Fetal Inflamation
Chorioamnionitis is a bacterial infection of the placenta and amniotic fluid, and it is frequently the consequence of a urinary tract infection that has spread. Pathogen-associated molecular patterns (PAMPS) released by the bacteria activate the immune system through the Toll-Like Receptors. There is an immediate upregulation and activation of multiple inflammatory cytokines, including interleukin (IL)-1β and IL-6, that then attract inflammatory cells to travel to the site of infection. Sterile inflammation (without an infection) can also result in intrauterine inflammation and PTB. Here, damage-associated molecular patterns released by the mother or fetus initiate the same inflammatory cascade (for a summary, see Pathway to Preterm Birth).
In all cases of intrauterine inflammation, the vulnerable fetus is bathing in a soup of damaging inflammatory molecules. Fetal inflammatory response syndrome (FIRS) is a systemic inflammation of the fetus that is often fatal. For those children who survive, many live with severe long-term health consequences because of permanent injuries to their fragile organs. Intrauterine inflammation is frequently asymptomatic and remains undetected until it is too late. Attempts to stop this damage by administrating antibiotics or anti-inflammatory medications are controversial due to numerous side effects and their limited effectiveness.
We believe the PTB therapeutics designed with our collaborators (Rytvela and HSJ633) will also protect the developing fetus from inflammation (for a summary, see Therapeutics). We have already demonstrated this several times in mouse models where we induced PTB with IL-1β or PAMP injections. When we co-administered our IL-1 receptor allosteric inhibitor (rytvela), it blocked fetal death and infiltration of leukocytes into the fetal brain (Figure 1A, B).
Intrauterine inflammation does not always result in PTB, but it is always harmful to the developing fetus. We are developing mouse models of non-PTB inducing inflammation to see if rytvela or HSJ633 treatments can also block fetal damage in these cases.
Figure 1 A: Protective Benefits of Rytvela Co-Administration in Fetuses from Pregnant Mice Treated with IL-1β. Taken from Lee H et al. Frontiers in Pharmacology 2022. Pregnant mice were treated with IL-1β on gestational day (GD) 16. This induced PTB on GD17 in 86% of the mice and caused fetal death. Co-administration of rytvela eliminated the IL-1β-induced PTB and fetal death.
Figure 1 B. Representative histological images of the brains of fetuses from pregnant mice treated on GD16 with either IL-1β alone or with rytvela. The red Hoechst 33342 is a control stain for DNA. The anti-Ly6g green stain is for a neutrophil (inflammatory cell) surface marker. The brains of fetuses isolated from mice treated with IL-1β alone had a large population of neutrophils. These mobilized neutrophils were not present in the brains of fetuses from mice co-treated with rytvela. Taken from Lee H et al. Frontiers in Pharmacology 2022.