Density of Stromal Cells and Macrophages Associated With Collagen Remodeling in the Human Cervix in Preterm and Term Birth

Abstract

Remodeling of the cervix occurs in advance of labor both at term and at preterm birth. Morphological characteristics associated with remodeling in rodents were assessed in cervix biopsies from women at term (39 weeks' gestation) and preterm (<33 weeks' gestation). Collagen I and III messenger RNA and hydroxyproline concentrations declined in cervix biopsies from women in labor at term and preterm compared to that in the cervix from nonlaboring women. Extracellular collagen was more degraded in sections of cervix from women at term, based on optical density of picrosirius red stain, versus that in biopsies from nonpregnant women. However, collagen structure was unchanged in the cervix from women at preterm labor versus the nonpregnant group. As an indication of inflammation, cell nuclei density was decreased in cervix biopsies from pregnant women irrespective of labor compared to the nonpregnant group. Moreover, CD68-stained macrophages increased to an equivalent extent in cervix subepithelium and stroma from groups in labor, both at term and preterm, as well as in women not in labor at term. Evidence for a similar inflammatory process in the remodeled cervix of women at term and preterm birth parallels results in rodent models. Thus, a conserved final common mechanism involving macrophages and inflammation may characterize the transition to a ripe cervix before birth at term and in advance of premature birth.

Immunobiology of Cervix Ripening

“…In mice, cervix length is increased with fewer cell nuclei/area evident in stroma with pregnancy (Figure 1). A similar finding is evident in women before pregnancy compared to those pregnant whether or not in labor (15). Reduced cell nuclei density may reflect hypertrophy of cells or an increase in extracellular space.…”

“…These effects on remodeling were overshadowed by evidence that treatment caused fetal demise without preterm birth possible through impaired placental function led. Finally, a study of cervix biopsies from around 30 weeks of pregnancy reinforces the conclusion that resident macrophages were increased compared to that in women at term not in labor (15). The collective implication is that morphological evidence has accumulated to reinforce the concept that the presence and likely activity of macrophages are an essential part of the process that remodels the cervix in preparation for parturition.…”

“…Evidence indicates that hydroxyproline content declines from about mid-pregnancy to term. Of critical relevance for remodeling is that hydroxyproline is lower in the cervix of preterm women not in labor (average gestation 30 weeks) vs. that in non-pregnant women (15,29). Similarly by 10-12 days of pregnancy in mice, hydroxyproline is reduced compared to that in non-pregnants (30).…”

Mapping out p38MAPK

“…In human cervix, p38 activation has been associated with parturition but this is likely due to inflammatory cell traffic macrophages 61–63 and or association with tissues such as the fetal membranes overlying the cervix at term 64, 65 as this tissue expresses an increased inflammatory signature. 66 …”

The pathophysiology of human premature cervical remodeling resulting in spontaneous preterm birth: Where are we now?

“…(55–65) However, although studies have shown an influx of immune cells into cervical tissue, it is unclear what triggers the immune cells to travel to the cervix. In addition, evidence from other studies suggest that immune cell activation is not vital for cervical ripening.…”