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Ibuprofen Does Not Prevent Inhibition of Fetal Breathing Movements Caused by Intrauterine Inflammation in Fetal Sheep

Year: 2025

Type: article

Abstract: Antenatal inflammation/infection is a major cause of neonatal apnoea and hypoventilation. Prostaglandin E2 (PGE2) is a key inflammatory mediator associated with depression of fetal and neonatal breathing. We aimed to determine whether antenatal ibuprofen, a cyclooxygenase inhibitor that reduces synthesis of PGE2, restores fetal breathing movements (FBM) in late-gestation fetal sheep exposed to systemic lipopolysaccharide (LPS). Fetal sheep (125 days gestation, d; term ~148 d) were instrumentally monitored for continuous measurement of FBM and physiological parameters. At 130 d fetuses were randomly allocated between groups receiving i.v. saline (CTLSAL, n = 9), escalating doses of LPS (i.v.) over 3 days (LPSSAL, n = 8), or ibuprofen one hour after each LPS dose (LPSIBU, n = 8). Regular plasma samples were collected for PGE2 assessment. At 135 d, cerebrospinal fluid and brainstem tissue were collected at autopsy for assessments of PGE2 expression, and immunohistochemical quantification of astrocytes and microglia within key brainstem respiratory centres was performed to assess inflammation. LPS exposure increased PGE2 levels in plasma, cerebrospinal fluid and the RTN/pFRG (p < 0.05) and decreased the incidence, amplitude and amount of the accentuated (>5 mmHg) FBMs. Ibuprofen reduced plasma and RTN/pFRG PGE2 expression (p < 0.01 and p = 0.031, respectively) but did not restore FBMs. Astrocyte and microglial density increased in the RTN/pFRG, NTS and raphe nucleus in LPSIBU fetuses, compared to LPSSAL (p < 0.05). Antenatal ibuprofen treatment did not restore depressed FBM, despite reducing the circulating and brainstem PGE2 levels in LPS-exposed fetal sheep. Other inflammatory pathways or more specific targeting of PGE2 may be more effective in preventing apnoea caused by exposure to intrauterine infection/inflammation.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms26125591