EXTRACELLULAR-MATRIX REMODELING AT THE EARLY STAGES OF LIVER-REGENERATION IN THE RAT

Previous studies have shown that activity of urokinase-type plasminoge n activator (u-PA) increases very rapidly (within 1 minute) after part ial hepatectomy, In view of the well-recognized roles of u-PA as one o f the major initiators of the matrix proteolysis cascade and as an act ivator of plasminogen and hepatocyte growth factor (HGF), we studied m atrix degradation in liver shortly after partial hepatectomy. The acti vation of plasminogen to plasmin following partial hepatectomy was exa mined by Western blot analysis, and a small increase in plasmin at app roximately 15 minutes followed by a large elevation at approximately 3 to 6 hours after partial hepatectomy was detected. In addition, we fo und that fibrinogen, the major substrate for plasmin, begins to be deg raded at approximately 15 to 30 minutes following partial hepatectomy, Using immunohistochemical staining, we detected that the distribution of fibrinogen in normal liver is localized to the perisinusoidal spac e surrounding the periportal region, A decreased distribution of fibri nogen in the periportal region was found by 15 minutes and continued t hrough 24 hours following partial hepatectomy. In addition, the distri bution of fibronectin in normal liver was localized to the perisinusoi dal space surrounding the periportal and the pericentral regions, A st rikingly decreased distribution of fibronectin in the periportal regio n was found at 5 minutes after partial hepatectomy, Furthermore, we ob served that the protein levels of laminin, entactin, and fibronectin i n an extracellular matrix: (ECM)-enriched preparation decreased shortl y after partial hepatectomy, and were restored later. No changes were observed with either vitronectin or the integrin chain alpha(v). In co ntrast to the protein levels of the ECM components, the messenger RNA (mRNA) levels of fibronectin, integrin chain beta(1), and integrin cha in alpha(v), gradually increased over 18 hours and then decreased ther eafter. Taken together, these results suggest that rapid reorganizatio n of selected ECM components are important for hepatocyte proliferatio n at the early stages of liver regeneration.