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Pharmacology and Therapeutics
Subclinical endotoxemia has been reported in HIV infected individuals and immune activation may be exacerbated in these patients due to immune dysregulation. As infection- induced inflammation can alter the expression of placental drug transporters, it is plausible that this may be potentiated in HIV pregnant women. Similar to humans the HIV -Tg develops immune disorders and AIDS associated conditions. Therefore, our objective was to examine the impact of low -dose endotoxin on the expression of placental drug transporters in HIV -Tg rats.
3 -5 month pregnant HIV -Tg rats or wild -type littermates (WT) were treated with low dose endotoxin (0.1 or 0.25 mg/kg) on GD18 (n=4 -8/group) and placentas harvested 18 hr later. Gene expression was measured us ing qRT -PCR and serum cytokine levels were measured using ELISA.
Following endotoxin administration, there was a dose- dependent increase in pro- inflammatory cytokine levels in both HIV -Tg and WT rats, but to a greater extent in HIV -Tg. Endotoxin administration decreased the expression of Abcb1a, Slco2b1 and Slco4a1 in a dose dependent manner in HIV -Tg but not WT rats. Changes in transporter expression significantly correlated to cytokine induction. Endotoxin was associated with higher expression of Abcg2 in HIV -Tg and WT but only reached significance in HIV -Tg. Abcc3 expression was increased in endotoxin- treated WT but not HIV - Tg. Endotoxin administration did not impose significant changes in the expression of Abcb1b, Abcc1, Abcc2 and Abcc4 in HIV -Tg and WT rats.
Our results indicate that the inflammatory response is augmented in HIV -Tg rats following low dose exposure to endotoxin. Immune activation is associated with significant changes in the expression of several drug transporters in the placenta of HIV -Tg rats. Overall, our data suggests that placental transfer of drugs may be altered in the HIV population due to subclinical endotoxemia and other co- existing infections.