Protease Inhibition Improves Healing of The Vaginal Wall after Obstetrical Injury: Results from a Preclinical Animal Model.
Animals
Delivery, Obstetric
/ adverse effects
Extracellular Matrix Proteins
/ antagonists & inhibitors
Female
Humans
Hydroxamic Acids
/ pharmacology
Obstetric Surgical Procedures
/ adverse effects
Pelvic Organ Prolapse
/ drug therapy
Pregnancy
Pregnancy Complications
/ drug therapy
Protease Inhibitors
/ pharmacology
Rats
Recombinant Proteins
/ genetics
Risk Factors
Uterine Prolapse
/ drug therapy
Vagina
/ drug effects
Wound Healing
/ drug effects
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
14 04 2020
14 04 2020
Historique:
received:
07
06
2019
accepted:
16
03
2020
entrez:
15
4
2020
pubmed:
15
4
2020
medline:
1
12
2020
Statut:
epublish
Résumé
Vaginal delivery with obstetrical trauma is a risk factor for pelvic organ prolapse later in life. Loss of fibulin-5 (FBLN5), an elastogenesis-promoting cellular matrix protein, results in prolapse in mice. Here, we evaluated effects of pregnancy, parturition, and obstetrical injury on FBLN5 content, elastic fibers, biomechanics, and histomorphology of the vaginal wall in rats. Further, we analyzed the effects of actinonin, a protease inhibitor, on obstetrical injury of the vaginal wall. Vaginal FBLN5 decreased significantly in pregnancy, and injury resulted in further downregulation. Stiffness of the vaginal wall decreased 82% in pregnant rats and 74% (p = 0.019) with injury relative to uninjured vaginal delivery controls at 3d. Actinonin ameliorated loss of FBLN5, rescued injury-induced loss of elastic fibers and biomechanical properties after parturition, and reduced the area of injury 10-fold. We conclude that pregnancy and parturition have a profound impact on vaginal FBLN5 and biomechanics of the vaginal wall. Further, obstetrical injury has significant deleterious impact on recovery of the vaginal wall from pregnancy. Actinonin, a non-specific matrix metalloprotease inhibitor, improved recovery of the parturient vaginal wall after obstetrical injury.
Identifiants
pubmed: 32286390
doi: 10.1038/s41598-020-63031-6
pii: 10.1038/s41598-020-63031-6
pmc: PMC7156712
doi:
Substances chimiques
Extracellular Matrix Proteins
0
Fbln5 protein, rat
0
Hydroxamic Acids
0
Protease Inhibitors
0
Recombinant Proteins
0
actinonin
P18SPA8N0K
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
6358Subventions
Organisme : NIH HHS
ID : S10 OD021684
Pays : United States
Références
Schaffer, J. I., Wai, C. Y. & Boreham, M. K. Etiology of pelvic organ prolapse. Clin Obstet Gynecol 48, 639–647 (2005).
doi: 10.1097/01.grf.0000170428.45819.4e
Kim, C. M. et al. Risk factors for pelvic organ prolapse. Int J Gynaecol Obstet 98, 248–251 (2007).
doi: 10.1016/j.ijgo.2007.02.019
Gyhagen, M., Bullarbo, M., Nielsen, T. F. & Milsom, I. Prevalence and risk factors for pelvic organ prolapse 20 years after childbirth: a national cohort study in singleton primiparae after vaginal or caesarean delivery. BJOG 120, 152–160 (2013).
doi: 10.1111/1471-0528.12020
Memon, H. & Handa, V. L. Pelvic floor disorders following vaginal or cesarean delivery. Current opinion in obstetrics & gynecology 24, 349–354 (2012).
doi: 10.1097/GCO.0b013e328357628b
Handa, V. L. et al. Pelvic floor disorders 5-10 years after vaginal or cesarean childbirth. Obstetrics and gynecology 118, 777–784 (2011).
doi: 10.1097/AOG.0b013e3182267f2f
Jelovsek, J. E. et al. Effect of Uterosacral Ligament Suspension vs Sacrospinous Ligament Fixation With or Without Perioperative Behavioral Therapy for Pelvic Organ Vaginal Prolapse on Surgical Outcomes and Prolapse Symptoms at 5 Years in the OPTIMAL Randomized Clinical Trial. Jama 319, 1554–1565 (2018).
doi: 10.1001/jama.2018.2827
Nygaard, I. et al. Long-term outcomes following abdominal sacrocolpopexy for pelvic organ prolapse. JAMA 309, 2016–2024 (2013).
doi: 10.1001/jama.2013.4919
Drewes, P. G. et al. Pelvic Organ Prolapse in Fibulin-5 Knockout Mice: Pregnancy-Induced Changes in Elastic Fiber Homeostasis in Mouse Vagina. The American Journal of Pathology 170, 578–589 (2007).
doi: 10.2353/ajpath.2007.060662
Yanagisawa, H. et al. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature 415, 168–171 (2002).
doi: 10.1038/415168a
Nakamura, T. et al. Fibulin-5/DANCE is essential for elastogenesis in vivo. Nature 415, 171–175 (2002).
doi: 10.1038/415171a
Budatha, M. et al. Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans. J Clin Invest 121, 2048–2059 (2011).
doi: 10.1172/JCI45636
Budatha, M. et al. Dysregulation of protease and protease inhibitors in a mouse model of human pelvic organ prolapse. Plos one 8, e56376 (2013).
doi: 10.1371/journal.pone.0056376
Rahn, D. D., Ruff, M. D., Brown, S. A., Tibbals, H. F. & Word, R. A. Biomechanical properties of the vaginal wall: effect of pregnancy, elastic fiber deficiency, and pelvic organ prolapse. Am J Obstet Gynecol 198(590), e591–596 (2008).
Chin, K. et al. Pelvic Organ Support in Animals with Partial Loss of Fibulin-5 in the Vaginal Wall. Plos one 11, e0152793 (2016).
doi: 10.1371/journal.pone.0152793
Florian-Rodriguez, M. et al. Effect of Protease Inhibitors in Healing of the Vaginal Wall. Sci Rep 9, 12354 (2019).
doi: 10.1038/s41598-019-48527-0
Delancey, J. O. Fascial and muscular abnormalities in women with urethral hypermobility and anterior vaginal wall prolapse. Am J Obstet Gynecol 187, 93–98 (2002).
doi: 10.1067/mob.2002.125733
Richardson, A. C., Edmonds, P. B. & Williams, N. L. Treatment of stress urinary incontinence due to paravaginal fascial defect. Obstet Gynecol 57, 357–362 (1981).
pubmed: 7465150
Liu, X. et al. Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nat Genet 36, 178–182 (2004).
doi: 10.1038/ng1297
Rahn, D. D. et al. Failure of pelvic organ support in mice deficient in fibulin-3. Am J Pathol 174, 206–215 (2009).
doi: 10.2353/ajpath.2009.080212
Downing, K. T. et al. The role of mode of delivery on elastic fiber architecture and vaginal vault elasticity: a rodent model study. J Mech Behav Biomed Mater 29, 190–198 (2014).
doi: 10.1016/j.jmbbm.2013.08.025
Nygaard, I. E. et al. Physical and cultural determinants of postpartum pelvic floor support and symptoms following vaginal delivery: a protocol for a mixed-methods prospective cohort study. BMJ Open 7, e014252 (2017).
doi: 10.1136/bmjopen-2016-014252
Lowder, J. L. et al. Biomechanical adaptations of the rat vagina and supportive tissues in pregnancy to accommodate delivery. Obstetrics and gynecology 109, 136–143 (2007).
doi: 10.1097/01.AOG.0000250472.96672.6c
Feola, A. et al. Impact of pregnancy and vaginal delivery on the passive and active mechanics of the rat vagina. Annals of biomedical engineering 39, 549–558 (2011).
doi: 10.1007/s10439-010-0153-9
Almine, J. F. et al. Elastin sequences trigger transient proinflammatory responses by human dermal fibroblasts. FASEB J 27, 3455–3465 (2013).
doi: 10.1096/fj.13-231787
Starcher, B. & Percival, S. Elastin turnover in the rat uterus. Connective tissue research 13, 207–215 (1985).
doi: 10.3109/03008208509152400
Fata, J. E., Ho, A. T., Leco, K. J., Moorehead, R. A. & Khokha, R. Cellular turnover and extracellular matrix remodeling in female reproductive tissues: functions of metalloproteinases and their inhibitors. Cell Mol Life Sci 57, 77–95 (2000).
doi: 10.1007/s000180050500