A new model for inflammation-induced preterm birth: the role of platelet-activating factor and Toll-like receptor-4

Am J Pathol. 2003 Nov;163(5):2103-11. doi: 10.1016/S0002-9440(10)63567-5.

Abstract

Preterm birth is a leading cause of neonatal morbidity and mortality. Despite a growing body of evidence correlating inflammation with preterm birth, the signal transduction pathways responsible for the emptying of the uterus in the setting of intrauterine inflammation has not been elucidated. We now report a unique, reproducible mouse model of localized intrauterine inflammation. This model results in 100% preterm delivery with no maternal mortality. Using our model, we also show that platelet-activating factor is a crucial mediator of both inflammation-induced preterm birth and fetal demise. Using C3H/HeJ mice, we demonstrate that toll-like receptor-4 (TLR-4) plays a role in lipopolysaccharide-induced preterm birth but not in inflammation-induced fetal death. Immunohistochemistry studies demonstrate the presence of the platelet-activating factor receptor in both endometrial glands and smooth muscle in uterine tissues. Molecular studies demonstrate the differential expression of platelet-activating factor receptor and TLR-4 in uterine and cervical tissue throughout gestation. Quantitative polymerase chain reaction revealed an up-regulation of TLR-4 in the fundal region of the uterus in response to intrauterine inflammation. The use of this model will increase our understanding of the significant clinical problem of inflammation-induced preterm birth and will elucidate signal transduction pathways involved in an inflammatory state.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Disease Models, Animal*
  • Female
  • Immunohistochemistry
  • Inflammation / complications*
  • Lipopolysaccharides / toxicity
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Obstetric Labor, Premature / chemically induced
  • Obstetric Labor, Premature / metabolism*
  • Obstetric Labor, Premature / pathology
  • Platelet Activating Factor / metabolism*
  • Platelet Activating Factor / pharmacology
  • Platelet Membrane Glycoproteins / metabolism
  • Polymerase Chain Reaction
  • Pregnancy
  • Receptors, Cell Surface / metabolism*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / physiology
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • Uterus / drug effects
  • Uterus / metabolism
  • Uterus / pathology

Substances

  • Lipopolysaccharides
  • Membrane Glycoproteins
  • Platelet Activating Factor
  • Platelet Membrane Glycoproteins
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Toll-Like Receptor 4
  • Toll-Like Receptors
  • platelet activating factor receptor