Sublobular veins as the main site of lymphocyte adhesion/transmigration and adhesion molecule expression in the porto-sinusoidal-hepatic venous system during concanavalin A-induced hepatitis in mice

Lymphocyte infiltration is a manifest feature of hepatitis. To reveal the m ain site and mechanism of lymphocyte adhesion/extravasation in the hepatic vasculature during inflammation, we morphometrically and histologically ana lyzed these events in relation to adhesion molecule expression using a muri ne model of T-cell mediated hepatitis induced by concanavalin A (Con A). Al though lymphocyte adhesion was restricted to the sinusoids in untreated mic e, it increased in all the segments of porto-sinusoidal-hepatic venous syst em 8 hours after Con A injection; the number of adhering lymphocytes per un it vascular circumference was the largest in the sublobular veins, relative ly large in the central veins and small hepatic veins, and relatively small in the sinusoids and negligible in the portal veins. At 20 hours, extravas cular lymphocytes showed similar distribution to lymphocyte adhesion at 8 h ours except in the portal veins, around which they were possibly accumulate d by the translocation of extrasinusoidal lymphocytes. E-selectin and vascu lar cell adhesion molecule-1 (VCAM-1) were transiently expressed at 4 to 6 hours, whereas P-selectin and intercellular adhesion molecule-1 were not ch anged between 0 and 48 hours. In particular, E-selectin expression coincide d with that of lymphocyte adhesion in distribution. Lymphocyte attachment w as inhibited by pretreatment with anti-E-selectin monoclonal antibody (MAb) or anti-VCAM-1 MAb, and expression of E-selectin and VCAM-1 was suppressed by pretreatment with anti-tumor necrosis factor-alpha (TNF-alpha) MAb, Ele ctron microscopically, lymphocytes were trapped by endothelial lamellipodia and traversed the endothelium by diapedesis. These results indicate that l ymphocyte adhesion/transmigration preferentially takes place in the sublobu lar veins in association with TNF-alpha-induced endothelial activation, i.e ., E-selectin and VCAM-1 expression and lamellipodia formation.