An unresolved question in wound contraction concerns the identity of integrins mediating the attachment of tissue myofibroblasts to matrix in the injury site. Previous studies with cell lines have focussed on ␣1␤1 and ␣2␤1, the principal collagen-binding integrins, but have yielded conflicting data. We have examined this issue in wound healing in the liver, isolating the myofibroblast population (activated stellate cells) and quantitating expression of the ␣1 and ␣2 integrin subunits during the in vivo injury. Normal stellate cells displayed ␣1 but no detectable ␣2. During injury, ␣1 expression was maintained; ␣2 became detectable at the mRNA level but at all times was <8% of ␣1 mRNA. Contraction of collagen lattices, studied with 24-h cultured cells and initiated by endothelin 1, was blocked 70% by anti-␣1 and 30% by anti-␣2 (both significant, p < 0.05). The inhibition by anti-␣2, which was unexpected, was attributable to culture-induced change in integrin expression; both the mRNA and protein for ␣2 increased strikingly within 24 h of plating stellate cells on a collagen gel. We conclude that ␣1␤1 is the sole integrin utilized by contracting myofibroblasts in vivo. Although ␣2␤1 is capable of mediating contraction, its expression by myofibroblasts occurs largely, if not exclusively, in response to culture.

The mammalian hepatic lobule is characterized by a Little is known about the alterations of metabolic ormarked functional heterogeneity. [1][2][3] According to their posiganization of the human liver tissue in chronic liver distion within the hepatic lobule, hepatocytes present signifieases. We therefore compared the distribution of the folcant differences in the level of many enzyme activities, such lowing zonal metabolic markers in 10 samples of normal as those involved in the carbohydrate, ammonia, lipid, and liver tissue, 10 samples of fibrotic tissue, and 22 samples xenobiotic metabolisms, 2-5 and in the expression of some seof cirrhotic tissue: (a) the enzymatic activities of glucosecreted products, such as plasma proteins. 6 The metabolic or-6-phosphatase (G6P), lactate dehydrogenase (LDH), ganization of the mammalian hepatic lobule is well exemplisuccinate dehydrogenase (SDH), nicotinamide-adeninefied in the rat. In this species, gluconeogenesis, fatty acid dinucleotide-phosphate [NADPH] dehydrogenase (ND), oxydation, ureagenesis, and albumin synthesis predominate b-hydroxybutyrate dehydrogenase (HBDH), and glutamate dehydrogenase (GDH); (b) the protein glutamine in the periportal region of the hepatic lobule, while glycolysis, synthetase (GLS); and (c) albumin messenger RNA fatty acid synthesis, glutamine formation, and xenobiotic me-(mRNA). The normal human hepatic lobule was charac-tabolism predominate in the perivenous region. 7 The metaterized by the periportal predominance of G6P and SDH bolic zonation of the mammalian hepatic lobule is thought to enzymatic activities and albumin mRNAs, the perive-play an important physiological role by enabling the liver to nous predominance of ND and GDH, the restriction of simultaneously perform anabolic and catabolic activities, and GLS to a small perivenous compartment, and the pre-by allowing quick responses of the hepatic parenchyma to dominance of b-HBDH at the contact of both portal changes in the physiological status. 2,3,8 It is currently tracts and centrilobular veins. In fibrosis, the overall thought 2,3,8 that the maintenance of the metabolic organizametabolic organization of the normal liver tissue was tion of the liver depends mainly on microenvironmental facretained. The expression of periportal markers predomi-tors, including: (a) blood-borne factors, such as the gradients nated around enlarged portal tracts and that of perive-in oxygen, substrates, and hormones determined by the uninous markers around residual centrilobular veins. GLS directional perfusion of the hepatic lobule by the portal blood was constantly detected at the contact of centrilobular flow, (b) pericellular factors, such as the zonal differences in veins. In cirrhotic nodules, no zonation was observed the pattern of innervation, the composition of the extracellufor most enzymatic activities or for albumin. Only G6P lar matrix, and the functional characteristics of nonparenchyusually predominated at the periphery of the nodules. mal liver cells; and possibly (c) paracrine interac...

The mammalian hepatic lobule is characterized by a Little is known about the alterations of metabolic ormarked functional heterogeneity. [1][2][3] According to their posiganization of the human liver tissue in chronic liver distion within the hepatic lobule, hepatocytes present signifieases. We therefore compared the distribution of the folcant differences in the level of many enzyme activities, such lowing zonal metabolic markers in 10 samples of normal as those involved in the carbohydrate, ammonia, lipid, and liver tissue, 10 samples of fibrotic tissue, and 22 samples xenobiotic metabolisms, 2-5 and in the expression of some seof cirrhotic tissue: (a) the enzymatic activities of glucosecreted products, such as plasma proteins. 6 The metabolic or-6-phosphatase (G6P), lactate dehydrogenase (LDH), ganization of the mammalian hepatic lobule is well exemplisuccinate dehydrogenase (SDH), nicotinamide-adeninefied in the rat. In this species, gluconeogenesis, fatty acid dinucleotide-phosphate [NADPH] dehydrogenase (ND), oxydation, ureagenesis, and albumin synthesis predominate b-hydroxybutyrate dehydrogenase (HBDH), and glutamate dehydrogenase (GDH); (b) the protein glutamine in the periportal region of the hepatic lobule, while glycolysis, synthetase (GLS); and (c) albumin messenger RNA fatty acid synthesis, glutamine formation, and xenobiotic me-(mRNA). The normal human hepatic lobule was charac-tabolism predominate in the perivenous region.7 The metaterized by the periportal predominance of G6P and SDH bolic zonation of the mammalian hepatic lobule is thought to enzymatic activities and albumin mRNAs, the perive-play an important physiological role by enabling the liver to nous predominance of ND and GDH, the restriction of simultaneously perform anabolic and catabolic activities, and GLS to a small perivenous compartment, and the pre-by allowing quick responses of the hepatic parenchyma to dominance of b-HBDH at the contact of both portal changes in the physiological status. 2,3,8 It is currently tracts and centrilobular veins. In fibrosis, the overall thought 2,3,8 that the maintenance of the metabolic organizametabolic organization of the normal liver tissue was tion of the liver depends mainly on microenvironmental facretained. The expression of periportal markers predomi-tors, including: (a) blood-borne factors, such as the gradients nated around enlarged portal tracts and that of perive-in oxygen, substrates, and hormones determined by the uninous markers around residual centrilobular veins. GLS directional perfusion of the hepatic lobule by the portal blood was constantly detected at the contact of centrilobular flow, (b) pericellular factors, such as the zonal differences in veins. In cirrhotic nodules, no zonation was observed the pattern of innervation, the composition of the extracellufor most enzymatic activities or for albumin. Only G6P lar matrix, and the functional characteristics of nonparenchyusually predominated at the periphery of the nodules. mal liver cells; and possibly (c) paracrine interact...

The coexpression of normally periportal and perivenous markers has been described in heterotopically transplanted hepatocytes. To determine whether such a coexpression might also occur in hepatocytes retaining their original intrahepatic location, we compared in bileduct-ligated livers and intrasplenically transplanted hepatocytes, the expression and distribution of the predominantly periportal glucose-6-phosphatase, succinate dehydrogenase, and lactate dehydrogenase, the predominantly perivenous glutamate dehydrogenase, NADPH-dehydrogenase, and ~-hydroxybutyrate dehydrogenase, and the strictly perivenous glutamine synthetase. The coexpression of high levels of the two periportal markers glucose-6-phosphatase and lactate dehydrogenase and of the perivenous marker NADPH dehydrogenase was observed in two situations: in clusters of hepatocytes isolated within the ductular proliferation in bile-duct-ligated livers and the majority of intrasplenically transplanted hepatocytes. The expression of glutamine synthetase was different according to the site. The protein was observed in certain intrasplenically transplanted hepatocytes bordering the splenic vessels but was never detected in hepatocyte clusters found in bile-duct-ligated livers. Our study therefore suggests that the coexpression of periportal and perivenous markers in the same hepatocytes is likely to be a non-specific consequence of the loss of the normal connections of hepatocytes with the normal liver microcirculation.