Open Access Dissertation
Date of Award
Preterm birth is defined as the delivery of a live baby prior to the 37th week of gestation. It is the leading cause of neonatal mortality worldwide. Preterm neonates are at a higher risk for short- and long-term complications, and prematurity places significant burden on our society. Elucidation of the mechanisms that lead to spontaneous preterm labor will enable development of therapies to prevent this syndrome. We aimed to study pathological inflammation that is implicated in the pathophysiology of spontaneous preterm labor.
Pathological inflammation can be initiated by the activation of innate immunity either by microorganisms or alarmins, which are endogenous danger signals derived cellular stress or injury. The inflammatory process initiated by alarmins in the amniotic cavity is referred to as sterile intraamniotic inflammation because it occurs in the absence of detectable microbial infection. Sterile intra-amniotic inflammation is more common than microbial-associated intra-amniotic inflammation in patients with intact chorioamniotic membranes who undergo spontaneous preterm labor, and administration of such alarmins as IL1α or HMGB1 was shown to induce preterm birth. Our major aim was to determine whether HMGB1 and three additional alarmins (S100A12, monosodium urate, and HSP70) are capable of inducing sterile inflammation of the chorioamniotic membranes and by what molecular mechanism.
Our findings show that HMGB1, S100A12, monosodium urate, and HSP70 greatly increase secretion of pro-inflammatory cytokine IL-1β from the chorioamniotic membranes and up-regulate other pro-inflammatory pathways leading to collagen remodeling and synthesis of labor promoting enzyme prostaglandin synthase 2. We also found that activation of iNKT cells, which was shown to occur via stimulation with alarmins, induces preterm birth in mice by activating CD4+ and CD8+ T cells as well as innate immune cells and by establishing pro-inflammatory microenvironment at the maternal-fetal interface. We also identified rosiglitazone, an anti-inflammatory drug that dampens iNKT-dependent inflammation, as a potent treatment for preterm labor in mice. Finally, our data demonstrates that preterm labor is associated with dysregulated expression of senescence-associated genes and accumulation of senescence markers. Cellular senescence is characterized by release of pro-inflammatory mediators, including alarmins, and thus may provide a source of inflammatory signaling in a subset of patients who undergo preterm parturition.
Plazyo, Olesya, "The Role Of Alarmins, Invariant Nkt Cells And Senescence In The Pathophysiology Of Sterile Intra-Amniotic Inflammation" (2016). Wayne State University Dissertations. 1575.