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In this review, we discuss recent reproductive organ-on-a-chip (OoC) experiments that encompass multiple target areas of investigation, including model fabrication strategies, transport mechanisms, and immunology. We highlight fetal membrane and placental biology, OoC history and background, and the designs of reproductive OoC platforms. Reproductive OoC designs include fetal membrane models such as the Fetal Membrane-on-a-chip (FMOC) and others, placental models such as the placenta on-a-chip, and full reproductive tract models such as EVATAR. Diverse fabrication strategies and the integration of multiple model materials are explored. OoC samples can be analyzed with many analytical techniques, including mass spectrometry, fluorescence microscopy, ELISAs, impedance spectroscopy, and electrochemical techniques. The future of reproductive OoC models is a promising technology for advancing preterm birth (PTB) research, pharmacology studies, and fertility technologies. [ABSTRACT FROM AUTHOR]

Fetal or gestational membranes extend from the placenta to enclose the fetus and amniotic fluid. While the membranes spontaneously rupture at term in normal pregnancies, they can rupture prematurely before the onset of labor, termed preterm prelabor rupture of membranes (PPROM). PPROM can be triggered by bacterial infection or sterile inflammation in the membranes, known as chorioamnionitis (CAM). The membranes derive their tensile strength from a collagen‐rich extracellular matrix (ECM); as such, understanding the enzymes and processes that can degrade the membrane ECM are of paramount importance. Matrix metalloproteinases (MMPs) are a class of enzymes capable of degrading collagen and other components of the ECM, and can be induced by inflammation. We used a scoping review to address the question of how MMP activity is associated with PPROM, particularly their induction due to sterile or nonsterile CAM. We have found that the most studied MMPs in PPROM were MMPs 2, 8, and 9. Additionally, some MMPs are constitutively active, while others are induced by inflammation. Mechanistic studies of the pathways that induce MMP activation are sparse, and this area is ripe for future studies. Targeting MMP activation could be a future strategy to delay or prevent PPROM. [ABSTRACT FROM AUTHOR]

The fetal membranes enclose the growing fetus and amniotic fluid. Preterm prelabor rupture of fetal membranes is a leading cause of preterm birth. Fetal membranes are composed of many different cell types, both structural and immune. These cells must coordinate functions for tensile strength and membrane integrity to contain the growing fetus and amniotic fluid. They must also balance immune responses to pathogens with maintaining maternal-fetal tolerance. Perturbation of this equilibrium can lead to preterm premature rupture of membranes without labor. In this review, we describe the formation of the fetal membranes to orient the reader, discuss some of the common forms of communication between the cell types of the fetal membranes, and delve into the methods used to tease apart this paracrine signaling within the membranes, including emerging technologies such as organ-on-chip models of membrane immunobiology. [ABSTRACT FROM AUTHOR]

Problem: Gestational membrane (GM) infection provokes inflammation and can result in preterm prelabor rupture of membranes (PPROM). The choriodecidual layer of the GM includes decidual stromal cells (DSC), cytotrophoblasts (CTB), and macrophages (Mφ). Our laboratory has previously shown that DSCs suppress Mφ TNF‐α production through secreted prostaglandin E2. We hypothesized that CTBs would also inhibit Mφ cytokine expression through secreted mediators. Method of Study: THP.1 Mφ‐like cells with an NF‐κB reporter construct or human blood monocyte‐derived Mφ were co‐cultured with the Jeg3 CTB cell line or primary human CTBs and challenged with group B streptococcus (GBS) or Toll‐like receptor (TLR) agonists. Conditioned medium generated from CTB cultures was applied to Mφ cultures before infection or treatment. Alternatively, CTBs were co‐incubated with, but physically separated from, Mφ and GBS or TLR‐stimulated. NF‐κB was assessed via alkaline phosphatase assay, and proinflammatory mediators were assessed by qRT‐PCR and ELISA. Results: CTBs suppressed GBS‐ or TLR‐stimulated Mφ NF‐κB activity, and TNF‐α and MMP9 production. Direct physical contact between CTBs and Mφ was required for full immunosuppression. Immunosuppression could be overcome by increasing the ratio of Mφ to CTB. Conclusions: CTBs limit Mφ NF‐κB activation and production of TNF‐α and MMP9 through an as‐yet unknown, cell‐to‐cell contact‐mediated mechanism. This suppression is distinct from the PGE2‐mediated Mφ TNF‐α suppression by DSC, suggesting that DSCs and CTBs regulate Mφ inflammation through distinct mechanisms. How Mφ integrates these signals in an intact GM will be paramount to determining causes and prevention of PPROM. [ABSTRACT FROM AUTHOR]

The scavenger receptor macrophage receptor with collagenous structure (MARCO) promotes protective innate immunity against bacterial and parasitic infections; however, its role in host immunity against fungal pathogens, including the major human opportunistic fungal pathogen Cryptococcus neoformans, remains unknown. Using a mouse model of C. neoformans infection, we demonstrated that MARCO deficiency leads to impaired fungal control during the afferent phase of cryptococcal infection. Diminished fungal containment in MARCO-/- mice was accompanied by impaired recruitment of Ly6Chigh monocytes and monocyte-derived dendritic cells (moDC) and lower moDC costimulatory maturation. The reduced recruitment and activation of mononuclear phagocytes in MARCO-/- mice was linked to diminished early expression of IFN-g along with profound suppression of CCL2 and CCL7 chemokines, providing evidence for roles of MARCO in activation of the CCR2 axis during C. neoformans infection. Lastly, we found that MARCO was involved in C. neoformans phagocytosis by resident pulmonary macrophages and DC. We conclude that MARCO facilitates early interactions between C. neoformans and lung-resident cells and promotes the production of CCR2 ligands. In turn, this contributes to a more robust recruitment and activation of moDC that opposes rapid fungal expansion during the afferent phase of cryptococcal infection. [ABSTRACT FROM AUTHOR]

Supplemental O(2) is commonly employed in patients with respiratory failure; however, hyperoxia is also a potential contributor to lung injury. In animal models, hyperoxia causes oxidative stress in the lungs, resulting in increased inflammation, edema, and permeability. We hypothesized that oxidative stress from prolonged hyperoxia leads to endoplasmic reticulum (ER) stress, resulting in activation of the unfolded protein response (UPR) and induction of CCAAT enhancer-binding protein homologous protein (CHOP), a transcription factor associated with cell death in the setting of persistent ER stress. To test this hypothesis, we exposed the mouse lung epithelial cell line MLE-12 to 95% O(2) for 8-24 h and evaluated for evidence of UPR induction and CHOP induction. Hyperoxia caused increased CHOP expression without other evidence of UPR activation. Because CHOP expression is preceded by phosphorylation of the α-subunit of the eukaryotic initiation factor-2 (eIF2α), we evaluated the role of double-stranded RNA-activated protein kinase (PKR), a non-UPR-associated eIF2α kinase. Hyperoxia caused PKR phosphorylation, and RNA interference knockdown of PKR attenuated hyperoxia-induced CHOP expression. In vivo, hyperoxia induced PKR phosphorylation and CHOP expression in the lungs without other biochemical evidence for ER stress. Additionally, Ddit3(-/-) (CHOP-null) mice had increased lung edema and permeability, indicating a previously unknown protective role for CHOP after prolonged hyperoxia. We conclude that hyperoxia increases CHOP expression via an ER stress-independent, PKR-dependent pathway and that increased CHOP expression protects against hyperoxia-induced lung injury.