Preventing Infection-induced Myometrial Inflammation by a Broad-spectrum Chemokine Inhibitor

Prophylactic administration of a Broad-Spectrum Chemokine Inhibitor (BSCI) led to the suppression of uterine activity, a complete blockade of preterm birth (PTB) induced by Group B Streptococcus in a nonhuman primate, and inhibition of uterine cytokine/chemokine secretion and bacterial endotoxin (LPS)-induced PTB in pregnant mice. This thesis aims to determine the mechanism(s) of the BSCI (FX125L) action on uterine smooth muscle (myometrium). I hypothesize that a BSCI prevents infection-induced contraction of uterine myocytes by inhibiting the expression of pro-inflammatory cytokines and contraction-associated proteins (CAPs). Myometrial biopsies were collected from women at term (not in labour) undergoing elective caesarean section and primary myocytes were isolated. I have shown that the BSCI inhibited: 1) LPS-induced activation of transcription factor NF-kB in myocytes, 2) which caused decrease in chemokine secretion, CAP expression and myocyte collagen gel contraction. I suggest that the BSCI could represent a novel class of therapeutics for PTB prevention in women.M.Sc

A Broad-Spectrum Chemokine Inhibitor Blocks Inflammation-Induced Myometrial Myocyte–Macrophage Crosstalk and Myometrial Contraction

Prophylactic administration of the broad-spectrum chemokine inhibitor (BSCI) FX125L has been shown to suppress uterine contraction, prevent preterm birth (PTB) induced by Group B Streptococcus in nonhuman primates, and inhibit uterine cytokine/chemokine expression in a murine model of bacterial endotoxin (LPS)-induced PTB. This study aimed to determine the mechanism(s) of BSCI action on human myometrial smooth muscle cells. We hypothesized that BSCI prevents infection-induced contraction of uterine myocytes by inhibiting the secretion of pro-inflammatory cytokines, the expression of contraction-associated proteins and disruption of myocyte interaction with tissue macrophages. Myometrial biopsies and peripheral blood were collected from women at term (not in labour) undergoing an elective caesarean section. Myocytes were isolated and treated with LPS with/out BSCI; conditioned media was collected; cytokine secretion was analyzed by ELISA; and protein expression was detected by immunoblotting and immunocytochemistry. Functional gap junction formation was assessed by parachute assay. Collagen lattices were used to examine myocyte contraction with/out blood-derived macrophages and BSCI. We found that BSCI inhibited (1) LPS-induced activation of transcription factor NF-kB; (2) secretion of chemokines (MCP-1/CCL2 and IL-8/CXCL8); (3) Connexin43-mediated intercellular connectivity, thereby preventing myocyte–macrophage crosstalk; and (4) myocyte contraction. BSCI represents novel therapeutics for prevention of inflammation-induced PTB in women

Landscape of Preterm Birth Therapeutics and a Path Forward

Preterm birth (PTB) remains the leading cause of infant morbidity and mortality. Despite 50 years of research, therapeutic options are limited and many lack clear efficacy. Tocolytic agents are drugs that briefly delay PTB, typically to allow antenatal corticosteroid administration for accelerating fetal lung maturity or to transfer patients to high-level care facilities. Globally, there is an unmet need for better tocolytic agents, particularly in low- and middle-income countries. Although most tocolytics, such as betamimetics and indomethacin, suppress downstream mediators of the parturition pathway, newer therapeutics are being designed to selectively target inflammatory checkpoints with the goal of providing broader and more effective tocolysis. However, the relatively small market for new PTB therapeutics and formidable regulatory hurdles have led to minimal pharmaceutical interest and a stagnant drug pipeline. In this review, we present the current landscape of PTB therapeutics, assessing the history of drug development, mechanisms of action, adverse effects, and the updated literature on drug efficacy. We also review the regulatory hurdles and other obstacles impairing novel tocolytic development. Ultimately, we present possible steps to expedite drug development and meet the growing need for effective preterm birth therapeutics