Trophoblastic apoptosis in mice with preterm delivery and its suppression by urinary trypsin inhibitor

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Abstract
Objective: To investigate histopathologic changes of the placenta in mice with preterm delivery induced by lipopolysaccharide and the effect of urinary trypsin inhibitor. Methods: Female C3H/HeN mice impregnated by male B6D2F1 mice were treated with lipopolysaccharide (50 μg/kg, intraperitoneally) or lipopolysaccharide plus urinary trypsin inhibitor (25 × 104 U/kg, intraperitoneally). At 3, 6, 9, and 18 hours after the second dose of lipopolysaccharide, and at delivery in the control and urinary trypsin inhibitor-treated groups, the concentrations of interleukin-1αa and tumor necrosis factor-α were determined in serum and amniotic fluid. Subsequently, the placentas were examined. In the same manner, we examined mice treated with interleukin-1α (250 μg/kg, subcutaneously) on day 15 of pregnancy and intact mice on days 15 and 18 of pregnancy as well as at delivery. To assess the direct action of cytokines, we cultured placental slices with tumor necrosis factor-α, interleukin-1α, or tumor necrosis factor-α plus urinary trypsin inhibitor and examined them morphologically. Results: Control mice were characterized by trophoblastic apoptosis and increased serum levels of tumor necrosis factor-α and interleukin-1α. In contrast, urinary trypsin inhibitor-treated mice showed suppression of apoptosis and lower cytokine levels. Interleukin-1α induced trophoblastic apoptosis and increased the serum level of tumor necrosis factor-α. The in vitro study showed that tumor necrosis factor-α directly induced trophoblastic apoptosis in placental slices. Conclusion: We demonstrated that trophoblastic apoptosis occurs in the placentas of a mouse model with preterm delivery induced by lipopolysaccharide. We postulated that apoptosis may lead to placental abruption, and its development may be prevented by treatment with urinary trypsin inhibitor.

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