RESUMO
Cell therapy with adipose tissue-derived stem cells (ASCs) is expected to be a candidate for the treatment of fulminant hepatic failure (FHF), which is caused by excessive immune responses. In order to evaluate the therapeutic effects of ASCs on FHF, the in vitro and in vivo immunomodulatory effects of ASCs were examined in detail in the mouse model. The in vitro effects of ASCs were examined by assessing their influence on the proliferation of lymphomononuclear cells (LMCs) stimulated with three kinds of mitogens: phorbol 12-myristate 13-acetate (PMA) plus ionomycin, concanavalin A (ConA), and lipopolysaccharide (LPS). The proliferation of LMCs was efficiently suppressed in a dose-dependent manner by ASCs in the cases of PMA plus ionomycin stimulation and ConA stimulation, but not in the case of LPS stimulation. The in vivo effects of transplanted ASCs were examined in the murine FHF model induced by ConA administration. The ALT levels and histological inflammatory changes in the ConA-administered mice were apparently relieved by the transplantation of ASCs. The analysis of mRNA expression patterns in the livers indicated that the expressions of the cytokines such as Il-6, Il-10, Ifn-γ, and Tnf-α, and the cell surface markers such as Cd3γ, Cd4, Cd8α, Cd11b, and Cd11c were downregulated in the ASC-transplanted mice. The immunomodulatory and therapeutic effects of ASCs were confirmed in the mouse model both in vitro and in vivo. These suggest that the cell therapy with ASCs is beneficial for the treatment of FHF.
RESUMO
Pyrethroid insecticide (PYR) is used worldwide in agriculture and for indoor extermination of harmful insects. Urinary PYR metabolites (e.g. 3-phenoxybenzoic acid, 3PBA) have been used as the most sensitive biomarker for environmental PYR exposure since the late 1990s. In this study, we examined the effect of organophosphorus insecticide (OP) dichlorvos (DDVP) on excretion levels of urinary cis-permethrin-derived 3PBA in rats. Concentration of urinary 3PBA and cis-permethrin in plasma was monitored using gas chromatography-mass spectrometry and high-performance liquid chromatography after cis-permethrin injection (20 mg/kg) via the tail vein of rats pretreated intraperitoneally with DDVP (low dose, 0.3 mg/kg; high dose, 1.5 mg/kg). The amount of urinary 3PBA excretion over 48 h after cis-permethrin administration in control was 21.5±5.1 µg (mean±S.D.). In the low- and high-dose DDVP groups, the amounts of urinary 3PBA excretion were decreased to 81.1% (17.4±2.7 µg) and 70.3% (15.1±2.6 µg) of control, respectively. The plasma concentrations of cis-permethrin-derived 3-phenoxybenzyl alcohol (3PBAlc), which is a metabolite derived following hydrolysis of cis-permethrin, in high-dose DDVP group (0.18±0.01 µg) were significantly lower than in control (0.23±0.03 µg) 1h after cis-permethrin injection. Both in the control and high-dose DDVP group, no differences were observed in the excretion levels of urinary 3PBA after injection of 3PBAlc (25mg/kg, i.v.). These results suggested that the effect of DDVP on the amount of urinary 3PBA excretion was caused by the DDVP-induced modification of the cis-permethrin metabolic pathway. In conclusion, the possible decrease in urinary excretion level of 3PBA due to co-exposure to OPs should be considered in the biological monitoring of PYR exposure.
