Sezik Mekin, Köker Afşin, Özmen Özlem, Halıgür Mehmet, Kaşıkcı Duygu, Aydoğan Ahmet, Özatik Orhan
Süleyman Demirel University Faculty of Medicine, Department of Obstetrics and Gynecology, Isparta, Turkey.
Burdur Mehmet Akif Ersoy University Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology, Burdur, Turkey.
Turk J Obstet Gynecol. 2020 Dec;17(4):259-269. doi: 10.4274/tjod.galenos.2020.19794. Epub 2020 Dec 10.
Pentoxifylline (PTX) has immunomodulatory properties and is known to reduce sepsis-associated infant mortality. We aimed to evaluate maternal oral and intra-amniotic administration of PTX for the prevention of fetal inflammation and injury in a caprine model.
Inflammation-mediated fetal injury was induced with maternal granulocyte-colony stimulating factor and intra-amniotic endotoxin at 0.76 of gestation in date-mated pregnant goats. Eight groups were formed (n=4 each): Control, fetal injury, oral 30 mg/kg/day and 60 mg/kg/day PTX for 15 days + fetal injury, intra-amniotic 400 mg/kg and 800 mg/kg estimated fetal weight single-dose PTX with and without fetal injury. Preterm delivery by hysterotomy was performed at 0.80 of gestation to evaluate the fetal and placental effects. Immunochemistry for various markers including interleukins, caspases, cyclooxygenases, vimentin, myelin basic protein, and surfactant proteins were carried out in the fetal lungs, fetal brain, and placenta. Fetal plasma and amniotic fluid interleukins were also evaluated. Kruskal-Wallis H test and Mann-Whitney U test were used for comparisons.
High-dose (60 mg/kg/day) maternal prophylactic oral treatment attenuated endotoxin-related histological injury and was related to low inflammatory marker expressions comparable to the controls (p>0.05 except cyclooxygenase 2). Following maternal oral administration, fetal plasma and amniotic fluid levels of the studied interleukins were also lower than the untreated endotoxin-exposed animals (p<0.05 for all comparisons). Intra-amniotic PTX was associated with inconsistent results and increased inflammatory markers in some fetuses.
Oral PTX before preterm birth mitigates intrauterine inflammation with neuroprotective effects in the fetus. PTX can be considered as a candidate drug for fetal brain injury prevention in the preterm period.
己酮可可碱（PTX）具有免疫调节特性，已知可降低脓毒症相关的婴儿死亡率。我们旨在评估孕羊模型中母体口服和羊膜腔内给予PTX对预防胎儿炎症和损伤的作用。
在配种后的妊娠山羊妊娠0.76时，用母体粒细胞集落刺激因子和羊膜腔内注射内毒素诱导炎症介导的胎儿损伤。分为八组（每组n = 4）：对照组、胎儿损伤组、口服30 mg/kg/天和60 mg/kg/天PTX 15天 + 胎儿损伤组、羊膜腔内注射估计胎儿体重400 mg/kg和800 mg/kg单剂量PTX伴或不伴胎儿损伤组。在妊娠0.80时通过子宫切开术进行早产，以评估对胎儿和胎盘的影响。对胎儿肺、胎儿脑和胎盘进行包括白细胞介素、半胱天冬酶、环氧化酶、波形蛋白、髓鞘碱性蛋白和表面活性蛋白等各种标志物的免疫化学检测。还评估了胎儿血浆和羊水白细胞介素。采用Kruskal-Wallis H检验和Mann-Whitney U检验进行比较。
高剂量（60 mg/kg/天）母体预防性口服治疗减轻了内毒素相关的组织学损伤，且与低炎症标志物表达相关，与对照组相当（除环氧化酶2外，p>0.05）。母体口服给药后，所研究白细胞介素的胎儿血浆和羊水水平也低于未治疗的内毒素暴露动物（所有比较p<0.05）。羊膜腔内注射PTX的结果不一致，一些胎儿的炎症标志物增加。
早产前口服PTX可减轻子宫内炎症，对胎儿具有神经保护作用。PTX可被视为预防早产胎儿脑损伤的候选药物。
