A single injection of D-galactosamine hydrochloride induces acute self-limiting liver disease in rats that morphologically resembles drug-induced hepatitis in human beings. In this immunohistochemical study we examined the localization and expression of the hepatic extracellular matrix components fibronectin, laminin, collagen type I, collagen type III and collagen type IV and of the cell surface receptors (integrins) for fibronectin and laminin. Sections of liver tissue obtained at intervals of 6, 12, 18, 24, 30, 36, 48 and 72 hr and 7 and 21 days after galactosamine administration were immunostained with a panel of polyclonal monospecific antibodies and studied independently by two of us. Fibronectin was the first extracellular matrix component found to be increased, 12 hr after galactosamine injection, followed by collagen type III, and, in a later phase, collagen type IV, type I and laminin. Increased deposition of extracellular matrix was found in areas with liver cell necrosis and along sinusoids. Extracellular matrix immunoreactivity reached a maximum at 36 to 48 hr and decreased thereafter to preinjury levels 3 wk after galactosamine. Immunostaining for the fibronectin and laminin receptors revealed tissue localization identical to that of their ligands. However, the intensity of staining was opposite of that for the extracellular matrix, with a decrease of immunoreactivity after 24 to 48 hr. The observed sequence of changes in hepatic extracellular matrix proteins after galactosamine injection resembles the repair reaction in other tissues and may reflect the particular function that each carries out during the process of liver healing after toxic injury.

Galactosamine hydrochloride induces liver disease in rats that morphologically resembles drug-induced hepatitis in man. In this study we analyzed the character of the inflammatory reaction following the toxic damage resulting from the administration of galactosamine hydrochloride using a broad panel of monoclonal antibodies to lymphocyte subsets and macrophages. Fat-storing cells were identified with a polyclonal anti-desmin antibody. Cellular proliferation was assessed by labeling S-phase cells with the thymidine analog bromodeoxyuridine. Injection of galactosamine hydrochloride was associated with conspicuous hepatocyte necrosis and parenchymal granulocyte influx in the first 24 hr. Thereafter, mononuclear inflammatory cells predominated, mainly T lymphocytes and macrophages, with maximal numbers at 48 hr. The majority of T lymphocytes were CD8-positive cells and were located in the portal tracts and parenchyma. CD4-positive T cells were scarce and confined to the portal tracts. Proliferation of fat-storing cells paralleled hepatocyte regeneration with maximal values after 48 to 72 hr. The temporal relationship between infiltrating mononuclear cells, mainly T lymphocytes of CD8 phenotype and macrophages, fat-storing cell proliferation and hepatic regeneration suggests pathophysiological interactions between these cell types in liver injury in the rat after galactosamine hydrochloride administration.

Multiple injections of D-galactosamine induce liver fibrosis and cirrhosis in rats. The purpose of this immunopathological study was to correlate inflammation and hepatic extracellular matrix remodeling after repeated administration of galactosamine. Rats were given 10, 20, 30, 40, 60, 80, 100 and 140 intraperitoneal injections of D-galactosamine (500 mg/kg body wt, three times weekly). Controls received injections of saline solution. Cryostat sections of liver tissue obtained on biopsy or autopsy were immunostained with a panel of monoclonal and polyclonal monospecific antibodies reactive with macrophages, T and B lymphocytes, desmin, the extracellular matrix components fibronectin; laminin; collagen types I, III and IV; and the fibronectin receptor alpha 5 beta 1. Total RNA was extracted and Northern-blot analysis was performed with a specific cDNA probe for rat collagen type III. Spotty liver cell necrosis and mild portal and parenchymal inflammation was seen after 10 injections of galactosamine. After 20 to 40 injections, expansion of protal tracts, prominent bile ductular proliferation and gradual formation of fibrous septa were encountered with the development of cirrhosis at later intervals. These progressive histological changes were paralleled by a gradual increase of desmin-positive cells in developing septa with deposition of fibronectin; collagen types I, III, and IV; and laminin. Northern-blot analysis showed that this accumulation of extracellular matrix was not accompanied by increase of mRNA for collagen type III. In conclusion, repetitive administration of galactosamine causes progressive liver disease with prominent bile ductule proliferation and development of fibrous septa. These pathological alterations bear some resemblance to the morphological changes in chronic biliary disease in human beings.

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