All-trans-retinol alteration of 1-nitronaphthalene-induced pulmonary and hepatic injury by modulation of associated inflammatory responses in the male Sprague-Dawley rat.

Large doses of retinol (vitamin A) have been shown to potentiate the hepatotoxicity of several chemicals in rats. The objective of this study was to determine how retinol would affect the pulmonary and hepatic toxicity caused by 1-nitronaphthalene (1-NN). All-trans-retinol (75 mg/kg/day, po) was administered for 7 days to male Sprague-Dawley rats. One day after the last dose of retinol, animals were given a single injection of 1-NN (100 mg/kg, ip). At 24 hr, animals receiving retinol vehicle and 1-NN exhibited respiratory distress syndrome and chromodacryorrhea. Pulmonary morphological changes included necrosis and exfoliation of the bronchiolar epithelium, as well as infiltration of inflammatory cells into the interstitial areas around affected bronchioles. The bronchioalveolar lavage fluid from these animals exhibited significant increases in the activities of gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH), as well as protein and inflammatory cell content. Following pretreatment with retinol, none of the animals treated with 1-NN exhibited outward signs of toxicity. In addition, the lavage fluid of these rats revealed significant reductions in inflammatory cells, protein, and LDH activity. However, lavage fluid GGT activity was significantly increased. Morphological evaluation of the lungs revealed nonciliated bronchiolar epithelial (Clara) cell damage with no associated inflammation. Retinol pretreatment resulted in potentiated hepatotoxicity as indicated by increases in plasma alanine aminotransferase and GGT activities, as well as plasma total bilirubin. The altered plasma enzyme activities correlated with increased hepatocyte and bile duct epithelial necrosis, as well as an increased infiltration of neutrophils into the areas around bile ducts. Retinol potentiation of 1-NN-induced hepatocyte necrosis was significantly reduced following pretreatment with gadolinium chloride (GdCl3). From these experiments, we conclude that in the lung pretreatment with retinol decreased the severity of 1-NN-induced toxicity apparently by an anti-inflammatory mechanism. In the liver, retinol potentiated 1-NN-induced liver injury apparently through a proinflammatory mechanism by activating Kupffer cells and increasing the infiltration of neutrophils into the periportal regions adjacent to bile ducts.