Partial regression of experimental decompensate cirrhosis after causal agent discontinuation. Vascular characterization and possible therapeutic targets to potentiate regression

Background: Hepatic fibrosis, considered irreversible for many years, is one of the main factors involved in cirrhotic portal hypertension. Experimental and clinical evidence showed that fibrosis can revert. The aim of our... [ view full abstract ]

Background: Hepatic fibrosis, considered irreversible for many years, is one of the main factors involved in cirrhotic portal hypertension. Experimental and clinical evidence showed that fibrosis can revert. The aim of our study was to evaluate, in two cirrhotic experimental models, hepatic and systemic hemodynamic, liver fibrosis, hepatic stellate cell (HSC) phenotype and liver function after causal agent discontinuation. Methods: Cirrhotic rats induced by CCl₄ inhalation or TAA injection were studied just after insult discontinuation (CCl4-CH, TAA-CH; n=10) or 8 weeks later (CCL4-Regression, TAA-Regression; n=10). 12 healthy rats were used as controls. Portal pressure (PP), mean arterial pressure (MAP), indocianine green clearance (ICGc), transaminases, hepatic fibrosis, HSC phenotype, inflammation, glucose tolerance and adipose tissue content were measured. Results: Regression rats had lower PP than CH rats (CCl4:-25%, TAA:-22%) without achieving normalization, a moderate increase in ICGc and reduction/normalization in transaminases levels, without changes in MAP. Hepatic fibrosis was markedly decreased in Regression rats (CCl4:-40%), without achieving normalization. Expression of HSC activation (α-SMA), proliferation (PDGFRβ) and contractibility (Moesin) markers was decreased in Regression rats (CCl4: -78%,-60%,-38%; TAA:-85%,-54%). Regression animals showed greater hepatic inflammation (CCl4:+125%), increased body weight (CCl4:+21%, TAA:+41%), worse glucose tolerance (CCl4:+137%, TAA:+200%) and increased adipose tissue content. Conclusions: Causal agent discontinuation in cirrhotic rats markedly reduces hepatic fibrosis and PP, probably due to an amelioration in HSC phenotype. This is associated with improved liver function. Increased inflammation and worsening in metabolic parameters in Regression rats could delay/interfere in the regression process representing possible therapeutic targets.