The Role of Danger Associated Molecular Patterns in Human Fetal Membrane Weakening

Abstract

The idea that cellular stress (including that precipitated by stretch), plays a significant role in the mechanisms initiating parturition, has gained considerable traction over the last decade. One key consequence of this cellular stress is the increased production of Danger Associated Molecular Patterns (DAMPs). This diverse family of molecules are known to initiate inflammation through their interaction with Pattern Recognition Receptors (PRRs) including, Toll-like receptors (TLRs). TLRs are the key innate immune system surveillance receptors that detect Pathogen Associated Molecular Patterns (PAMPs) during bacterial and viral infection. This is also seen during Chorioamnionitis. The activation of TLR commonly results in the activation of the pro-inflammatory transcription factor Nuclear Factor Kappa-B (NF-kB) and the downstream production of pro-inflammatory cytokines. It is thought that in the human fetal membranes both DAMPs and PAMPs are able, perhaps via their interaction with PRRs and the induction of their downstream inflammatory cascades, to lead to both tissue remodeling and weakening. Due to the high incidence of infection-driven Pre-Term Birth (PTB), including those that have preterm Premature Rupture of the Membranes (pPROM), the role of TLR in fetal membranes with Chorioamnionitis has been the subject of considerable study. Most of the work in this field has focused on the effect of PAMPs on whole pieces of fetal membrane and the resultant inflammatory cascade. This is important to understand, in order to develop novel prevention, detection, and therapeutic approaches, which aim to reduce the high number of mothers suffering from infection driven PTB, including those with pPROM. Studying the role of sterile inflammation driven by these endogenous ligands (DAMPs) activating PRRs system in the mesenchymal and epithelial cells in the amnion is important. These cells are key for the maintenance of the integrity and strength of the human fetal membranes. This review aims to (1) summarize the knowledge to date pertinent to the role of DAMPs and PRRs in fetal membrane weakening and (2) discuss the clinical potential brought by a better understanding of these pathways by pathway manipulation strategies.

Why Do the Fetal Membranes Rupture Early after Fetoscopy? A Review

“…Despite biomechanical differences, the inflammatory responses to injury and membrane weakening cascades involving MMPs are consistent among humans and most domestic species [18,36,39,[55][56][57]. This suggests that preclinical animal studies investigating iPPROM and potential therapies should focus on the biology of membrane injury and weakening rather than changes in mechanical rupture properties [74,102].…”

“…Collagen weakening and thinning of the chorionic trophoblasts and decidua weakening and rupture [37,74]. Puncturing the membranes with the fetoscopic port, distending the uterus with unconditioned CO 2 , and diluting the residual amniotic fluid during fetoscopy may all damage the fetal membranes intraoperatively and increase the risk of iPPROM.…”

High‐mobility group box 1 is a driver of inflammation throughout pregnancy

“…In addition, circulating levels of HMGB1 levels in maternal serum are also higher in PTL and pPROM 40,41 . Although the mechanism is not yet fully understood in the fetal membranes, together these data suggest elevated levels and expression of HMGB1 may increase the risk of pPROM and be important for their weakening 54 …”

“…40,41 Although the mechanism is not yet fully understood in the fetal membranes, together these data suggest elevated levels and expression of HMGB1 may increase the risk of pPROM and be important for their weakening. 54 A recent study detected HMGB1 gene and protein expressed throughout pregnancy in human fetal membranes and also showed increased gene and protein expression of HMGB1 in amnion compared to choriodecidua within the zone of altered morphology (ZAM) area. 42 These data further support the idea that HMGB1 may be an important contributor to the initiation of fetal membrane weakening in rupture of membranes (ROM) and pPROM.…”

“… 52 It is thought that hyperacetylation at its lysine residues located within the nuclear localization signals (NLS) NLS1 and NLS2 (Figure 1B) leads to its cytosolic accumulation and subsequent passive release by necrotic or damaged cells (Figure 1C). 53 It is thought that HMGB1 release can be caused by many different kinds of cellular stress, 54 such as in response to a change in environmental oxidation status. Interestingly, key cysteine residues of HMGB1 can also be modified to form the disulfide, thiol, and oxidized HMGB1 isoforms.…”