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To understand better the cellular and molecular mechanisms of chemical-induced occupational asthma, we examined the effects of the Th2 cytokine antagonists interferon-gamma (IFN-?), interleukin (IL)-12 and anti-IL-4 on the balance of the Th1[sol ]Th2 response induced by trimellitic anhydride (TMA) and phthalic anhydride (PA). Eight- to ten-week-old BALB[sol ]c mice were assigned to be exposed to either TMA or PA plus one of these Th2 cytokine antagonists. Both TMA (25% and 12.5% for sensitization and challenge, respectively) and PA (12.5% and 6.25% for sensitization and challenge, respectively) induced a Th2 response marked by an increasing production of IL-4 and IL-10 in the supernatants of ex vivo spleen cells cultured with concanavalin A and also of serum total IgE. Co-administration of IL-12 and antiIL-4 deviated these PA- or TMA-induced Th2 responses, as judged by an increasing serum total IgG2a production (up to 14-fold), associated with a slight decrease of IL-4 in three out of four experiments and of IL-10 in all four experiments. Co-administration of IFN-?, however, had only one weak effect. These findings suggest that the chemical-induced Th2-biased response may be diverted during an induction period by exogenous administration of the Th2 cytokine antagonists, particularly IL-12 and the anti-IL-4 antibody. These results would significantly enhance our understanding of the Th1[sol ]Th2 response induced by chemicals. Copyright 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The role of cytochrome P450 activity in the nephrotoxicity of chlorotrifluoroethylene (CTFE) and 1,1-dichloro-2,2-difluoroethylene (DCDFE) was investigated in the male rat. Hepatic cytochrome P450 1A1 and principally P450 2B1[sol ]2 were induced by -naphthoflavone and phenobarbital, respectively. Nephrotoxicity was evaluated by investigating urine biochemical parameters, kidney histochemistry and histopathological modifications.Both CTFE and DCDFE induce severe nephrotoxicity in rats after 4 h of exposure to 200 and 100 ppm, respectively. Compared with controls, activity levels of ?-glutamyltranspeptidase (?GT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and N-acetyl--d-glucosaminidase (NAG) in 24-h urine were increased similarly, but urinary excretion of glucose, proteins and 2-microglobulin (2-m) and serum urea and creatinine levels were increased. Histopathological and histochemical examinations of kidney sections of CTFE- and DCDFE-exposed rats revealed cellular necrosis and tubular lesions 24 h after exposure.-Naphthoflavone-pretreated rats were afforded some protection against the nephrotoxicity of CTFE and DCDFE. Phenobarbital did not modify DCDFE nephrotoxicity but afforded some protection against CTFE nephrotoxicity. In conclusion, CTFE and DCDFE are strong nephrotoxins. Cytochrome P450 1A1 is implicated in CTFE and DCDFE metabolism and one or several cytochromes induced by phenobarbital are implicated in CTFE metabolism. The P450 cytochromes involved in CTFE and DCDFE metabolism probably constitute detoxication metabolic pathways. The nephrotoxicity of CTFE and DCDFE is therefore subordinated to the cytochrome P450 activity involved in their metabolism. Copyright 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]