Resveratrol prevents fibrosis, NF‐κB activation and TGF‐β increases induced by chronic CCl₄ treatment in rats

Abstract

Resveratrol is a nonflavonoid polyphenol with antioxidant, anticancer and antiinflammatory properties. Moreover, it has been reported that this compound inhibits NF-kappaB, which regulates the transcription of several genes including cytokines such as the profibrogenic TGF-beta. The aim of this work was to evaluate the pharmacological effects of resveratrol on CCl(4)-induced cirrhosis in the rat. Four groups were formed: the control group that received the vehicles only; the CCl(4) group that received the toxin (0.4 g kg(-1), i.p., three times a week, for 8 weeks); the CCl(4) plus resveratrol (10 mg kg(-1), daily) group; and the resveratrol alone group. Alanine aminotransferase, alkaline phosphatase and bilirubins were increased by CCl(4), but resveratrol afforded some degree of protection. Glycogen was decreased markedly by CCl(4) and resveratrol prevented almost completely this effect. No antioxidant effect of resveratrol was observed. One of the most prominent effects was on fibrosis which increased near 5-fold (hydroxyproline) in the CCl(4) group; resveratrol preserved the content of collagen. These results were corroborated by histopathology. To elucidate the antifibrogenic mechanism of resveratrol, the activation of NF-kappaB and the production of TGF-beta were measured; in both cases CCl(4) increased them and resveratrol abolished them; however, changes in NF-kappaB were modest and did not reach statistical significance, while the increase in TGF-beta was about three fold and resveratrol decreased it under control values. Together, the present results indicate that resveratrol possesses a strong antifibrogenic effect at least in the CCl(4) model of cirrhosis. Moreover, the action mechanism is probably associated with its ability to reduce NF-kappaB activation and TGF-beta content.

NF‐κB in liver diseases: a target for drug therapy

“…Therefore, we sought to investigate if resveratrol was capable of preventing CCl 4 -induced liver cirrhosis. We observed that CCl 4 produced fibrosis, activation of NF-κB and production of TGF-β; resveratrol completely prevented fibrosis and this effect was accompanied by prevention of the translocation of NF-κB to the nucleus and down-regulation of the profibrotic cytokine TGF-β (Chávez et al, 2008).…”

The melatonin immunomodulatory actions in radiotherapy

“…So, a decrease in TGF-β level after exposure to ionizing radiation can help the amelioration of oxidative damage (Michaeloudes et al 2011). Its seems that the inhibition of TGF-β gene expression is one important pathway for the induction of antioxidant enzymes, and a decrease of oxidative damage and subsequent consequences (Chávez et al 2008). …”

“…The long-term upregulation of NF-κB, inflammatory cytokines and chemokines, adhesion molecules such as VCAM and ICAM-1, immune cell infiltration, etc. are associated with different pathological damages (Michaeloudes et al 2011;Chávez et al 2008;Wu and Miyamoto 2007;Rayet and Gelinas 1999). The lung, heart, brain, liver, intestine, kidneys, spleen, and colon are the most important tissues affected by irreversible pathological changes.…”

Targeting extracellular matrix remodeling in disease: Could resveratrol be a potential candidate?

“…60 Similar observations were made on animals models of hepatic fibrosis, 22,23 enterocolitis, 25 allergic airways disease 30 and in MCF-7/TR cells. 61 TGF-b is also a potent inducer of the differentiation of fibroblasts to myofibroblasts, which are an important source of ECM proteins.…”

“…20 Resveratrol (2.5 mg/kg) was also shown to alleviate cardiac fibrosis and functional abnormalities in spontaneously hypertensive rats. 21 Similar antifibrotic effects of resveratrol have been observed in liver, 22,23 33 SPARC is a glycoprotein that has counter-adhesive properties. 34 It also takes part in proteolytic pathways by increasing the expression of collagenase and MMP-9, and activating MMP-2.…”