LPS-Induced Hypotension in Pregnancy: The Effect of Progesterone Supplementation

Abstract

Our previous work has shown that pregnancy exacerbates the hypotensive response to both infection and LPS. The high levels of progesterone (P4) associated with pregnancy have been suggested to be responsible for the pregnancy-induced changes in the cardiovascular response to infection. Here, we test the hypothesis that P4 supplementation exacerbates the hypotensive response of the maternal cardiovascular to LPS. Female CD1 mice had radiotelemetry probes implanted to measure haemodynamic function non-invasively and were time-mated. From day 14 of pregnancy, mice received either 10mg of P4 or vehicle alone per day and on day 16, intraperitoneal LPS (10µg of serotype 0111:B4) was injected. In two identically treated cohorts of mice, tissue and serum (for RNA, protein studies) were collected at 6 and 12 hours. Administration of LPS resulted in a fall in blood pressure in vehicle treated, but not P4 supplemented mice. This occurred with similar changes in the circulating levels of cytokines, vasoactive factors and in both circulating and tissue inflammatory cell numbers, but with reduced left ventricular expression of cytokines in P4-supplemented mice. However, left ventricular expression of markers of cardiac dysfunction and apoptosis were similar. This study demonstrates that P4 supplementation prevented LPS-induced hypotension in pregnant mice in association with reduced myocardial inflammatory cytokine gene expression. These observations suggest that rather than being detrimental, P4 supplementation has a protective effect on the maternal cardiovascular response to sepsis.

Therapeutic potential of procathepsin L-inhibiting and progesterone-entrapping dimethyl-β-cyclodextrin nanoparticles in treating experimental sepsis

“…Consequently, PRO-carrying DM-β-CD nanoparticles rescued both male and female mice from microbial infections even when they were initially given at 24 hours post the disease onset. This finding mirrored previous observations that systemic administration of PRO attenuated endotoxin-induced hypotension ( 46 ), CLP-induced systemic inflammation ( 47 ), as well as dysregulated inflammatory responses elicited by viral infections with SARS-CoV-2 ( 48 , 49 ) and hepatitis C virus ( 50 ). When given locally, however, subcutaneous implanting PRO adversely thinned the cervicovaginal epithelium and adversely enhanced vaginal transmission of Simian immunodeficiency virus (SIV) ( 51 ), genital herpes infection ( 52 ) or HIV infection ( 53 ).…”