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  • Title: Regulation of p38 mitogen-activated kinase-mediated fetal membrane senescence by statins.
    Author: Ayad MT, Taylor BD, Menon R.
    Journal: Am J Reprod Immunol; 2018 Oct; 80(4):e12999. PubMed ID: 29911323.
    Abstract:
    PROBLEM: Oxidative stress (OS)-induced, p38 mitogen-activated protein kinase (p38MAPK)-mediated chorioamniotic senescence and inflammation (senescence-associated secretory phenotype [SASP]) are associated with parturition. In response to OS-inducing risk factors, premature senescence contributes to preterm premature rupture of the membranes (pPROM) and spontaneous preterm birth (PTB). We determined the effect of simvastatin, rosuvastatin, and progesterone in downregulating p38MAPK-mediated senescence and SASP. METHOD OF STUDY: Normal term, not-in-labor fetal membranes (n = 8) were exposed to cigarette smoke extract (CSE: OS inducer) alone or combined with simvastatin (100 and 200 ng/mL), rosuvastatin (100 and 200 ng/mL), and progesterone (10-6  mol/L). p38MAPK expression changes were studied by Western blot, senescence was determined by senescence-associated β-Galactosidase (SA-β-Gal) staining, and multiplex analysis determined changes associated with 4 SASP markers (IL-8, IL-10, TNF-α, and GM-CSF). A pairwise comparison between groups was conducted by ANOVA. RESULTS: Compared to untreated controls, CSE induced p38MAPK-mediated senescence and SASP. CSE cotreatment with simvastatin and rosuvastatin significantly reduced p38MAPK activation, senescence (decrease in SA-β-Gal) and SASP markers, GM-CSF, and TNF, but not IL-8, while increasing anti-inflammatory IL-10 in a dose-dependent manner. Cotreatment of CSE and progesterone had no effect on reducing p38MAPK activation, senescence, or SASP. CONCLUSION: Both simvastatin and rosuvastatin downregulated OS-induced p38MAPK activation, senescence, and SASP, while rosuvastatin showed a pronounced effect. Progesterone did not reduce OS-induced fetal membrane senescence and SASP. Simvastatin or rosuvastatin may reduce the incidences of OS-associated PTB and pPROM by preventing premature senescence and SASP.
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