analyzed. We found that CCl4 induces severe liver injury, with elevated serum ALT levels, centrilobular and periportal necrosis, infiltrating myeloid cells and an increase of inflammatory cytokines in the liver. Furthermore, as expected, inflammation peaked at 24 h and subsided after 7 d. However, the knockdown of Smad7 in myeloid cells did not affect any of the investigated parameters in the CCl4-treated animals. In summary, our results suggest that the inhibition of TGF-β signaling via Smad7 expression in myeloid cells is dispensable for the induction and control of acute CCl4-induced liver injury.

scholarly journals Podoplanin discriminates distinct stromal cell populations and a novel progenitor subset in the liver

2016 ◽  
Vol 310 (1) ◽  
pp. G1-G12 ◽  
Author(s):  
Christoph Eckert ◽  
Yong Ook Kim ◽  
Henrike Julich ◽  
Eva-Carina Heier ◽  
Niklas Klein ◽  
...  
Keyword(s):  
Liver Injury ◽  
Progenitor Cell ◽  
Chronic Liver ◽  
Biliary Cirrhosis ◽  
Liver Inflammation ◽  
Parenchymal Liver ◽  
Functional Regulation ◽  
Human Livers ◽  
Cell Niche

Podoplanin/gp38+ stromal cells present in lymphoid organs play a central role in the formation and reorganization of the extracellular matrix and in the functional regulation of immune responses. Gp38+ cells are present during embryogenesis and in human livers of primary biliary cirrhosis. Since little is known about their function, we studied gp38+ cells during chronic liver inflammation in models of biliary and parenchymal liver fibrosis and steatohepatitis. Gp38+ cells were analyzed using flow cytometry and confocal microscopy, and the expression of their steady state and inflammation-associated genes was evaluated from healthy and inflamed livers. Gp38+ cells significantly expanded in all three models of liver injury and returned to baseline levels during regression of inflammation. Based on CD133 and gp38 expression in the CD45−CD31−Asgpr1− liver cell fraction, numerous subsets could be identified that were negative for CD133 (gp38hiCD133−, gp38lowCD133−, and gp38−CD133−). Moreover, among the CD133+ cells, previously identified as progenitor population in injured liver, two subpopulations could be distinguished based on their gp38 expression (gp38−CD133+ and CD133+gp38+). Importantly, the distribution of the identified subsets in inflammation illustrated injury-specific changes. Moreover, the gp38+CD133+ cells exhibited liver progenitor cell characteristics similar to the gp38−CD133+ population, thus representing a novel subset within the classical progenitor cell niche. Additionally, these cells expressed distinct sets of inflammatory genes during liver injury. Our study illuminates a novel classification of the stromal/progenitor cell compartment in the liver and pinpoints a hitherto unrecognized injury-related alteration in progenitor subset composition in chronic liver inflammation and fibrosis.

Hot Water Extracted Lycium Barbarum and Rehmannia Glutinosa Inhibit Liver Inflammation and Fibrosis in Rats

2011 ◽  
Vol 39 (06) ◽  
pp. 1173-1191 ◽  
Author(s):  
Po-Shan Wu ◽  
Shu-Ju Wu ◽  
Ya-Hui Tsai ◽  
Yun-Ho Lin ◽  
Jane C.-J. Chao
Keyword(s):  
Liver Fibrosis ◽  
Liver Injury ◽  
Transforming Growth Factor ◽  
Normal Diet ◽  
Hot Water ◽  
Herbal Extract ◽  
Liver Inflammation ◽  
Rehmannia Glutinosa ◽  
Sprague Dawley ◽  
Lycium Barbarum

Polysaccharide-rich Lycium barbarum and Rehmannia glutinosa have been considered to have immune-modulating activity. This study investigated the effects of water extracted Lycium barbarum and Rehmannia glutinosa (HE) on carbon tetrachloride ( CCl4 )-induced liver injury in rats. Male Sprague-Dawley rats were randomly divided into: normal diet + peritoneal injection of olive oil (control), normal diet + CCl4 injection ( CCl4 ), 1 × HE (0.05% HE for each) + CCl4 (1 × HE), and 3 × HE (0.15% HE for each) + CCl4 (3 × HE) groups. Rats were injected with 40% CCl4 at a dose of 0.75 ml/kg body weight once a week for seven weeks, one week after herbal extract treatment. After eight week herbal extract treatment, pathohistological examination showed that both 1× and 3 × HE treatments diminished necrotic hepatocytes, chemoattraction of inflammatory cells, and liver fibrosis. Both 1× and 3 × HE treatments decreased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, and reduced hepatic levels of pro-inflammatory cytokines — tumor necrosis factor-α and interleukin-1β — compared to CCl4 treatment alone. The 1 × HE treatment increased hepatic anti-inflammatory cytokine IL-10 levels. Both the 1× and 3 × HE treatments suppressed liver fibrosis biomarkers — transforming growth factor-β1 and hydroxyproline. Therefore, treatment with water extracted Lycium barbarum and Rehmannia glutinosa (0.05% and 0.15% for each) for eight weeks protects against necrotic damage, indicated by decreases in plasma ALT and AST activities, and suppresses liver fibrosis by down-regulation of liver inflammation in rats with CCl4-induced liver injury.

scholarly journals The Potential Protective Effect of Oligoribonucleotides-d-Mannitol Complexes against Thioacetamide-Induced Hepatotoxicity in Mice

2018 ◽  
Vol 11 (3) ◽  
pp. 77 ◽  
Author(s):  
Tetiana Marchyshak ◽  
Tetiana Yakovenko ◽  
Igor Shmarakov ◽  
Zenoviy Tkachuk
Keyword(s):  
Liver Injury ◽  
Protective Effect ◽  
Transforming Growth Factor ◽  
Elevated Serum ◽  
Transforming Growth Factor Β1 ◽  
Hepatoprotective Activity ◽  
Protein Carbonyl ◽  
Glutathione S Transferase ◽  
Sh Group ◽  
Factor Α

This study investigated the potential hepatoprotective effect of oligoribonucleotides-d-mannitol complexes (ORNs-d-M) against thioacetamide (TAA)-induced hepatotoxicity in mice. The hepatoprotective activity of ORNs-d-M was evaluated in thioacetamide (TAA)-treated C57BL/6J. Results indicate that treatment with ORNs-d-M displayed a protective effect at the TAA-induced liver injury. Treatment with ORNs-d-M, starting at 0 h after the administration of TAA, decreased TAA-elevated serum alanine aminotransferase (ALT) and γ-glutamyl transpeptidase (GGT). Activities of glutathione S-transferase (GST) and glutathione peroxidase (GPx), and levels of glutathione (GSH), were enhanced with ORNs-d-M administration, while the hepatic oxidative biomarkers (TBA-reactive substances, protein carbonyl derivatives, protein-SH group) and myeloperoxidase (MPO) activity were reduced. Furthermore, genetic analysis has shown that the ORNs-d-M decreases the expression of mRNA pro-inflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6), profibrogenic cytokine-transforming growth factor β1 (TGF-β1), as well as the principal protein of the extracellular matrix—collagen I. The present study demonstrates that ORNs-d-M exerts a protective effect against TAA-induced liver injury, which may be associated with its anti-inflammatory effects, inhibition of overexpression of mRNA cytokines, and direct effects on the metabolism of the toxin.

Liver fibrosis: a balance of ACEs?

2007 ◽  
Vol 113 (3) ◽  
pp. 109-118 ◽  
Author(s):  
Fiona J. Warner ◽  
John S. Lubel ◽  
Geoffrey W. McCaughan ◽  
Peter W. Angus
Keyword(s):  
Angiotensin Ii ◽  
Growth Factor ◽  
Liver Fibrosis ◽  
Liver Injury ◽  
Angiotensin Converting Enzyme ◽  
Transforming Growth Factor ◽  
Tissue Growth ◽  
Chronic Liver ◽  
Converting Enzyme ◽  
Chronic Liver Injury

There is an increasing body of evidence to suggest that the RAS (renin–angiotensin system) contributes to tissue injury and fibrosis in chronic liver disease. A number of studies have shown that components of a local hepatic RAS are up-regulated in fibrotic livers of humans and in experimental animal models. Angiotensin II, the main physiological effector molecule of this system, mediates liver fibrosis by stimulating fibroblast proliferation (myofibroblast and hepatic stellate cells), infiltration of inflammatory cells, and the release of inflammatory cytokines and growth factors such as TGF (transforming growth factor)-β1, IL (interleukin)-1β, MCP (monocyte chemoattractant protein)-1 and connective tissue growth factor. Furthermore, blockade of the RAS by ACE (angiotensin-converting enzyme) inhibitors and angiotensin type 1 receptor antagonists significantly attenuate liver fibrosis in experimental models of chronic liver injury. In 2000 ACE2 (angiotensin-converting enzyme 2), a human homologue of ACE, was identified. ACE2 efficiently degrades angiotensin II to angiotensin-(1–7), a peptide which has recently been shown to have both vasodilatory and tissue protective effects. This suggests that ACE2 and its products may be part of an alternate enzymatic pathway in the RAS, which counterbalances the generation and actions of angiotensin II, the ACE2–angiotensin-(1–7)–Mas axis. This review focuses on the potential roles of the RAS, angiotensin II and ACE2 in chronic liver injury and fibrogenesis.

scholarly journals Deletion of Wntless in myeloid cells exacerbates liver fibrosis and the ductular reaction in chronic liver injury

2015 ◽  
Vol 8 (1) ◽  
Author(s):  
Katharine M. Irvine ◽  
Andrew D. Clouston ◽  
Victoria L. Gadd ◽  
Gregory C. Miller ◽  
Weng-Yew Wong ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Liver Injury ◽  
Myeloid Cells ◽  
Chronic Liver ◽  
Chronic Liver Injury ◽  
Ductular Reaction

Suppression of transforming growth factor-β results in upregulation of transcription of regeneration factors after chronic liver injury

2004 ◽  
Vol 41 (6) ◽  
pp. 974-982 ◽  
Author(s):  
Toru Nakamura ◽  
Takato Ueno ◽  
Masaharu Sakamoto ◽  
Ryuichiro Sakata ◽  
Takuji Torimura ◽  
...  
Keyword(s):  
Growth Factor ◽  
Liver Injury ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Chronic Liver ◽  
Chronic Liver Injury

scholarly journals Eritoran Attenuates Hepatic Inflammation and Fibrosis in Mice with Chronic Liver Injury

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1562
Author(s):  
Yun-Cheng Hsieh ◽  
Kuei-Chuan Lee ◽  
Pei-Shan Wu ◽  
Teh-Ia Huo ◽  
Yi-Hsiang Huang ◽  
...  
Keyword(s):  
Liver Injury ◽  
Fast Food ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Chronic Liver ◽  
Therapeutic Effects ◽  
Hepatic Inflammation ◽  
Chronic Liver Injury ◽  
Tlr4 Signaling ◽  
Primary Mouse

Toll-like receptor 4 (TLR4) signaling plays a key role in liver inflammation and fibrosis. The therapeutic effects of eritoran, a TLR4 antagonist, in mice with chronic liver injury remained unclear. C57BL/6 mice were fed a fast-food diet (FFD) or treated with carbon tetrachloride (CCl4) to induce chronic liver injury. Eritoran (10 mg/kg) or a vehicle was randomly intraperitoneally administered to the FFD-fed mice and the CCl4-injured mice. Primary mouse liver cells were cultured with lipopolysaccharide (LPS) or eritoran. In both FFD and CCl4 mouse models, eritoran significantly reduced serum ALT levels and decreased hepatic inflammatory cell infiltration without altering hepatic steatosis. Additionally, eritoran attenuated liver fibrosis by decreasing hepatic stellate cells (HSCs) activation and the abundance of α-smooth muscle actin and transforming growth factor-β1. Hepatic TLR4 downstream signaling including MyD88 expression, NF-κB p65 nuclear translocation, p38 and JNK phosphorylation were successfully inhibited by eritoran. In the in vitro study, LPS-induced nuclear translocation of NF-κB in primary HSCs and Kupffer cells was significantly suppressed by eritoran. In conclusion, eritoran attenuated hepatic inflammation and fibrosis by inhibition of the TLR4 signaling pathway in mice with chronic liver injury. Eritoran may serve as a potential drug for chronic liver disease.

Novel Drivers of the Inflammatory Response in Liver Injury and Fibrosis

2019 ◽  
Vol 39 (03) ◽  
pp. 275-282 ◽  
Author(s):  
Alexander Wree ◽  
Theresa Maria Holtmann ◽  
Maria Eugenia Inzaugarat ◽  
Ariel E. Feldstein
Keyword(s):  
Cell Death ◽  
Liver Injury ◽  
Inflammatory Response ◽  
Liver Damage ◽  
Chronic Liver ◽  
Liver Inflammation ◽  
Chronic Liver Damage ◽  
Recent Developments

AbstractHepatocyte demise as well as signals released by stressed hepatocytes have been now recognized as important triggers of liver inflammation. While traditional concepts classically viewed hepatocyte cell death to occur by either a nonlytic, noninflammatory form (apoptosis), or lytic, proinflammatory nonregulated cell death (necrosis), recent studies have provided evidence for additional mechanisms that can contribute to both acute and chronic liver damage. Two novel forms of cell death, pyroptosis and necroptosis, are of particular importance as they are highly regulated and intrinsically proinflammatory. Additionally, stressed hepatocytes may also release signals to attract and activate monocytes into proinflammatory macrophages. In this review, the authors discuss recent developments supporting the role of novel triggers of liver inflammation in various forms of liver injury and their potential translational implications.

Sign in / Sign up

Export Citation Format

Share Document