Karisnan Kanakeswary, Bakker Anthony J, Song Yong, Noble Peter B, Pillow J Jane, Pinniger Gavin J
School of Anatomy, Physiology and Human Biology, University of Western Australia, Crawley, WA, Australia.
School of Anatomy, Physiology and Human Biology, University of Western Australia, Crawley, WA, Australia; Centre for Neonatal Research and Education, School of Paediatrics and Child Health, University of Western Australia, Crawley, WA, Australia.
PLoS One. 2015 Apr 10;10(4):e0124390. doi: 10.1371/journal.pone.0124390. eCollection 2015.
Chorioamnionitis (inflammation of the fetal membranes) is strongly associated with preterm birth and in utero exposure to inflammation significantly impairs contractile function in the preterm lamb diaphragm. The fetal inflammatory response to intra-amniotic (IA) lipopolysaccharide (LPS) is orchestrated via interleukin 1 (IL-1). We aimed to determine if LPS induced contractile dysfunction in the preterm diaphragm is mediated via the IL-1 pathway. Pregnant ewes received IA injections of recombinant human IL-1 receptor antagonist (rhIL-1ra) (Anakinra; 100 mg) or saline (Sal) 3 h prior to second IA injections of LPS (4 mg) or Sal at 119d gestational age (GA). Preterm lambs were killed after delivery at 121d GA (term = 150 d). Muscle fibres dissected from the right hemi-diaphragm were mounted in an in vitro muscle test system for assessment of contractile function. The left hemi-diaphragm was snap frozen for molecular and biochemical analyses. Maximum specific force in lambs exposed to IA LPS (Sal/LPS group) was 25% lower than in control lambs (Sal/Sal group; p=0.025). LPS-induced diaphragm weakness was associated with higher plasma IL-6 protein, diaphragm IL-1β mRNA and oxidised glutathione levels. Pre-treatment with rhIL-1ra (rhIL-1ra/LPS) ameliorated the LPS-induced diaphragm weakness and blocked systemic and local inflammatory responses, but did not prevent the rise in oxidised glutathione. These findings indicate that LPS induced diaphragm dysfunction is mediated via IL-1 and occurs independently of oxidative stress. Therefore, the IL-1 pathway represents a potential therapeutic target in the management of impaired diaphragm function in preterm infants.
绒毛膜羊膜炎（胎膜炎症）与早产密切相关，子宫内暴露于炎症会显著损害早产羔羊膈肌的收缩功能。胎儿对羊膜内（IA）脂多糖（LPS）的炎症反应是通过白细胞介素1（IL-1）来调控的。我们旨在确定LPS诱导的早产膈肌收缩功能障碍是否通过IL-1途径介导。妊娠母羊在妊娠119天（GA）第二次IA注射LPS（4mg）或生理盐水（Sal）前3小时接受IA注射重组人IL-1受体拮抗剂（rhIL-1ra）（阿那白滞素；100mg）或生理盐水（Sal）。早产羔羊在妊娠121天（足月=150天）分娩后处死。从右半膈肌分离的肌纤维安装在体外肌肉测试系统中以评估收缩功能。左半膈肌速冻用于分子和生化分析。暴露于IA LPS的羔羊（Sal/LPS组）的最大比力比对照羔羊（Sal/Sal组）低25%（p=0.025）。LPS诱导的膈肌无力与血浆IL-6蛋白、膈肌IL-1β mRNA和氧化型谷胱甘肽水平升高有关。rhIL-1ra预处理（rhIL-1ra/LPS）改善了LPS诱导的膈肌无力并阻断了全身和局部炎症反应，但未阻止氧化型谷胱甘肽的升高。这些发现表明，LPS诱导的膈肌功能障碍是通过IL-1介导的，且独立于氧化应激发生。因此，IL-1途径代表了早产婴儿膈肌功能受损管理中的一个潜在治疗靶点。
