MODULATION OF CHEMICAL-INDUCED LUNG AND LIVER TOXICITY BY ALL-TRANS-RETINOL IN THE MALE SPRAGUE-DAWLEY RAT

We have previously shown that retinol pretreatment limits the amount o f pulmonary injury caused by 1-nitronaphthalene in male Sprague-Dawley rats. The main objective of this study was to determine if retinol pr etreatment can protect the lung from the toxicity of other systemic pn eumotoxicants. Furthermore because retinol has been shown to alter the hepatotoxicity of several chemicals, a secondary objective was to eva luate its effects on the liver injury caused by these toxicants. Rats were pretreated with all-trans-retinol (75 mg/kg/day, p.o.) for 1 week , and given 2-nitronaphthalene (200 mg/kg, i.p.) or paraquat (25 mg/kg , i.p.). At 24 h after 2-nitronaphthalene treatment, pulmonary morphol ogical changes associated with the bronchiolar epithelium, as well as a moderate pneumonitis were observed. Pretreatment of rats with retino l inhibited the majority of 2-nitronaphthalene-induced pulmonary damag e including the infiltration of inflammatory cells and associated edem a. However, these animals possessed limited lesions associated with th eir non-ciliated bronchiolar epithelial (Clara) cells. Interestingly, pretreatment with retinol also caused a significant potentiation of 2- nitronaphthalene-induced liver damage. The potentiated hepatotoxicity consisted of centrilobular hepatocyte necrosis with infiltration of in flammatory cells. Gadolinium chloride (GdCl3), an inhibitor of Kupffer cell function, significantly decreased the potentiated hepatocellular injury. In paraquat-treated rats focal areas of damage to the alveola r parenchyma, consisting of inflammatory cell infiltration and alveola r sac remodeling, were observed at 48 h. Pretreatment with retinol cau sed significant protection from the pulmonary damaged caused by paraqu at. Specifically, there was a lack of alveolar parenchymal cell damage and inflammatory cell infiltration in these animals. From these exper iments, we conclude that retinol pretreatment decreases the severity o f 2-nitronaphthalene and paraquat-induced pulmonary toxicity, apparent ly by inhibiting the inflammatory responses associated with the progre ssion of toxic injury. In the liver, retinol potentiated 2-nitronaphth alene-induced hepatotoxicity by a mechanism which directly involves Ku pffer cells.