**3. Hypothesis and realities on gestational cervical remodeling timing: molecular insights**

Two mouse models have provided new insights into distinct processes of preterm CR: infectious/inflammatory model [68, 69] and progesterone loss/withdrawn/noninfectious model, with differences in gene pathways in preterm, and term. Analyzes of preterm mice collagen structure changes [36] showed that immune pathways system activation is sufficient but not necessary for premature ripening [33, 37, 43, 48] being differences regarding collagen fibers in preterm P4 withdrawn/mifepristoneinduced, infected-induced, and term ripening.

#### **3.1 Inflammation in premature cervical ripening**

Lipopolysaccharide (LPS) administration in amniotic sac surroundings elicits a proinflammatory response similar to infection, preterm labor progressing without P4 concentration loss in circulation several hours after administration [68]. SHG demonstrated an interfibrillar spacing increase in collagen fibrils, with increased pores lacking collagen signal in SHG, when LPS treated mice, and preferential disruption collagen fiber architecture in the subepithelial region compared to mid-stroma region, and neutrophils infiltration. Rodents models demonstrated that ripening may be characterized as a physiologic inflammatory process, by myeloid immune cells, as neutrophils, with their chemotactic factors [69], with a temporal coincidence of decreased density of cell nuclei, decline in cross-linked extracellular collagen, and increased presence of macrophages, sustaining the immune cells hypothesis [70–72], so cervical increased biomechanic distensibility is before uterine contractile capabilities for labor. Flow cytometry and cell sorting were used to determine immune cells role in ECM remodeling before, during, and after parturition. Myeloid immune cells/leukocytes invade EMC and are activated to product proinflammatory mediators [IL-8, monocyte chemo-attractant protein-1 (MCP-1), IL-1β, and TNF-α], and proteolytic enzymes [73] altering EMC. Markers of myeloid cell differentiation and activation were used to define phenotype and function [73]. Peripheral blood does not reflect changes in cervical myeloid cell numbers. The proinflammatory mediators are ripening inducers, through prostaglandins [74], high concentrations of inflammatory cytokines (IL-6, IL-8, and MCP-1) are depicted in human PTB cervix [75]. Monocytes and eosinophils increase in cervix before birth, in a progesteroneregulated fashion, whereas macrophages number is unchanged. The cytologic conclusion is that myeloid-derived cells do not orchestrate processes required for cervical ripening initiation before birth [73].

Macrophages are analyzed in many studies. They are present in gestational cervix with different phenotypes (M1 and M2), considered to be most involved in tissue postpartum repair, sustained by increased mRNA expression of Csfr1, and markers of alternatively activated M2 in labor, or shortly after fetal expulsion [73]. Hunter

### *Abnormal Cervical Remodeling Early Depiction by Ultrasound Elastography: Potential… DOI: http://dx.doi.org/10.5772/intechopen.113314*

et al. [34] described a special phenotype of macrophages or phagocytic leukocytes, partially similar with blood—born monocytes, present from the 12th week in normal cases, their absence being a sPTB risk marker. These cells have critical role in cervical immunity, by preventing microbial translocation to feto-placental unit. Leukocyte insufficient recruitment to cervix is supposed to be associated with sPTB recurrence (<34 weeks). The cytokines, and MMPs are increased only in inflammation-induced sPTB, not in term ripening, where is no infection [34].

Prostaglandins are used to induce labor, according to their essential intervention in LPS-mediated preterm ripening, but not term or antiprogestin-driven preterm ripening [76].

Actually, there is a connection between amniotic fluid inflammation and imminent PTB prediction when short cervix in asymptomatic cases, starting with amniotic proteome analysis [77]; inflammation is a giant disruptor of gestational maternalfetal homeostasis.
