Modulatory effects of exogenous estradiol during endotoxemia

This study explores the effects of exogenous estradiol on inflammatory, metabolic, and organ-function responses to lipopolysaccharide (LPS)-induced endotoxemia using a murine model. Male, female, and estradiol-supplemented female mice were administered equal dose of LPS injections and observed over a 6-hour period for systemic physiological changes, including blood pressure, glomerular filtration rate (GFR), blood gases, and temperature. Post-mortem analyses evaluated inflammatory pathway markers, biomarkers of organ injury, and targeted metabolomics from plasma samples. Estradiol supplementation was associated with attenuated early markers of hepatic and cardiac injury, reduced cardiac nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression, and changes from baseline post-LPS on metabolite profiles compared with control female and male mice. These effects were organ- and endpoint-dependent, with renal functional differences emerging primarily at later time points. Metabolite changes involving L-carnitine, methionine sulfoxide, and octanoic acid were consistent with altered metabolic and redox responses, but do not directly demonstrate changes in mitochondrial or antioxidant function. Together, these findings indicate that elevated estradiol levels are associated with modulation of early inflammatory and metabolic responses during endotoxemia, rather than uniform protection across organs or sexes. This work highlights biological sex and hormonal status as important variables in endotoxemia models and provides hypothesis-generating evidence for future studies examining hormone-dependent regulation of immune-metabolic pathways during systemic inflammation.