Effect of Pregnancy and Delivery on Cytokine Expression in a Mouse Model of Pelvic Organ Prolapse

Couri, Bruna M.; Borazjani, Ali; Balog, Brian; Kuang, Mei; Butler, Robert S.; Penn, Marc S.; Damaser, Margot S.

doi:10.1097/spv.0000000000000394

Cited by 6 publications

(3 citation statements)

References 42 publications

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“…Additionally, unlinked cell culture experiments [53], the presence of both elongated and round macrophages positive for M1 and M2 markers in IpL indicates that, in this specific tissue remodeling microenvironment, a more complex macrophage polarization spectra may be necessary to guarantee tissue homeostasis. This balance between proinflammatory and anti-inflammatory mediators is crucial to develop a process that could be considered “orderly” inflammation necessary for the activation of the wound-healing response and for tissue homeostasis to be restored [62], which seem to be essential to proper remodeling of the IpL since mouse LOXL1 −/− pelvic floor disorders after parturition are associated with both increased proinflammatory cytokine production at the pelvic organs [63] and exacerbated interpubic tissue relaxation during labor [12].…”

Section: Discussionmentioning

confidence: 99%

Recruitment of monocytes and mature macrophages in mouse pubic symphysis relaxation during pregnancy and postpartum recovery†

Castelucci

Consonni

Rosa

et al. 2019

Biology of Reproduction

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Appropriate remodeling of the female lower reproductive tract and pelvic floor is essential during normal mammalian pregnancy, labor, and postpartum recovery. During mouse pregnancy, in addition to reproductive tract modifications, the pubic symphysis (PS) is remodeled into a soft interpubic ligament (IpL) to provide safe delivery of the offspring and fast postpartum recovery. Although temporal changes in the phenotypes of myeloid cells, such as mononuclear phagocytes, are crucial to remodeling the lower reproductive tract organs in preparation for a safe delivery, little is known about the involvement of recruited monocytes or macrophages in mouse PS remodeling. We used combined light microscopy, electron microscopy, and qPCR analysis to investigate the profile of recruited monocytes and macrophage polarization markers in C57Bl6 mouse interpubic tissues during pregnancy (D12, D18, and D19) and early days postpartum (1 dpp and 3 dpp) to better identify their presence in proper remodeling of the mouse PS. Our morphological data show that the number of recruited monocytes is increased in interpubic tissues and that recruited monocytes differentiate into proinflammatory or anti-inflammatory macrophage phenotypes from D18 to 3 dpp, which may contribute to dynamic changes in the gene expression of specific inflammatory mediators involved in interpubic tissue remodeling at these time points. Therefore, our morphological and quantitative gene expression data suggest that both differentiated macrophages from recruited monocytes and polarized macrophages may collaborate for IpL relaxation at labor and the appropriate repair of the PS after the first pregnancy.

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Section: Discussionmentioning

confidence: 99%

Recruitment of monocytes and mature macrophages in mouse pubic symphysis relaxation during pregnancy and postpartum recovery†

Castelucci

Consonni

Rosa

et al. 2019

Biology of Reproduction

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“…The results of a separate study ( 37 ) showed that compared with the levels in WT mice, the total and unit cell amounts of elastin and unit cell amount produced by non-epithelial vaginal cells in LOXL1-deficient mice were significantly reduced, while the ratio of MMP-9/TIMP-1 was relatively high. A recent study by Couri et al ( 64 ) indicated that in contrast to WT mice, the mRNA levels of chemokine C-X-C motif ligand 12 and chemokine C-C motif ligand 7 (mediators of inflammatory response) were differentially upregulated in the tissues of virgin Loxl1-KO mice, and they were significantly upregulated in the vagina, urethra, bladder, and rectum of pregnant Loxl1-KO mice. However, in Loxl1-KO mice after vaginal childbirth, cytokines were expressed differently in terms of time, tissue, and concentration.…”

Section: Fbln5 and Loxl1mentioning

confidence: 99%

Potential molecular targets for intervention in pelvic organ prolapse

Wu,

Liu,

2023

Front. Med.

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Pelvic organ prolapse (POP) is a concerning gynecological benign illness in middle-aged and senior women. Its etiology is complex, the incidence rate is high, symptoms are clinically subjective, and its influence tends to be polarized. At present, for those who need medical treatment, whether surgical or non-surgical, complications cannot be ignored, and treatment effect needs to be optimized. However, there is a lack of accurate molecular biological interventions for the prevention, diagnosis, progression delay, and treatment of POP. Here, we reviewed the current state of understanding of the molecular mechanisms and factors associated with POP etiology. These factors include cyclins, matrix metal peptidases/tissue inhibitors of metalloproteinases, microRNAs, homeobox A11, transforming growth factor β1, insulin-like growth factor 1, fibulin 5, lysyl oxidase-like 1, oxidative stress, inflammatory response, estrogen, and other potential biomarkers associated with POP. In addition, relevant molecular targets that may be used to intervene in POP are summarized. The aim of this review was to provide more information to identify accurate potential biomarkers and/or molecular targets for the prevention, diagnosis, progression delay, and treatment of POP, with the goal of improving medical treatment for patients at-risk for POP or having POP. Continued research is needed to identify additional details of currently accepted molecular mechanisms and to identify additional mechanisms that contribute to POP.

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“…These endogenous signals trigger a fast macrophage response and interact with toll-like receptors (TLRs), leading to a sterile inflammation process to solve the adverse condition that initially led to DAMP release 31 – 33 . Interestingly, aberrant modifications in the mouse reproductive tract or pelvic floor EMC molecules seem to be intimately associated with increased pro-inflammatory cytokine production in pelvic organs 34 and lead to exacerbated interpubic tissue relaxation for labor 15 .…”

Section: Introductionmentioning

confidence: 99%

Evidence of macrophage modulation in the mouse pubic symphysis remodeling during the end of first pregnancy and postpartum

Castelucci

Pereira

Fioramonte

et al. 2020

Sci Rep

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pregnancy (D19) is due to the combined action of hormones and a wide variety of proteolytic enzymes, such as matrix metalloproteinases (Mmps), dipeptidyl peptidases (ADAMTs) and tissue inhibitor of metalloproteinases (Timps) and hyaluronidases (Hyals) 8,16. These molecules change the levels of proteoglycan, hyaluronic acid (HA), collagen, elastic fibers and water of IpL, leading to the increase in compliance and extendibility of this ligament before parturition 8-10,17. At IpL involution in postpartum, proteolytic enzymes and Hyals activity gradually decreased after 3dpp 8,16 , allowing bones and cartilage reformation by 10dpp to 40dpp at first pregnancy 12-14. Along with reproductive tissue remodeling, temporal changes in immune cell phenotypes reveal dynamic and multifaceted functions that are crucial to proper pregnancy development and successful labor 18-22. Among immune cells, macrophages are involved in a wide range of gestational processes, including regulation of immune cell activities, placental cell invasion, initiation of labor and postpartum reproductive organ remodeling 19,23-29. These cells show significant heterogeneity in function, majorly affected by their microenvironment. Under physiological conditions such as pregnancy connective tissue remodeling 30 , enzymatic breakdown of ECM components (proteoglycans and HA) produces soluble fragments that can act as damage-associated molecular patterns (DAMP). These endogenous signals trigger a fast macrophage response and interact with toll-like receptors (TLRs), leading to a sterile inflammation process to solve the adverse condition that initially led to DAMP release 31-33. Interestingly, aberrant modifications in the mouse reproductive tract or pelvic floor EMC molecules seem to be intimately associated with increased pro-inflammatory cytokine production in pelvic organs 34 and lead to exacerbated interpubic tissue relaxation for labor 15. In addition to recognizing the importance of immune cells in female reproductive tract modifications during pregnancy, studies showing immune cell involvement in PS remodeling in mice are scarce 12,14,20,35. Although neither neutrophils nor eosinophils are associated with this process 12,20,35 , recent data showed that both proinflammatory (M1) and anti-inflammatory (M2) activated macrophage phenotypes are present in the IpL from labor to early postpartum, suggesting that the differential gene expression of inflammatory mediators found in mouse interpubic tissues during this period may reflect IpL macrophage activities 36. Although significant PS ECM turnover gives rise to ECM fragments, it is still unknown whether macrophages interact with extracellular DAMPs or actively participate in IpL ECM remodeling for labor and postpartum recovery. The absence of mouse PS widening in the late stage of pregnancy leading to abnormal parturition and dystocia was observed in both genetically manipulated relaxin and relaxin receptor genes 37-39. Interestingly, a similar female mouse phenotype was also reported under combined abla...

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Effect of Pregnancy and Delivery on Cytokine Expression in a Mouse Model of Pelvic Organ Prolapse

Cited by 6 publications

References 42 publications

Recruitment of monocytes and mature macrophages in mouse pubic symphysis relaxation during pregnancy and postpartum recovery†

Recruitment of monocytes and mature macrophages in mouse pubic symphysis relaxation during pregnancy and postpartum recovery†

Potential molecular targets for intervention in pelvic organ prolapse

Evidence of macrophage modulation in the mouse pubic symphysis remodeling during the end of first pregnancy and postpartum

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