In an in-vitro model using human fetal membranes, α-lipoic acid inhibits inflammation induced fetal membrane weakening. (August 2018)

• Record Type: Journal Article
• Authors: Kumar, Deepak; Moore, Robert M.; Sharma, Anudeepa; Mercer, Brian M.; Mansour, Joseph M.; Moore, John J.
• Is Part Of: Placenta. Volume 68(2018)
• Page Start: 9
• Page End: 14
• Publication Date: 2018-08
• Subjects: Fetal membranes -- Biomechanical weakening -- α-Lipoic acid -- GM-CSF -- TNF-α -- Thrombin -- Progestogens -- pPROM; Placenta -- Periodicals; Reproduction -- Periodicals; Placenta -- Periodicals; Placenta -- Périodiques; Reproduction -- Périodiques; 612.63
• DOI: 10.1016/j.placenta.2018.06.305
• Languages: English
• ISSNs: 0143-4004

Abstract

Abstract: Introduction: We established an in-vitro model for the study of human fetal membrane (FM) weakening leading to pPROM. In this model, granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical intermediate for both tumor necrosis factor-α (TNF; modeling infection/inflammation) and thrombin (modeling decidual bleeding/abruption)-induced weakening. Thus, inhibitors of FM weakening can be categorized as targeting GM-CSF production, GM-CSF downstream action, or both. Most progestogens inhibit both, except 17-α hydroxyprogesterone caproate which inhibits FM weakening at only one point, GM-CSF production. α-lipoic acid (LA), an over-the-counter dietary supplement, has also been previously shown to inhibit TNF and thrombin induced FM weakening. Objective: To determine the point of action of LA inhibition of FM weakening. Methods: FM fragments were mounted in Transwell inserts and preincubated with/without LA/24 h, then with/without addition of TNF, thrombin or GM-CSF. After 48 h, medium was assayed for GM-CSF, and FM fragments were rupture-strength tested. Results: TNF and thrombin both weakened FM and increased GM-CSF levels. GM-CSF also weakened FM. LA inhibited both TNF and thrombin induced FM weakening and concomitantly inhibited the increase in GM-CSF in a concentration-dependent manner. In addition, LA inhibited GM-CSF induced FM weakening in a concentration dependent manner. Conclusions: LA blocks TNF and thrombin induced FM weakening at two points, inhibiting both GM-CSF production and downstream action. Thus, we speculate that LA may be a potential standalone therapeutic agent, or supplement to current therapy for prevention of pPROM related spontaneous preterm birth, if preclinical studies to examine feasibility and safety during pregnancy are successfully accomplished. Highlights: GM-CSF is a critical intermediate in inflammation induced fetal membrane weakening. TNF and thrombin each increase GM-CSF while also weakening fetal membranes. GM-CSF alone also directly weakens fetal membranes. α-lipoic acid inhibits both GM-CSF production and its downstream weakening action. α-lipoic acid may be a therapeutic agent or supplement to current pPROM therapy.