Electroporative α-MSH gene transfer attenuates thioacetamide-induced murine hepatic fibrosis by MMP and TIMP modulation

Abstract

Hepatic fibrosis represents a process of healing and scarring in response to chronic liver injury. a-Melanocyte-stimulating hormone (a-MSH) is a 13-amino-acid peptide with potent anti-inflammatory effects. We have previously demonstrated that a-MSH gene therapy protects against thioacetamide (TAA)-induced acute liver failure. Therefore, the aim of this study is to investigate whether a-MSH gene therapy possesses antihepatic fibrogenic effect. Liver fibrosis was induced by long-term TAA administration in mice. a-Melanocyte-stimulating hormone expression plasmid was delivered via electroporation after liver fibrosis was established. Our results showed that a-MSH gene therapy attenuated liver fibrosis in TAA-treated mice. Reverse transcription polymerase chain reaction revealed that a-MSH gene therapy attenuated the liver transforming growth factor-b1, collagen a1 and cell adhesion molecule mRNA upregulation. Following gene transfer, the expression of a-smooth muscle actin and cyclooxygenase-2 were both significantly attenuated. Further, a-MSH significantly increased matrix metalloproteinase (MMP), while tissue inhibitors of matrix metalloproteinase (TIMPs) were inactivated. In summary, a-MSH gene therapy reversed established liver fibrosis in mice and prevented the upregulated fibrogenic and pro-inflammatory gene responses after TAA administration. Its collagenolytic effect might be attributed to MMP and TIMP modulation. Hence, a-MSH gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use.

Differential Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Thioacetamide-Induced Chronic Liver Injury

“…TAA, a selective hepatotoxin, can induce acute and chronic hepatic injury (17-19). In the current study, we showed that TAA injection induced hepatomegaly, reduced weight gain, and produced abnormalities of serum hepatic enzymes, and a grossly cirrhotic liver.…”

The Melanocortin Agonist AP214 Exerts Anti-Inflammatory and Proresolving Properties

“…10 The ␣-MSH-derived C-terminal tripeptide KPV is anti-inflammatory in crystal-induced peritonitis 11 and in two models of inflammatory bowel disease. 12 New therapeutic strategies based on this line of research have also explored ␣-MSH gene therapy in a model of thioacetamide-induced hepatic fibrosis, 13 affording tissue protection, and the oral administration of recombinant Lactobacillus casei, which secretes ␣-MSH, which reduced body weight loss, survival, clinical score, and myeloperoxidase (MPO) activity in a model of ulcerative colitis. 14 In in vitro settings, MC agonists display anticytokine effects on macrophages 15 and can induce the development of cytotoxic CD8 ϩ T cells 16 and CD25 ϩ CD4 ϩ regulatory T cells.…”

Hypermethylation of the <i>N-Myc Downstream-Regulated Gene 2</i> Promoter in Peripheral Blood Mononuclear Cells is Associated with Liver Fibrosis in Chronic Hepatitis B

“…NDRG2 plays a major role in liver fibrosis in the following four aspects: 1. by suppressing the activation of HSCs (Yang et al 2011); 2. by regulating liver extracellular matrix degradation (Wang et al 2006;Yang et al 2011);3. by regulating the growth of liver cells (Yang et al 2010); and 4. through resistance to hypoxia stress damage (Corpechot et al 2002;Wang et al 2008). We found that both NDRG2 hypermethylation and down-regulated expression were correlated with liver fibrosis stages.…”

“…NDRG2 is a potential regulator of liver fibrosis and can regulate liver regeneration via the cell cycle and apoptosis (Hu et al 2004;Liu et al 2007;Shon et al 2009). Increased NDRG2 expression inhibits hepatic stellate cell (HSC) activation, promotes degradation of the extracellular matrix, and regulates regeneration of the liver (Wang et al 2006;Yang et al 2010;Yang et al 2011). HSCs play an important role during the development of liver fibrosis and are regulated by multiple pathways and factors, primarily through transforming growth factor (TGF)-β1/Smad signaling (Dooley et al 2001;Friedman 2004;Bataller and Brenner 2005;Inagaki and Okazaki 2007).…”