Novel carbon-based nanoscale therapeutics for the modulation of macrophages in liver inflammation, fibrosis, and regeneration

[eng] INTRODUCTION: Chronic liver disease (CHD) is the consequence of prolonged liver damage and is characterized by a process of inflammation and fibrosis in the liver, which causes about 2 million deaths per year. It can take several years for CHD to progress from early fibrosis to cirrhosis, ultimately leading to liver failure and death. There are currently no curative therapies for cirrhosis beyond liver transplantation and, therefore, the development of new therapeutic strategies is necessary. Hepatic macrophages play essential roles in all stages of CHD, both in the initiation and progression of the inflammatory response and in the development of fibrosis. The microenvironment of chronic liver inflammation perpetuates the pro-inflammatory and profibrogenic activity of hepatic macrophages. However, macrophages are also essential in the processes that regulate the resolution of fibrosis, both by promoting an anti-inflammatory and regenerative response, and by secreting enzymes that remodel the extracellular matrix. Peroxisome proliferator-activated receptor gamma (PPARγ) and E3 ubiquitin ligase RNF41 have been associated with anti-inflammatory polarization of macrophages. HYPOTHESIS: Selective activation of the anti-inflammatory pathways PPARγ and RNF41 in hepatic macrophages by macrophage-selective carbon nanoparticles may induce a pro-resolutive phenotype in these immune cells that promotes a reduction in inflammation and fibrosis, and stimulates liver regeneration in CHD.