Toll-like Receptor-4: A New Target for Preterm Labour Pharmacotherapies?

Abstract

Inflammatory activation, a major driver of preterm birth and subsequent neonatal morbidity, is an attractive pharmacological target for new preterm birth therapeutics. Inflammation elicited by intraamniotic infection is causally associated with preterm birth, particularly in infants delivered ≤34 weeks' gestation. However, sterile triggers of PTB, including placental ischaemic injury, uterine distention, cervical disease, or imbalance in the immune response, also act through inflammatory mediators released in response to tissue damage. Toll-like Receptors (TLRs) are critical upstream gate-keepers controlling the inflammatory activation that precedes preterm delivery, as well as in normal term labour. In particular, TLR4 is implicated for its capacity to sense and integrate a range of disparate infectious and sterile pro-inflammatory triggers, and so acts as a point-ofconvergence through which a range of infectious and sterile agents can activate and accelerate the parturition cascade. Recent studies point to the TLR4 signalling complex as a tractable target for the inhibition of fetal, placental & intraamniotic inflammatory cytokine production. Moreover, studies on mice show that novel small molecule antagonists of TLR4 signalling are highly effective in preventing preterm birth induced by bacterial mimetic LPS, heat-killed E. coli or the TLR4-dependent pro-inflammatory lipid, Platelet Activating Factor (PAF). In this review, we discuss the role of TLR4 in regulating the timing of birth and the potential utility of TLR4 antagonists as novel therapeutics for preterm delivery.

Endothelial Cells in the Decidual Bed Are Potential Therapeutic Targets for Preterm Birth Prevention

“…Until now, the mechanism by which TLR4-induced inflammation induces PTB has largely been descriptive. There are reports that decidual macrophages and neutrophils express TLR4 and may play a role in inflammation-induced PTB (Kadam et al, 2017; Robertson et al, 2018; Yan et al, 2018); whether other TLR4-expressing cells are involved in inflammation-induced PTB remains unknown. Using genetic mouse models and breeding strategies, we sought to dissect the role of maternal decidua apart from the fetal-placental entity in response to systemic LPS injection.…”

Challenges and prospects of preterm birth prediction in multiple pregnancies

“…Значительный объем доказательств подтверждает роль инфекционно-воспалительных факторов в патогенезе преждевременных родов [5,[40][41][42][43][44]. Согласно данным большинства исследований развитие 25-40 % преждевременных родов обусловлено внутриматочной инфекцией [5,32,[40][41][42], поэтому микробиологический скрининг является неотъемлемой частью прогнозирования преждевременных родов как при одноплодной, так и при многоплодной беременности.…”

“…Согласно современным представлениям система врожденного иммунитета представляет собой первую линию иммунологической защиты от различных инфекционных агентов, а первичный воспалительный ответ на патогены опосредуется специфическими рецепторами (Toll-подобные рецепторов (TLR)) [44,45]. Под влиянием лигандов Toll-подобные рецепторы увеличивают локальный синтез хемокинов, цитокинов и простагландинов, что запускает механизм реализации воспалительного ответа (синтез ИЛ-1, который, в свою очередь, инициирует выброс других цитокинов, таких как ФНО-α, ИЛ-6 и ИЛ-8) [46][47][48].…”

Mesenchymal Stem Cells Attenuate Lipopolysaccharide-Induced Inflammatory Response in Human Uterine Smooth Muscle Cells

“…15 LPS-mediated activation of TLR-4 followed by MAPK protein activation triggers production of proinflammatory cytokines, activating the NF-κB pathway, and increasing the risk of preterm birth. 17,26 Mesenchymal stem cells (MSCs) are unique multipotent cells that possess powerful immunomodulatory properties. 27 MSCs are currently being tested in clinical trials at different phases for a variety of pathologic conditions including graft versus host disease, inflammatory airway diseases, and inflammatory bowel diseases.…”

“… 15 LPS-mediated activation of TLR-4 followed by MAPK protein activation triggers production of proinflammatory cytokines, activating the NF-κB pathway, and increasing the risk of preterm birth. 17 26 …”