Abstract
Lipopolysaccharide (LPS) in high doses inhibits placental multidrug resistance P-glycoprotein (P-gp - Abcb1a/b) and breast cancer resistance protein (BCRP - Abcg2). This potentially impairs fetal protection against harmful factors in the maternal circulation. However, it is unknown whether LPS exposure, at doses that mimic sub-lethal clinical infection, alters placental multidrug resistance. We hypothesized that sub-lethal (fetal) LPS exposure reduces placental P-gp activity. Acute LPS (n = 19;150 µg/kg; ip) or vehicle (n = 19) were given to C57BL/6 mice at E15.5 and E17.5. Placentas and fetal-units were collected 4 and 24 h following injection. Chronic LPS (n = 6; 5 µg/kg/day; ip) or vehicle (n = 5) were administered from E11.5–15.5 and tissues were collected 4 h after final treatment. P-gp activity was assessed by [3H]digoxin accumulation. Placental Abcb1a/b, Abcg2, interleukin-6 (Il-6), Tnf-α, Il-10 and toll-like receptor-4 (Tlr-4) mRNA were measured by qPCR. Maternal plasma IL-6 was determined. At E15.5, maternal IL-6 was elevated 4 h after single (p<0.001) and chronic (p<0.05) LPS, but levels had returned to baseline by 24 h. Placental Il-6 mRNA was also increased after acute and chronic LPS treatments (p<0.05), whereas Abcb1a/b and Abcg2 mRNA were unaffected. However, fetal [3H]digoxin accumulation was increased (p<0.05) 4 h after acute LPS, and maternal [3H]digoxin myocardial accumulation was increased (p<0.05) in mice exposed to chronic LPS treatments. There was a negative correlation between fetal [3H]digoxin accumulation and placental size (p<0.0001). Acute and chronic sub-lethal LPS exposure resulted in a robust inflammatory response in the maternal systemic circulation and placenta. Acute infection decreased placental P-gp activity in a time- and gestational age-dependent manner. Chronic LPS decreased P-gp activity in the maternal myocardium and there was a trend for fetuses with smaller placentas to accumulate more P-gp substrate than their larger counterparts. Collectively, we demonstrate that acute sub-lethal LPS exposure during pregnancy impairs fetal protection against potentially harmful xenobiotics in the maternal circulation.
Highlights
Inflammatory processes can occur in response to a wide variety of pathological stimuli, including infection, tissue damage, trauma and cellular stress
interleukin 6 (IL-6) measurements were conducted since it is a sensitive marker of systemic inflammation and preterm delivery (PTD), IL-6 is highly augmented after LPS [30,31]
We discovered that P-gp activity and placental responsiveness to inflammatory insult vary according to placental size
Summary
Inflammatory processes can occur in response to a wide variety of pathological stimuli, including infection, tissue damage, trauma and cellular stress. Neonates born with inflammatory related conditions are at an increased risk for short- and long-term complications, including neonatal encephalopathy, long-term cognitive impairment and cerebral palsy [1,4] In this context, multidrug resistance transporters such as Pglycoprotein (P-gp; encoded by Abcb1a/b genes in the mouse) and breast cancer resistance protein (BCRP; encoded by Abcg gene), are functionally modulated by pro-inflammatory agents in different tissues/cell types [5,6,7,8,9,10]. P-gp and BCRP are extensively expressed in different tissue barriers such as the placenta, bloodbrain barrier, mammary gland, colon and small intestine [11] They play an important physiological role in extruding a large number of cellular substrates, such as small organic cations, carbohydrates, polysaccharides and proteins [8]. In addition to extruding physiological substrates, multidrug resistance proteins extrude a wide range of xenobiotics such as chemotherapeutics and environmental toxins [12]
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