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 h epatotoxicity of several chemicals in rats. The objective of this stud y was to determine how retinol would affect the pul monary and hepatic toxicity caused by 1-nitronaphthalene (1-NN). All-trans-retinol (75 m g/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 i njection of 1-NN (100 mg/ kg, ip). At 24 hr, animals receiving retinol vehicle and 1-NN exhibited respiratory distress syndrome and chromoda cryorrhea. Pulmonary morphological changes included necrosis and exfol iation of the bronchiolar epithelium, as well as infiltration of infla mmatory cells into the interstitial areas around affected bronchioles. The bronchioalveolar lavage fluid from these animals exhibited signif icant increases in the activities of gamma-glutamyl transpeptidase (GG T), lactate dehydrogenase (LDH), as well as protein and inflammatory c ell content. Following pretreatment with retinol, none of the animals treated with 1-NN exhibited outward signs of toxicity. In addition, th e lavage fluid of these rats revealed significant reductions in inflam matory cells, protein, and LDH activity. However, lavage fluid GGT act ivity was significantly increased. Morphological evaluation of the lun gs revealed nonciliated bronchiolar epithelial (Clara) cell damage wit h no associated inflammation. Retinol pretreatment resulted in potenti ated hepatotoxicity as indicated by increases in plasma alanine aminot ransferase 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 infiltratio n of neutrophils into the areas around bile ducts. Retinol potentiatio n of 1-NN-induced hepatocyte necrosis was significantly reduced follow ing pretreatment with gadolinium chloride (GdCl3). From these experime nts, we conclude that in the lung pretreatment with retinol decreased the severity of 1-NN-induced toxicity apparently by an anti-inflammato ry mechanism. In the liver, retinol potentiated 1-NN-induced liver inj ury apparently through a proinflammatory mechanism by activating Kupff er cells and increasing the infiltration of neutrophils into the perip ortal regions adjacent to bile ducts. (C) 1995 Academic Press,Inc.