Oral Presentation ESA-SRB-APEG-NZSE 2022

Lipopolysaccharide induced inflammation in fetal membranes can be mitigated by treatment with Angiotensin-(1-7)     (#88)

Sarah J Delforce 1 2 , Eugenie R Lumbers 1 2 , Grace Burns 1 , Tess Symington 1 2 , Mark Marsland 1 , Kirsty G Pringle 1 2
  1. School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia
  2. Mothers and Babies Research Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia

Inflammation has long been implicated as a key mediator in the onset of parturition in both preterm and term births. Tissue renin-angiotensin systems (RASs) can regulate inflammation. The angiotensin converting enzyme 2 (ACE2)/Angiotensin-(1-7)/Mas receptor anti-inflammatory pathway, has been shown to inhibit the pro-inflammatory cytokines interleukin (IL)-6, IL-8 and tumour necrosis factor (TNF)-α levels and enhance the anti-inflammatory cytokine, IL-10, in pancreatic acinar cells. We aimed to investigate whether activation of the ACE2/Angiotensin-(1-7)/Mas receptor pathway protects against lipopolysaccharide (LPS) induced inflammatory cytokine expression in term fetal membranes.

Term non-labouring choriodecidual explants were treated with AVE0991 (100 µM, Mas receptor agonist) for 24h after which lipopolysaccharide (0.2μg/ml, O55:B5) was introduced for 6h. Tissue and culture medium was collected for analysis (n=12). Levels of IL-1β, IL-6, and IL-10 and TNF-α were measured via qPCR and ELISA.

Low dose LPS treatment of choriodecidual explants enhanced the expression of TNF-α, IL-6, IL-1β and IL-10 relative by 4-15-fold relative to vehicle control explants (all P<0.0001). Similarly, LPS induced a significant increase in the secretion of TNF-α and IL-6 from explants relative to vehicle control explants (P<0.0001 and P=0.001 respectively). Pre-treatment of choriodecidual explants with 100 µM AVE0991 was able to mitigate LPS induced mRNA expression of pro-inflammatory cytokines IL-6 and IL-1β compared with explants pre-treated with 0 µM AVE0991 (P=0.01 and 0.02 respectively). This effect however was not seen with pre-treatment with 10 µM AVE0991. Pre-treatment with both 10 and 100 µM AVE0991 was unable to mitigate the effects of LPS induced inflammation on the mRNA expression and protein secretion of TNF-α or IL-10 mRNA.

These data suggest that the ACE2/Ang-(1-7)/MasR pathway may play a role in regulating inflammation within the choriodecidua during pregnancy and thus pose as a novel therapeutic target to prevent inflammation induced preterm birth.