Prenatal Melatonin Therapy Enhances Postnatal Lung Development in a Mouse Model of Inflammation-Induced Preterm Birth.

Abstract

Inflammation-induced preterm birth (PTB) significantly impacts neonatal development, particularly due to fetal lung immaturity. The lungs undergo critical development both in utero and postnatally, and PTB disrupts this process, leading to impaired pulmonary function. Current treatments for promoting lung maturation in preterm infants have limited efficacy and safety. Melatonin, known for its potent antioxidant and anti-inflammatory properties, has shown promise in preventing PTB, but its effects on fetal and postnatal lung maturation remain unclear. This study evaluated the therapeutic efficacy of melatonin in a mouse model of intrauterine inflammation-induced PTB (IPTB). Pregnant mice (Pregnancy Day 17, [PD17]) were assigned to control, lipopolysaccharide (LPS), and LPS + melatonin groups. LPS (25 µg) was injected into the right uterine horn, with melatonin (10 mg/kg) administered intraperitoneally 30 min prior. Uterine tissues were collected at 6 and 24 h post-LPS administration for molecular and histological analyses. PTB occurred in seven out of eleven (63.6%) IPTB mice within 24 h of LPS injection, whereas melatonin significantly reduced this rate to 25% (2/8). In melatonin-treated mice, the downregulation of pro-inflammatory genes in uterine tissues, restoration of placental blood flow, increased lamellar body counts, and prevention of LPS-induced vacuolation in PD18 fetal lungs were observed. Furthermore, melatonin administration enhanced surfactant protein B expression and improved lung structure. In the offspring of IPTB mice that survived, melatonin further suppressed pro-inflammatory markers and promoted lung septal thickening at postnatal day 3. In conclusion, melatonin prevents PTB, mitigates inflammation, and supports fetal lung maturation in IPTB mice, highlighting its therapeutic potential for improving neonatal pulmonary outcomes.