Esther M Speer1, Xinhua Lin2, Amitasrigowri Murthy3, Wei Hou4, Shahidul Islam5, Nazeeh Hanna6. 1. Department of Pediatrics, Stony Brook University School of Medicine, 100 Nicolls Road, Stony Brook, NY 11794, USA. Electronic address: Esther.Speer@stonybrookmedicine.edu. 2. Department of Pediatrics, Division of Neonatology, NYU-Winthrop Hospital, 259 First Street, Mineola, NY 11501, USA. Electronic address: XALin@winthrop.org. 3. Department of Obstetrics and Gynecology, NYU School of Medicine, 462 First Avenue, New York, NY 10016, USA. Electronic address: Amitasrigowri.Murthy@nyumc.org. 4. Family, Population, and Preventive Medicine Department, Stony Brook University School of Medicine, 100 Nicolls Road, Stony Brook, NY 11794, USA. Electronic address: wei.hou@stonybrookmedicine.edu. 5. Department of Biostatistics, Winthrop University Hospital, 259 First Street, Mineola, NY 11501, USA. Electronic address: sislam@Winthrop.org. 6. Department of Pediatrics, Division of Neonatology, NYU-Winthrop Hospital, 259 First Street, Mineola, NY 11501, USA. Electronic address: Nhanna@NYUWINTHROP.ORG.
Abstract
BACKGROUND: Intrauterine infection and inflammation during pregnancy, which leads to up-regulation of inflammatory cytokines and prostaglandin synthesis, has been implicated in the pathogenesis of preterm delivery and other pregnancy complications. Effective preventive and therapeutic strategies to reduce these outcomes are lacking to date. Pentoxifylline (PTX) is a non-specific phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate and decreases production of pro-inflammatory mediators while enhancing anti-inflammatory cytokines. We hypothesized that pentoxifylline will decrease lipopolysaccharide (LPS)-induced pro-inflammatory cytokines production in human placental explants. METHODS: Placental explants derived from normal second trimester human placentas were treated with PTX, stimulated with LPS and cultured at 37 °C in 5% CO2. Conditioned media were assayed for pro- and anti-inflammatory mediators with multiplex immunoassays or ELISA, and explant tissues for mRNA with real time PCR. Means of PTX-treated and untreated samples were compared using paired t tests and Wilcoxon-signed rank tests. RESULTS: PTX preferentially inhibited placental expression and production of LPS-induced pro-inflammatory cytokines including TNF-α (25461 vs. 1908 pg/ml, p < 0.001), IL-1β (2921 vs. 1067 pg/ml, p < 0.001) and IFN-γ (2190 vs 427 pg/ml, p < 0.001) with relative preservation of anti-inflammatory mediators. The suppressive effects on LPS-induced placental inflammation were independent of the timing of PTX administration in relation to LPS-induced stimulation. CONCLUSION: Our study suggests that PTX attenuates the LPS-induced pro-inflammatory milieu in human placental explants. We speculate that PTX may have utility as a candidate anti-inflammatory agent for prophylaxis and/or treatment of human placental inflammation.
BACKGROUND:Intrauterine infection and inflammation during pregnancy, which leads to up-regulation of inflammatory cytokines and prostaglandin synthesis, has been implicated in the pathogenesis of preterm delivery and other pregnancy complications. Effective preventive and therapeutic strategies to reduce these outcomes are lacking to date. Pentoxifylline (PTX) is a non-specific phosphodiesterase inhibitor which raises intracellular cyclic adenosine monophosphate and decreases production of pro-inflammatory mediators while enhancing anti-inflammatory cytokines. We hypothesized that pentoxifylline will decrease lipopolysaccharide (LPS)-induced pro-inflammatory cytokines production in human placental explants. METHODS: Placental explants derived from normal second trimester human placentas were treated with PTX, stimulated with LPS and cultured at 37 °C in 5% CO2. Conditioned media were assayed for pro- and anti-inflammatory mediators with multiplex immunoassays or ELISA, and explant tissues for mRNA with real time PCR. Means of PTX-treated and untreated samples were compared using paired t tests and Wilcoxon-signed rank tests. RESULTS:PTX preferentially inhibited placental expression and production of LPS-induced pro-inflammatory cytokines including TNF-α (25461 vs. 1908 pg/ml, p < 0.001), IL-1β (2921 vs. 1067 pg/ml, p < 0.001) and IFN-γ (2190 vs 427 pg/ml, p < 0.001) with relative preservation of anti-inflammatory mediators. The suppressive effects on LPS-induced placental inflammation were independent of the timing of PTX administration in relation to LPS-induced stimulation. CONCLUSION: Our study suggests that PTX attenuates the LPS-induced pro-inflammatory milieu in human placental explants. We speculate that PTX may have utility as a candidate anti-inflammatory agent for prophylaxis and/or treatment of human placental inflammation.
Authors: Caterina Tiozzo; Mark Bustoros; Xinhua Lin; Claudia Manzano De Mejia; Ellen Gurzenda; Martin Chavez; Iman Hanna; Paola Aguiari; Laura Perin; Nazeeh Hanna Journal: Am J Obstet Gynecol Date: 2021-06-26 Impact factor: 8.661