Faculty Bibliography

Ductular reaction (DR) is observed in virtually all liver diseases in both humans and rodents. Depending on the injury, DR is confined within the periportal area or invades the parenchyma. On severe hepatocellular injury, invasive DR has been proposed to arise for supplying the liver with new hepatocytes. However, experimental data evidenced that DR contribution to hepatocyte repopulation is at the most modest, unless replicative capacity of hepatocytes is abrogated. Herein, we proposed that invasive DR could contribute to operating hepatobiliary junctions on hepatocellular injury. We used the choline-deficient ethionine-supplemented mouse model of hepatocellular injury and human liver samples to evaluate the hepatobiliary junctional role of the invasive form of DR. We showed that choline-deficient ethionine-supplemented-induced DR expanded as biliary epithelium into the lobule and established new junctions with the canaliculi. By contrast, no new ductular-canalicular junctions were observed in mouse models of biliary obstructive injury exhibiting noninvasive DR. Similarly, in humans, an increased number of hepatobiliary junctions were observed in hepatocellular diseases (viral, drug induced, or metabolic) in which DR invaded the lobule but not in biliary diseases (obstruction or cholangitis) in which DR was contained within the portal mesenchyme. In conclusion, our data in rodents and humans support that invasive DR plays a hepatobiliary junctional role to maintain structural continuity between hepatocytes and ducts in disorders affecting hepatocytes.

Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare vascular liver disease that has attained a new interest in recent years. It is characterized by clinical signs of portal hypertension in the absence of cirrhosis or severe fibrosis and any known cause of portal hypertension. Since much uncertainty exists about INCPH pathophysiology and no definite diagnostic tests are available, liver biopsy is an essential tool to achieve a definite diagnosis. Unfortunately, the histological diagnosis of INCPH is not always straightforward, since the characteristic lesions are unevenly distributed, vary greatly in their severity and are often very subtle, and not all are necessarily present in a single case. Furthermore, specifically for the characteristic portal vessel changes observed in INCPH, the terminology and definition is ambiguous, which adds complexity to the already complex clinical-pathological scenario. An international study group of liver pathologists and hepatologists pursued a consensus on nomenclature for the portal vascular lesions of INCPH. Such standardization may assist pathologists in the recognition of such lesions and will possibly facilitate further advancement in this field.

BACKGROUND & RATIONALE/OBJECTIVE:High-mobility group box-1 (HMGB1) is a damage-associated molecular pattern (DAMP) increased in response to liver injury. Since HMGB1 is a ligand for the receptor for advanced glycation end-products (RAGE), we hypothesized that induction of HMGB1 could participate in the pathogenesis of liver fibrosis via RAGE cell-specific signaling mechanisms. RESULTS:) and RAGE neutralization prevented liver fibrosis. Lastly, we identified that HMGB1 stimulated HSC migration and signaled via RAGE to upregulate Collagen type I expression by activating the pMEK1/2/pERK1/2/pcJun signaling pathway. CONCLUSION/CONCLUSIONS:hepatocyte and KC-derived HMGB1 participates in the pathogenesis of liver fibrosis by signaling via RAGE in HSC to activate the pMEK1/2/pERK1/2/pcJun pathway and increase Collagen type I deposition.