INDOMETHACIN CAN PROTECT PLACENTAL INFLAMMATION AND DELAY PRETERM BIRTH IN THE LPS-INDUCED PRETERM DELIVERY MODEL

Abstract

The major cause of prematurity is preterm birth (PTB), associated with intrauterine inflammation. Defects in the Notch pathway harm placentation, and there is evidence between Notch activation and the inflammatory environment. In the action of PTB, surfactant A (SP-A) may have a pro-inflammatory or anti-inflammatory effect, and increased synthesis of prostaglandins illustrates their crucial roles in gestational tissues at parturition. Altogether, the potential of SP-A and prostaglandin inhibitors to prevent PTB through the placenta is worth exploring. This study evaluates the preventive effect of SP-A and Indomethacin (IND) treatment on placental inflammation in the LPS-induced PTB model. Forty-eight female CD-1 mice were distributed to pregnant control (PC), Sham, PBS, IND (2 mg/kg; intraperitoneally), LPS (25μg/100μl; intrauterine), LPS+IND, SP-A block (SP-A B; 20ug/100μl; intrauterine) groups. The injections were performed on day 14.5 of pregnancy. Placentae were removed on day 15.5 of pregnancy, and immunohistochemical analyzes were performed. Differences in staining intensities between the groups for Cox-1, Notch-1 (N1), Dll-1, Jagged-2 (Jag-2), SP-A, Tlr-2, and Tlr-4 proteins were compared using ANOVA and Sidak’s Multiple Comparison test. P values <0.05 were considered statistically significant. PTB rates were; 100%, 66% (in this group, delivery delayed for about 5 hours), and 50% in LPS, LPS+IND, SP-A B groups, respectively. LPS application caused damage to fetal and maternal vascular structures in the placenta, especially in the labyrinth zone (LZ). Placental volume decreased, and lymphocyte infiltration was observed. The morphological distinction between the compartments was unclear. N1 expression increased in both the junctional zone (JZ) and LZ. Cox-1 expression in the LZ decreased significantly (p<0.05), while the expression of N1, Dll- 1, and Jag-2 increased significantly (p<0.05). Tlr-2 and Tlr-4 expression increased significantly in LZ and JZ, respectively. In the LPS+IND group, the LZ morphology was similar to the control, and placenta zone boundaries were distinguishable. In the LPS+IND group, N1, Jag-2, and Tlr-4 expression decreased significantly (p<0.05). In the SP-A B group, Cox-1 expression increased significantly (p<0.05). In the PTB model, Notch signaling, SP-A, and prostaglandin-associated signaling are disturbed in the maternal-fetal exchange site, the LZ and hormonal production site, the JZ of the placentae. While SP-A modulates the LPS-induced inflammatory response related to PTB, IND can prevent PTB via decreasing inflammation in the LZ.