Reprogramming by gestational naproxen of the sex-related lung injury in adult offspring of preeclamptic rats

Abstract

The offspring of preeclamptic mothers are at a higher risk of end-organ damage than offspring of normal pregnancies. Here we investigated whether prenatal treatment with the nonsteroidal antiinflammatory drug naproxen would impact lung damage induced by preeclampsia (PE) in the adult rat offspring. Sexual dimorphism and molecular mechanisms of this interaction were also assessed. PE was induced by oral administration of L-nitro-arginine-methyl ester (L-NAME, 50 mg/kg/day for 7 days) to pregnant dams prior to labor and lung tissues were excised from 3-month-old offspring. Histopathological examination showed greater interstitial inflammation and fibrosis in lungs of PE, compared with non-PE, offspring. The lung damaging effect of PE was more prominent in male than in female PE offspring and was coupled with greater increments in pulmonary expression of AXL tyrosine kinase receptor and downstream inflammatory (IL-1α) and antiangiogenic (sFlt1) effectors. These sex-related defects largely disappeared in the offspring of PE dams treated prenatally with naproxen (1 mg/kg/day for 7 days). We also report that PE offspring exhibited elevations in other inflammatory cytokines (e.g. IL-2 and TNFα) and apoptotic markers (e.g. caspase-3 and M-30 and M-65 fragments of the caspase-cleaved cytokeratin 18). These latter effects, however, were evenly seen in male and female offspring and were similarly offset by gestational naproxen. The data implicate the AXL/IL-1α/sFlt1 signaling in the more pronounced lung injurious action of PE in adults male offspring and suggest a counterbalancing effect for gestational naproxen therapy on the developed toxicity. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.