The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C1 1The authors thank Wanda Delogu and Nadia Navari for skillful technical help, Dr. Roberto G. Romanelli for help in collecting liver biopsy specimens, and Dr. Mario Strazzabosco (Ospedali Riuniti di Bergamo, Italy) for providing part of the tissue samples with primary biliary cirrhosis.

Bonacchi, Andrea; Petrai, Ilaria; DeFranco, Raffaella; Lazzeri, Elena; Annunziato, Francesco; Efsen, Eva; Cosmi, Lorenzo; Romagnani, Paola; Milani, Stefano; Failli, Paola; Batignani, Giacomo; Liotta, Francesco; Laffi, Giacomo; Pinzani, Massimo; Geñtilini, Paolo; Marra, Fabio

doi:10.1016/s0016-5085(03)01194-6

Cited by 130 publications

(28 citation statements)

References 42 publications

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“…Chemokines and their receptors are up-modulated in the injured liver [51]. In line with this, we observed that Tan IIA and Sal B suppressed LPS-induced mRNA expressions of CCL2, CCL3, and CCL5 genes.…”

Section: Discussionsupporting

confidence: 85%

Inhibitory Effect of Tanshinone IIA on Rat Hepatic Stellate Cells

Liu¹,

Huang

2014

PLoS ONE

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BackgroundAnti-inflammation via inhibition of NF-κB pathways in hepatic stellate cells (HSCs) is one therapeutic approach to hepatic fibrosis. Tanshinone IIA (C19H18O3, Tan IIA) is a lipophilic diterpene isolated from Salvia miltiorrhiza Bunge, with reported anti-inflammatory activity. We tested whether Tan IIA could inhibit HSC activation.Materials and MethodsThe cell line of rat hepatic stellate cells (HSC-T6) was stimulated with lipopolysaccharide (LPS) (100 ng/ml). Cytotoxicity was assessed by MTT assay. HSC-T6 cells were pretreated with Tan IIA (1, 3 and 10 µM), then induced by LPS (100 ng/ml). NF-κB activity was evaluated by the luciferase reporter gene assay. Western blotting analysis was performed to measure NF-κB-p65, and phosphorylations of MAPKs (ERK, JNK, p38). Cell chemotaxis was assessed by both wound-healing assay and trans-well invasion assay. Quantitative real-time PCR was used to detect gene expression in HSC-T6 cells.ResultsAll concentrations of drugs showed no cytotoxicity against HSC-T6 cells. LPS stimulated NF-κB luciferase activities, nuclear translocation of NF-κB-p65, and phosphorylations of ERK, JNK and p38, all of which were suppressed by Tan IIA. In addition, Tan IIA significantly inhibited LPS-induced HSCs chemotaxis, in both wound-healing and trans-well invasion assays. Moreover, Tan IIA attenuated LPS-induced mRNA expressions of CCL2, CCL3, CCL5, IL-1β, TNF-α, IL-6, ICAM-1, iNOS, and α-SMA in HSC-T6 cells.ConclusionOur results demonstrated that Tan IIA decreased LPS-induced HSC activation.

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Section: Discussionsupporting

confidence: 85%

Inhibitory Effect of Tanshinone IIA on Rat Hepatic Stellate Cells

Liu¹,

Huang

2014

PLoS ONE

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“…Although the most prominent features of activation include enhanced extracellular matrix production, and the expression of smooth muscle α actin, activation is also associated with other important cellular phenotypes including enhanced proliferation, release of proinflammatory cytokines 29 , release of matrix degrading enzymes and their inhibitors, and recruitment and activation of other cell types such as hepatocellular cancer and cholangiocarcinoma cells 30, 31 and inflammatory cells 32 . When deisgning therapeutics focused on liver fibrogenesis, is important to emphasize that each of these features of activation (and fibrogenesis) represent a potential target for therapy.…”

Section: Fibrogenesis – Pathophysiologymentioning

confidence: 99%

Translating an Understanding of the Pathogenesis of Hepatic Fibrosis to Novel Therapies

Rockey

2013

Clinical Gastroenterology and Hepatology

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The response to injury is one of wound healing and fibrogenesis, which ultimately leads to fibrosis. The fibrogenic response to injury is a generalized one across virtually all organ systems. In the liver, the injury response, typically occuring over a prolonged period of time, leads to cirrhosis (although it should be pointed out that not all patients with liver injury develop cirrhosis). The fact that many different diseases result in cirrhosis suggests a common pathogenesis. The study of hepatic fibrogenesis over the past 2 decades has been remarkably active, leading to a considerable understanding of this process. It has been clearly demonstrated that the hepatic stellate cell is a central component in the fibrogenic process. It has also been recognized that other “effector” cells are important in the fibrogenic process, including resident fibroblasts, bone marrow derived cells, fibrocytes, and even perhaps cells derived from epithelial cells (i.e., through epithelial to mesenchymal transition or EMT). A key aspect of the biology of fibrogenesis is that the fibrogenic process is dynamic; thus, even advanced fibrosis (or cirrhosis) is reversible. Together, an understanding of the cellular basis for liver fibrogenesis, along with multiple aspects of the basic pathogenesis of fibrosis, have highlighted many exciting potential therapeutic opportunities. Thus, while the most effective “anti-fibrotic” therapy is treatment of the underlying disease, in situations in which this not possible, specific anti-fibrotic therapy is likely to not only become feasible, but will soon become a reality. The goal of this review is to highlight the mechanisms underlying fibrogenesis that may be translated into future anti-fibrotic therapies and to review the current state of clinical development.

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“…After hybridization, protected fragments were separated on a sequencing gel and autoradiographed, as previously described. 25 …”

Section: Rnase Protection Assaymentioning

confidence: 99%

Resistin as an Intrahepatic Cytokine

Bertolani

Sancho‐Bru

Failli

et al. 2006

The American Journal of Pathology

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134

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Obesity and insulin resistance accelerate the progression of fibrosis during chronic liver disease. Resistin antagonizes insulin action in rodents, but its role in humans is still controversial. The aims of this study were to investigate resistin expression in human liver and to evaluate whether resistin may affect the biology of activated human hepatic stellate cells (HSCs), key modulators of hepatic fibrogenesis. Resistin gene expression was low in normal human liver but was increased in conditions of severe fibrosis. Up-regulation of resistin during chronic liver damage was confirmed by immunohistochemistry. In a group of patients with alcoholic hepatitis, resistin expression correlated with inflammation and fibrosis, suggesting a possible action on HSCs. Exposure of cultured HSCs to recombinant resistin resulted in increased expression of the proinflammatory chemokines monocyte chemoattractant protein-1 and interleukin-8, through activation of nuclear factor (NF)-B. Resistin induced a rapid increase in intracellular calcium concentration , mainly through calcium release from intracellular inositol triphosphate-sensitive pools. The intracellular calcium chelator BAPTA-AM blocked resistin-induced NF-B activation and monocyte chemoattractant protein-1 expression. In conclusion, this study shows a role for resistin as an intrahepatic cytokine exerting proinflammatory actions in HSCs, via a Ca 2؉ /NF-B-dependent pathway and suggests involvement of this adipokine in the pathophysiology of liver fibrosis.

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Cited by 130 publications

References 42 publications

Inhibitory Effect of Tanshinone IIA on Rat Hepatic Stellate Cells

Inhibitory Effect of Tanshinone IIA on Rat Hepatic Stellate Cells

Translating an Understanding of the Pathogenesis of Hepatic Fibrosis to Novel Therapies

Resistin as an Intrahepatic Cytokine

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