Pathway to Preterm Birth
For over 35 years, our lab has studied the physiological details of the uterine transition from a pregnant state to parturition (physiological state of giving birth). Our goal is to identify therapeutic targets to block preterm birth (PTB), the leading contributor to neonatal death and adverse long-term health outcomes in those babies who survive.
Figure 1: The Pathway to Preterm Birth
Initiation of the Inflammatory Cascade for Parturition:
Before the clinical signs of labour, parturition starts as a silent inflammatory event (Figure 1). Toll-like receptors (TLRs) are activated by damage-associated molecular patterns (DAMPs) likely released by the fetus. This starts a self-perpetuating amplification of many inflammatory pathways.
We now know that the inflammatory mechanisms leading to PTB are similar to term-birth but differ in timing and sometimes cause. Circumstances such as genetics, maternal or transgenerational stress, epigenetic factors, multiple fetuses, and early rupture of membranes can result in premature inflammatory events, leading to PTB (Figure 1). Pathogen-associated molecular patterns (PAMPs) are markers released by infectious agents that also interact with TLRs and activate the innate immune system. Indeed, 40% of PTBs are linked to maternal infections.
Amplification of Inflammatory Signals & Leukocyte Activation:
Activated TLRs induce the expression of many proinflammatory cytokines, chemokines, and their receptors. They also activate inflammasome assembly. Inflammasomes convert the potent interleukin (IL)-1β cytokine into its active form. The expression of these cytokines results in a feed-forward process where these proinflammatory molecules continuously promote more proinflammatory events. For example, IL-1β activates the nuclear factor kappa B (NF-κB) transcription factor that increases the expression of many players in the innate immune system, including IL-1β itself. Leukocytes from the maternal plasma respond to the released chemokines and mobilize to the uterine and fetal membrane tissues. On arrival, these cells release multiple proinflammatory cytokines and chemokines, amplifying the inflammatory cascade further.
Once inflammation reaches a threshold, it induces changes to levels of uterine activation proteins (UAPs), such as matrix metalloproteases (MMPs) and connexin 43 (CX-43). These UAPs transition the uterine tissues so they can perform the physiological events of parturition, such as membrane rupture and contractions. Proinflammatory mediators, including IL-1β and IL-6, accelerate the expression and activation of UAPs so an untimely inflammatory event can initiate early labour. Prostaglandin F2α (PGF2α) is another central mediator of parturition that coordinates UAP expression and stimulates contractions. However, PGF2α is also a proinflammatory molecule that feeds the inflammatory cascade.
Like stopping an accelerating train, we believe the key to successfully blocking PTB is catching it before it reaches top speed. We need to develop the clinical capacity to identify and inhibit the inflammatory event that occurs several days before uterine activation. The synergistic activities of DAMPs/PAMPs, crosstalk between tissues, leukocyte mobilization, and cooperative actions between cytokines, chemokines, and UAPs feed and accelerate this inflammation. Once the inflammatory cascade peaks, it starts a chain reaction leading to myometrial contractions, which are almost impossible to stop.
Birth is Complex:
This explanation of the physiological changes leading to parturition is simplified for readability. Birth is a complex event where a quiet uterus that nurtures the growth of a fetus changes dramatically to perform the function of labour and delivery. Recent transcriptome analyses show that the expression patterns of 471 genes change in the myometrium (Mittal P et al. 2010) and 796 in the choriodecidua (Stephen GL et al. 2015) in preparation for labour. Progesterone withdrawal is also a necessary step for uterine activation.