Protease Inhibition Improves Healing of The Vaginal Wall after Obstetrical Injury: Results from a Preclinical Animal Model

Sci Rep. 2020 Apr 14;10(1):6358. doi: 10.1038/s41598-020-63031-6.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Delivery, Obstetric / adverse effects
  • Extracellular Matrix Proteins / antagonists & inhibitors
  • Extracellular Matrix Proteins / genetics*
  • Female
  • Humans
  • Hydroxamic Acids / pharmacology
  • Obstetric Surgical Procedures / adverse effects
  • Pelvic Organ Prolapse / drug therapy*
  • Pelvic Organ Prolapse / etiology
  • Pelvic Organ Prolapse / genetics
  • Pregnancy
  • Pregnancy Complications / drug therapy
  • Pregnancy Complications / physiopathology
  • Pregnancy Complications / prevention & control
  • Protease Inhibitors / pharmacology
  • Rats
  • Recombinant Proteins / genetics*
  • Risk Factors
  • Uterine Prolapse / drug therapy
  • Uterine Prolapse / physiopathology
  • Uterine Prolapse / prevention & control
  • Vagina / drug effects*
  • Vagina / physiopathology
  • Vagina / surgery
  • Wound Healing / drug effects
  • Wound Healing / genetics*

Substances

  • Extracellular Matrix Proteins
  • Fbln5 protein, rat
  • Hydroxamic Acids
  • Protease Inhibitors
  • Recombinant Proteins
  • actinonin