Fibrogenic effect of oxidative stress on rat hepatic stellate cells

Abstract

Oxidative stress is associated with liver fibrosis and with hepatic stellate cell (HSC) activation in vivo. However, it remains controversial whether oxidative stress contributes to HSC activation either directly or through a paracrine stimulation by damaged hepatocytes. A medium containing products released from cells undergoing oxidative stress was obtained after incubation of hepatocytes with (HCM/Fe) or without (HCM) 0.1 mmol/L ferric nitrilotriacetate complex (FeNTA). Exposure of HSC to HCM/Fe for 24 hours significantly increased the number of proliferating HSC compared with HCM and to controls at all dilutions tested. The simultaneous coincubation of HSC with HCM/Fe and desferrioxamine (50 micromol/L) did not reduce the observed increase in cell proliferation, thus excluding a role for eventually contaminating iron in HCM/Fe. HCM/Fe induced also a significant increase in collagen type I accumulation in HSC culture media. To study the cellular mechanism underlying HCM/Fe effects, we evaluated the activity of the Na+/H+ exchanger, which plays a role in regulating HSC proliferation. The incubation of HSC for 24 hours with HCM/Fe significantly increased baseline intracellular pH (pHi) and Na+/H+ exchanger activity, indicating a plausible role of this antiport in mediating cell response. In conclusion, hepatocytes undergoing oxidative stress release factors which are fibrogenic for HSC, thereby, confirming what has been only hypothesized in vivo. In addition, HSC proliferation is associated with changes in the Na+/H+ exchanger activity, thus providing a useful target for the evaluation of inhibitors of this pathway for the treatment of hepatic fibrosis.

NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis

“…The most accepted theory is that ROS derived from damaged hepatocytes, activated Kupffer cells, and infiltrating neutrophils stimulate HSCs in a paracrine manner (23,54,55). Exogenous ROS would activate redox-sensitive intracellular pathways in HSCs to increase collagen synthesis (14,16). Here, we present evidence that HSCs are also an important source of ROS in liver fibrosis.…”

“…Increased ROS and resulting oxidative stress are commonly detected in livers from patients with alcohol abuse, hepatitis C virus infection, iron overload, or chronic cholestasis, as well as in most types of experimental liver fibrogenesis (14)(15)(16)(17)(18). Moreover, antioxidant agents attenuate hepatic fibrosis in rodents and may exert beneficial effects in patients with chronic liver diseases (19,20).…”

Ameliorative effect of supplementation with l-glutamine on oxidative stress, DNA damage, cell viability and hepatotoxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat hepatocyte cultures

“…Forgacs et al (2010) suggested that TCDD altered the expression of genes associated with mitochondrial function including complexes I (NADH dehydrogenase), III (cytochrome c reductase), IV (cytochrome c oxidase), and V (ATP synthase) which might contribute to TCDD-elicited mitochondrial toxicity. ROS produced by activated macrophages and a consequent rise of lipid peroxidation caused direct activation of hepatic cells, leading to liver lesions (Svegliati et al 1998). In our study, the level of TOS also significantly increased after treatment by TCDD compared to control cells.…”

A standardized extract from Paeonia lactiflora and Astragalus membranaceus attenuates liver fibrosis induced by porcine serum in rats

“…Several lines of evidence have suggested the important role of oxidative stress in the etiopathogenesis of liver fibrosis (7). Furthermore, oxidative stress aggravates liver fibrosis via HSCs activation, and lipid peroxidation stimulates transcription of the collagen gene (8).…”