Auranofin prevents liver fibrosis by system Xc-mediated inhibition of NLRP3 inflammasome

Demand for a cure of liver fibrosis is rising with its increasing morbidity and mortality. Therefore, it is an urgent issue to investigate its therapeutic candidates. Liver fibrosis progresses following ‘multi-hit’ processes involving hepatic stellate cells, macrophages, and hepatocytes. The NOD-like receptor protein 3 (NLRP3) inflammasome is emerging as a therapeutic target in liver fibrosis. Previous studies showed that the anti-rheumatic agent auranofin inhibits the NLRP3 inflammasome; thus, this study evaluates the antifibrotic effect of auranofin in vivo and explores the underlying molecular mechanism. The antifibrotic effect of auranofin is assessed in thioacetamide- and carbon tetrachloride-induced liver fibrosis models. Moreover, hepatic stellate cell (HSC), bone marrow-derived macrophage (BMDM), kupffer cell, and hepatocyte are used to examine the underlying mechanism of auranofin. Auranofin potently inhibits activation of the NLRP3 inflammasome in BMDM and kupffer cell. It also reduces the migration of HSC. The underlying molecular mechanism was inhibition of cystine-glutamate antiporter, system Xc. Auranofin inhibits system Xc activity and instantly induced oxidative burst, which mediated inhibition of the NLRP3 inflammasome in macrophages and HSCs. Therefore, to the best of our knowledge, we propose the use of auranofin as an anti-liver fibrotic agent.

Experimental evaluation of antifibrotic effect of pirfenidone in dacryocystorhinostomy

One of the main reasons of failure in surgical treatment of dacryocystitis is cicatrical closure of the ostium. Considering controversial data on efficacy and safety of antifibrotic methods currently employed during dacrycystorhinostomy, searching for new ways to prevent fibrosis remains one of the main directions of research in dacryology. Pirfenidone, a small-molecule agent, was demonstrated to have a pronounced antifibrotic effect in experiments both in the eye and various other organs. Aim. To experimentally evaluate the antifibrotic effect of pirfenidone in dacryocystorhinostomy. Material and methods. 18 shinshilla rabbits were used in the current study. Subjects underwent modified dacryocystorhinostomy followed by 0,15 or 0,3 mg/ml pirfenidone injection circumostially. Animals were divided into groups based on pirfenidone dosage used. Control group animals received no injection. Rabbits were killed on the 7th (6 rabbits), 14th (6 rabbits) and 28th day (6 rabbits) following surgery. Ostium patency was evaluated using lacrimal irrigation and morphologically once the animal was killed. Ostium tissue samples were analyzed histologically. Results. Cicatrical closure of the ostium was observed in 4 subjects from control group on days 14 and 28 following surgery. The most pronounced fibrotic changes were also noted in tissue specimens obtained from these rabbits. Fibrotic changes in groups 1 and 2 were notably less severe than in control group. Conclusion. Data obtained in the current study evidences high antifibrotic efficacy of pirfenidone. This necessitates further research of pirfenidone use in dacryocystorhinostomy. Key words: dacryocystorhinostomy, ostium closure, dacryostoma, pirfenidone, antifibrotic therapy.