GASTROENTEROLOGY 1992;102:255-262

Intrahepatic Up-Regulated Expression of Extracellular Matrix Protein Receptors in Chronic Active Hepatitis Type B CARMELO GARCÍA-MONZÓN, RICARDO MORENO-OTERO, LUISA GARCÍA-BUEY, ASUNCIÓN GARCÍA-SÁNCHEZ, MIGUEL R. CAMPANERO, and FRANCISCO SÁNCHEZ-MADRID Liver Unit, Pathology and Immunology Services, Hospita1 de la Princesa, Universidad Autónoma, Madrid, Spain

The aim of the present study was to investigate the differences in expression of & integrins between normal liver and the inflamed livers of patients with chronic active hepatitis B. Immunohistochemical staining with monoclonal antibodies that specifically recognize the common j31 chain and five different a subunits has been performed in frozen liver biopsy sections from 10 patients with chronic active hepatitis B and from 4 patients with normal livers. The major findings of our study were de novo expression in liver with chronic active hepatitis B of a, and a, subunits on both periportal hepatocytes and on lobular hepatocytes in close proximity to lymphocyte infiltrates. These results indicate the existente of an up-regulatory process in the expression of j$ integrins, especially the a, and u, subunits, in the inflamed liver tissue from patients with chronic active hepatitis B, suggesting that these integrins could play an important role in the development of liver fibrosis and in regulating intrahepatic lymphocyte migration.

finally this molecule was implicated as a collagen receptor” as wel1 as a putative laminin receptor.” Very late-activation antigen 2 behaves functionally as a receptor for type 1 co11agen.13 Very late-activation antigen 3 binds laminin, collagen, and fibronecfin.14*15Very late-activation antigen 4 is the only integrin of the VLA family whose expression is rsstricted to leukocytes and that has been involved in cell-to-cel1 adhesive interactions.‘” Thus, VLA-4 can bind fibronectin in an arginine-glycine-aspartate tripeptide-independent site and, unlike other VLA members, is also able to interact with a cell-surface molecule, termed vascular cell-adhesion molecule 1 (VCAM-l), on activated endothelial cells.17*18Very late-activation antigen 5 is the prototype fibronectin receptor, lg and VLA-6 mediates attachment to laminin.” To address the possible role of VLA integrins in the pathogenesis of chronic active hepatitis B (CAHB), we have investigated its expression in the liver tissue from patients with this disease. Material and Methods

ecent studies have been focused on the roles of PI integrins as adhesion receptors for extracellular matrix (ECM) proteins and as cell-to-cel1 adhesion receptors.1-3 The p, integrins, also known as very late-activation antigen (VLA) proteins, are heterodimeric membrane glycoproteins composed of a common p chain of 110-130 kilodaltons noncovalently bound to one of at least six different a subunits of 140-200 kilodaltons.4 Additional associations of a and p subunits that expand the VLA molecular and functional repertoire have been reported.5-g The VLA integrin subfamily includes at least six distinct molecules (termed VLA-1 to VLA-6) that functionally behave as receptors for different ECM proteins. Very late-activation antigen 1 was originally discovered on T cells, appearing very late (2-4 weeks) after in vitro lymphocyte activation.” NO VLA-1 functions were known for several years, but

R

Patients and Controls Ten patients with CAHB were included in this study. The diagnosis was based on standard, internationally accepted criteria.‘l Biochemical, serological, and histological features of the patients are given in Table 1. After written consent, liver biopsy was performed in these patients for evaluation of chronic liver disease. Of the 10 patients studied, 8 were positive for hepatitis B virus (HBV) DNA in serum and 2 were negative. Al1 of them were negative for antibodies against delta hepatitis and human immunodeficiency viruses. NO patients received antiviral or immunosuppressive therapy at the time of the study. As controls, 4 patients with histologically normal livers were also studied. After informed written consent, they underwent surgical liver biopsy during iaparotomy for noncom0 1992 by the American Gastroenterological 6616-5065/92/$3.66

Association

256 GARCÍA-MONZÓN ET AL.

Table 1. Biochemical,

Serological,

and Histological

Features

(Yd

ALT UU/Ll

HBsAg (serum)

HBV DNA (serum)

34 27 41 18 23 30 29 36 30 34

182 108 115 220 154 190 247 132 70 85

+ + + +

+ + + +

&e Patient 1

2 3 4 5 6 7 0 9 10

GASTROENTEROLOGY Vol. 102,No. 1

of the Patients

t

+

+ + + + +

+ + + _ _

Diagnosis

Knodell Index

CAH CAH CAH CAH CAH CAH CAH CAH CAH CAH

17 16 10 12 12 14 14 12 10 10

ALT, alanine aminotransferase.

plicated cholecystectomy. Al1 these controls were negative for hepatitis B surface, antigen (HBsAg) and had normal aminotransferase levels in serum. Viral Markers Hepatitis B surface antigen and anti-delta and antihuman immunodeficiency virus antibodies were determined using commercially available immunoassay kits (Abbott Laboratories, North Chicago, IL). Serum HBV DNA was detected using a commercially available molecular hybridization assay kit (Abbott Genostics, North Chicago, IL). MonocJonaJ

Antibodies

Monoclonal antibodies used were HP2/6 antiCD4,” B9 .4

Intrahepatic up-regulated expression of extracellular matrix protein receptors in chronic active hepatitis type B.

The aim of the present study was to investigate the differences in expression of beta 1 integrins between normal liver and the inflamed livers of pati...
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