The cytotrophoblast of human placenta transitions into an outer multinucleated syncytiotrophoblast (STB) layer that covers chorionic villi which are in contact with maternal blood in the intervillous space. During pregnancy, the Zika virus (ZIKV) poses a serious prenatal threat. STB cells are resistant to ZIKV infections, yet placental cells within the mesenchyme of chorionic villi are targets of ZIKV infection. We seek to determine whether ZIKV can open the paracellular pathway of STB cells. This route is regulated by tight junctions (TJs) which are present in the uppermost portion of the lateral membranes of STB cells. We analyzed the paracellular permeability and expression of E-cadherin, occludin, JAMs –B and –C, claudins -1, -3, -4, -5 and -7, and ZO-1, and ZO-2 in the STB of placentae from ZIKV-infected and non-infected women. In ZIKV-infected placentae, the pattern of expression of TJ proteins was preserved, but the amount of claudin-4 diminished. Placentae from ZIKV-infected women were permeable to ruthenium red, and had chorionic villi with a higher mean diameter and Hofbauer hyperplasia. Finally, ZIKV added to the basolateral surface of a trophoblast cell line reduced the transepithelial electrical resistance. These results suggest that ZIKV can open the paracellular pathway of STB cells.

Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 is present in a variety of placental cells, including endothelium. Here, we analyze the impact of COVID-19 in placental endothelium, studying by immunofluorescence the expression of von Willebrand factor (vWf), claudin-5, and vascular endothelial (VE) cadherin in the decidua and chorionic villi of placentas from women with mild and severe COVID-19 in comparison to healthy controls. Our results indicate that: (1) vWf expression increases in the endothelium of decidua and chorionic villi of placentas derived from women with COVID-19, being higher in severe cases; (2) Claudin-5 and VE-cadherin expression decrease in the decidua and chorionic villus of placentas from women with severe COVID-19 but not in those with mild disease. Placental histological analysis reveals thrombosis, infarcts, and vascular wall remodeling, confirming the deleterious effect of COVID-19 on placental vessels. Together, these results suggest that placentas from women with COVID-19 have a condition of leaky endothelium and thrombosis, which is sensitive to disease severity.

Ions and molecules move across epithelial barriers by two pathways, the transcellular and the paracellular. The former is taken by lipophilic compounds, or by ions and molecules that move across the plasma membrane through pumps, carriers or exchangers. The second route is regulated by the tight junction (TJ) that through paracellular channels, allows the transport of ions across epithelial barriers. Since, a wide variety of bioactive molecules like peptides, proteins and oligonucleotides cannot use the transcellular route, due to their hydrophilic nature, interest has arisen in devising procedures to open the TJ in a reversible manner for paracellular drug delivery. Here, we describe how different strategies have been devised to enhance the paracellular intestinal absorption of drugs; to open the blood-brain barrier (BBB) to allow the penetration of drugs for the treatment of disorders and tumors of the central nervous system; or to deliver antigens into the subjacent mucosa associated lymphoid tissues, for the development of mucosal vaccines. The strategies described, include the use of peptides, antibodies and miRNAs that target proteins of the apical junctional complex, as well as toxins derived from microorganisms that open the TJ by inducing the contraction of the cortical actomyosin ring. Also, we describe how paracellular absorption, is enhanced by drugs that extract cholesterol from the plasma membrane, surfactants, fatty acids, oligosaccharides, cationic polymers, nitric oxide donors and calcium chelators. Likewise, we explain how the BBB has been opened by employing tumor necrosis factor-α, bradykinin, short chain alkylglycerols, hyperosmotic mannitol and focused ultrasound.

Resolution of inflammation and mucosal wound healing are crucial processes required to re-establish homeostasis following injury of mucosal tissues. Maresin-2 (MaR2), a lipid specialized pro-resolving mediator derived from omega-3 polyunsaturated fatty acid, has been reported to promote resolution of inflammation. However, a potential role for MaR2 in regulating mucosal repair remains undefined. Using lipidomic analyses, we demonstrate biosynthesis of MaR2 in healing intestinal mucosal wounds in vivo. Importantly, administration of exogenous MaR2 promoted mucosal repair following dextran sulfate sodium-induced colitis or biopsy-induced colonic mucosal injury. Functional analyses revealed that MaR2 promotes mucosal wound repair by driving intestinal epithelial migration through activation of focal cell-matrix adhesion signaling in primary human intestinal epithelial cells. Because of its labile nature, MaR2 is easily degradable and requires ultracold storage to maintain functionality. Thus, we created thermostable polylactic acid MaR2 nanoparticles that retain biological activity following extended storage at 4 °C or above. Taken together, these results establish MaR2 as a potent pro-repair lipid mediator with broad therapeutic potential for use in promoting mucosal repair in inflammatory diseases.