Advances in gene therapy of liver cirrhosis: a review.

Abstract

Liver fibrosis or cirrhosis is a common progressively pathological lesion of chronic liver diseases in response to various liver-damaging factors. The main mechanisms of fibrotic or cirrhotic initiation and progression at the level of cellular and molecular events have been elucidated in the past two decades[1,2]. Various causes, including hepatitis virus infections, toxification, ischemia, congestion, parasites infection, abnormal cooper or iron load, etc, result in chronic inflammation and/or wound healing responses, of which the main characteristics manifest in the absolute increase of the excessive extracellular martrix (ECM) synthesis and the relative decrease of them, leading to ECM deposit. With the stimulation of inflammation or toxins, activated hepatic stellate cells(Ito cells), injuried or regenerated hepatocytes, Kupffer cells, sinusoidal cells and natural killer (NK) cells produce certain cytokines or immunoreactive factors, which exert various biological effects on their respective target cells or organs in an autocrine or paracrine manner. These consist of the cellular basis of hepatic fibrosis advances[3,4]. It is the vital molecular event in fibrosis progression that activated hepatic stellate cell exocrine ECM components and fibrosis-implementing factors, for example, the transforming growth factor β (TGF-β), which is considered the key cytokine to accelerate cirrhotic procession[5,6]. Various factors participate in fibrosis or cirrhosis formation. They could be simply divided into the fibrosis-implementing factors, such as TGF-β, platelet-derived growth factor (PDGF), epithelial growth factor (EGF), and antifibrotic factors, such as interferon γ and interleukin-10. These cytokines play important and unique roles in the interactive complicated network. Excessive ECM deposit, disappearance of sinusoidal endothelial fenestra and subsequent capillary vascularization cause the dysfunction of hepatocytes. The unblocked progressively pathological lesions with inevitably result in, lobular reconstruction, pseudolobule formation and nodular regeneration. With the elucidation of vital cellular and molecular events, gene delivery strategies for treatment of liver fibrosis or cirrhosis emerge on the basis of gene manipulations. Our interest focuses on the recent advances of gene therapy for liver fibrosis or cirrhosis. Effective antifibrotic treatments, including medicinal or gene therapy, should satisfy several essential criteria. First, any therapy should have a sound biological basis. Additionally, the pharmacologically active drugs or compounds should reach or reside in the liver at a high concentration and have little side effect outside the liver. Specific targeting to hepatic stellate cells were preferentially chosen. Finally, in the ideal case, a therapeutic agent should keep the regional target environment for a relatively long period[7].