Granulocyte macrophage colony stimulating factor (GM-CSF), the critical intermediate of inflammation-induced fetal membrane weakening, primarily exerts its weakening effect on the choriodecidua rather than the amnion

Anudeepa Sharma; Deepak Kumar; Robert M Moore; Aditi Deshmukh; Brian M Mercer; Joseph M Mansour; John J Moore

doi:10.1016/j.placenta.2019.10.003

Granulocyte macrophage colony stimulating factor (GM-CSF), the critical intermediate of inflammation-induced fetal membrane weakening, primarily exerts its weakening effect on the choriodecidua rather than the amnion

Placenta. 2020 Jan 1:89:1-7. doi: 10.1016/j.placenta.2019.10.003. Epub 2019 Oct 5.

Authors

Anudeepa Sharma¹, Deepak Kumar¹, Robert M Moore¹, Aditi Deshmukh¹, Brian M Mercer², Joseph M Mansour³, John J Moore⁴

Affiliations

¹ Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA.
² Reproductive Biology, Case Western Reserve University, Cleveland, OH, USA.
³ Mechanical and Aerospace Engineering, Case Western Reserve University, Cleveland, OH, USA.
⁴ Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA; Reproductive Biology, Case Western Reserve University, Cleveland, OH, USA. Electronic address: jmoore@metrohealth.org.

PMID: 31665659
DOI: 10.1016/j.placenta.2019.10.003

Abstract

Introduction: We have previously demonstrated two associations of PPROM, (1) inflammation/infection (modeled by tumor necrosis factor (TNF)) and (2) decidual bleeding (modeled by thrombin), both decrease fetal membrane (FM) rupture strength in-vitro. Furthermore, Granulocyte-Macrophage-Colony-Stimulating-Factor (GM-CSF) induced by both TNF and thrombin is a critical intermediate, necessary and sufficient for weakening by either agent. The amnion is the strength component of FM and must weaken for FM to rupture. It is unclear whether GM-CSF weakens amnion (AM) directly, or initially targets choriodecidua (CD) which secondarily releases agents to act on amnion.

Methods: Full thickness FM fragments were treated with/without GM-CSF. Some were preincubated with alpha-lipoic acid (LA), a known inhibitor of FM weakening. The FM fragments were then strength-tested. Separately, FM fragments were initially separated to AM and CD. AM fragments were cultured with Medium ± GM-CSF and then strength-tested. In other experiments, CD fragments were cultured with Medium, GM-CSF, LA, or LA + GM-CSF. Conditioned medium from each group was then incubated with AM. AM was then strength-tested. Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) were analyzed by Mutiplex Elisa.

Results: GM-CSF weakened intact FM which was blocked by LA. GM-CSF did not weaken isolated AM. However, GM-CSF conditioned CD media weakened AM and this weakening was inhibited by LA. GM-CSF treatment of CD increased MMPs 2, 9, and 10, and decreased TIMPs 1-3. LA reversed these effects.

Conclusions: GM-CSF does not weaken amnion directly; GM-CSF acts on CD to increase proteases and decrease anti-proteases which secondarily weaken the amnion.

Keywords: 17-α hydroxyprogesterone caproate (17-OHPC); Biomechanical weakening; Fetal membranes; GM-CSF; MMP; TIMP; TNF-α; Thrombin; pPROM; α-Lipoic acid.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amnion / drug effects*
Amnion / metabolism
Chorion / drug effects*
Chorion / metabolism
Culture Media, Conditioned
Female
Fetal Membranes, Premature Rupture / metabolism*
Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology*
Humans
Matrix Metalloproteinases / metabolism*
Pregnancy
Thioctic Acid / pharmacology
Tissue Inhibitor of Metalloproteinases / metabolism*

Substances

Culture Media, Conditioned
Tissue Inhibitor of Metalloproteinases
Thioctic Acid
Granulocyte-Macrophage Colony-Stimulating Factor
Matrix Metalloproteinases

Supplementary concepts

Preterm Premature Rupture of the Membranes