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M2 macrophages exhibit potent anti-inflammatory activity and serve important roles in wound healing. Although gradations occur in macrophage classifications, in general, macrophages differentiate into two phenotypes: Classical interferon-γ (IFN-γ)-activated macrophages (M1 macrophages) by T helper 1 (Th1)-type responses play a role of cellular immunity to infections whereas alternative activated macrophage (M2 macrophages) activated by Th2-type cytokines IL-4 and IL-13 are important in allergic reactions, parasitic infections, fetal tolerance, and tissue repair 8, 9. Macrophage also releases various growth factors and cytokines at the wound site, reconstituting the wound site by forming new blood vessels and regulating fibroblast recruitment. Macrophages phagocytose pathologic organisms and matrix debris, removing necrotic tissue.

Macrophages play an important role in wound healing 6, 7. The mechanisms that promote healing of the fetal membranes are unknown. A small proportion, however, remain undelivered 2 with spontaneous sealing of the membranes 5. It is generally thought that rupture of membrane is irreversible event because most women with pPROM begin labor spontaneously within several days. In addition, iatrogenic pPROM is caused by amniocentesis or fetoscopy, and accidental rupture of membrane during surgery such as cervical cerclage. On the other hand, the majority of pPROM cases are unrelated to infection but may be associated with smoking, low body mass-index, maternal stress, and intrauterine bleeding. Infection-related pPROM requires immediate intervention (delivery) for fear of infection to fetus such as fetal inflammatory syndrome, which is a risk of severe neonatal morbidity with respiratory distress syndrome, neonatal sepsis, pneumonia, chronic lung disease, necrotizing enterocolitis, intraventricular hemorrhage, and cerebral palsy 4, as well as maternal complication such as sepsis. Amniotic fluid cultures indicate that 30% of pPROM are positive for microbial organisms 3. Preterm premature rupture of membrane (pPROM) is defined as the rupture of membrane occurring before 37 weeks of gestation, which is associated with 30–40% of preterm deliveries and occurs in approximately 1–3% of all pregnancies 2. Preterm labor is the leading cause of perinatal morbidity and mortality 1. These findings provide novel insights regarding unique healing mechanisms of amnion. Migration and healing of the amnion mesenchymal compartment, however, remained compromised. Arg1 + macrophages dominated within 24 h.

Recruited macrophages released limited and well-localized amounts of IL-1β and TNF which facilitated epithelial-mesenchymal transition (EMT) and epithelial cell migration. Fetal macrophages from amniotic fluid were recruited to the wounded amnion where macrophage adhesion molecules were highly expressed. Small rupture induced transient upregulation of cytokines whereas large ruptures elicited sustained upregulation of proinflammatory cytokines in the fetal membranes. Using a preclinical mouse model, we found that small ruptures of the fetal membrane closed within 72 h whereas healing of large ruptures was only 40%. Here, we investigated mechanisms of amnion healing. Interestingly, in some pregnancies complicated by preterm premature rupture of membranes (pPROM), membranes heal spontaneously and pregnancy continues until term. Only 30%, however, are positive for microbial organisms by amniotic fluid culture. Infection is considered a leading cause of pPROM due to increased levels of proinflammatory cytokines in amniotic fluid. Preterm premature rupture of membrane (pPROM) is associated with 30–40% of preterm births.