Fibrosis is an important wound-healing process in injured tissues, but excessive fibrosis is often observed in patients with chronic inflammation. Although oncostatin M (OSM) has been reported to play crucial roles for recovery from acute liver injury by inducing tissue inhibitor of metalloproteinase 1 (Timp1) expression, the role of OSM in chronic liver injury (CLI) is yet to be elucidated. Here, we show that OSM exerts powerful fibrogenic activity by regulating macrophage activation during CLI. Genetic ablation of the OSM gene alleviated fibrosis in a mouse model of chronic hepatitis. Conversely , continuous expression of OSM in a normal mouse liver by hydrodynamic tail vein injection (HTVi) induced severe fibrosis without necrotic damage of hepatocytes, indicating that OSM is involved in the fundamental process of liver fibrosis (LF) after hepatitis. In a primary coculture of hepatic stellate cells (HSCs) and hepatic macrophages (HMs), OSM up-regulated the expression of fibrogenic factors, such as transforming growth factor-b and platelet-derived growth factor in HMs, while inducing Timp1 expression in HSCs, suggesting the synergistic roles of OSM for collagen deposition in the liver. Fluorescence-activated cell sorting analyses using OSM-HTVi and OSM knockout mice have revealed that bone-marrow-derived monocyte/macrophage are responsive to OSM for profibrotic activation. Furthermore, depletion or blocking of HMs by administration of clodronate liposome or chemokine inhibitor prevented OSM-induced fibrosis. Conclusion: OSM plays a crucial role in LF by coordinating the phenotypic change of HMs and HSCs. Our data suggest that OSM is a promising therapeutic target for LF. (HEPATOLOGY 2018;67:296-312). P atients with advanced liver fibrosis (LF) have poor prognosis because of impaired liver functions , adverse symptoms such as gastroesopha-geal varices and ascites, and hepatocellular carcinoma (HCC). (1,2) In the injured liver, activated hepatic stellate cells (HSCs) are the main producer of extracel-lular matrix (ECM), including type1 collagen, whereas the ECM can be degraded by various proteinases such as matrix metalloproteinases (MMPs). The balance between ECM production and degradation is
Patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) develop more rapid fibrosis than those infected with HCV only. In HIV/HCV‐coinfected patients, fibrosis progression correlates with HIV RNA levels, suggesting a direct role of HIV in liver fibrogenesis. Chemokine (C‐C motif) receptor 5 (CCR5) and cysteine‐X‐cysteine receptor 4 (CXCR4), the two major coreceptors required for HIV entry into cells, are expressed on activated hepatic stellate cells (HSCs), the principle fibrogenic cell type in the liver. We therefore examined whether HIV can infect HSCs, explored the potential mechanisms of viral entry, and assessed the impact of infection as reflected by the ability of HSCs to transfer virus to T lymphocytes and elicit a proinflammatory and profibrogenic response. We report that the laboratory‐adapted viruses HIV‐IIIB (CXCR4‐tropic or X4) and HIV‐BaL (CCR5‐tropic or R5) and primary HIV isolates can infect both a human stellate cell line, LX‐2, and primary human HSCs. HIV entry and gene expression in HSCs was confirmed using HIV–green fluorescent protein (GFP) expression viral constructs in the presence or absence of the reverse‐transcriptase inhibitor azidothymidine. CD4 expression on a subset of primary HSCs was demonstrated using fluorescence‐activated cell sorting and immunofluorescence staining. Blocking experiments in the presence of anti‐CD4, anti‐CXCR4, and anti‐CCR5 revealed that HIV entry into HSCs is predominantly CD4/chemokine coreceptor–independent. HIV infection promoted HSC collagen I expression and secretion of the proinflammatory cytokine monocyte chemoattractant protein‐1. Furthermore, infected LX‐2 cells were capable of transferring GFP‐expressing virus to T lymphocytes in a coculture system. Conclusion: Taken together, our results suggest a potential role of HIV in liver fibrosis/inflammation mediated through effects on HSCs. The role of early highly active antiretroviral therapy initiation in patients with HIV/HCV coinfection warrants further investigation. (HEPATOLOGY 2010)
Chemokines are small molecular weight proteins primarily known to drive migration of immune cell populations. In both acute and chronic liver injury, hepatic chemokine expression is induced resulting in inflammatory cell infiltration, angiogenesis, and cell activation and survival. During acute injury, massive parenchymal cell death due to apoptosis and/or necrosis leads to chemokine production by hepatocytes, cholangiocytes, Kupffer cells, hepatic stellate cells, and sinusoidal endothelial cells. The specific chemokine profile expressed during injury is dependent on both the type and course of injury. Hepatotoxicity by acetaminophen for example leads to cellular necrosis and activation of Toll-like receptors while the inciting insult in ischemia reperfusion injury produces reactive oxygen species and subsequent production of pro-inflammatory chemokines. Chemokine expression by these cells generates a chemoattractant gradient promoting infiltration by monocytes/macrophages, NK cells, NKT cells, neutrophils, B cells, and T cells whose activity are highly regulated by the specific chemokine profiles within the liver. Additionally, resident hepatic cells express chemokine receptors both in the normal and injured liver. While the role of these receptors in normal liver has not been well described, during injury, receptor up-regulation, and chemokine engagement leads to cellular survival, proliferation, apoptosis, fibrogenesis, and expression of additional chemokines and growth factors. Hepatic-derived chemokines can therefore function in both paracrine and autocrine fashions further expanding their role in liver disease. More recently it has been appreciated that chemokines can have diverging effects depending on their temporal expression pattern and the type of injury. A better understanding of chemokine/chemokine receptor axes will therefore pave the way for development of novel targeted therapies for the treatment of liver disease.
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