title: Interleukin-1 receptor antagonist protects against lipopolysaccharide induced diaphragm weakness in preterm lambs.
abstract: 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.
authors: School of Anatomy, Physiology and Human Biology, University of Western Australia, Crawley, WA, Australia.
authors: Kanakeswary
authors: K
authors: Karisnan
authors: School of Anatomy, Physiology and Human Biology, University of Western Australia, Crawley, WA, Australia.
authors: Anthony J
authors: AJ
authors: Bakker
authors: 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.
authors: Yong
authors: Y
authors: Song
authors: 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.
authors: Peter B
authors: PB
authors: Noble
authors: 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.
authors: J Jane
authors: JJ
authors: Pillow
authors: School of Anatomy, Physiology and Human Biology, University of Western Australia, Crawley, WA, Australia.
authors: Gavin J
authors: GJ
authors: Pinniger
mesh_terms: D000818:Animals; D002821:Chorioamnionitis / Q000097:blood / Q000503:physiopathology / Q000517:prevention & control; D003964:Diaphragm / Q000187:drug effects* / Q000503:physiopathology*; D004195:Disease Models, Animal; D005260:Female; D005312:Fetal Blood / Q000378:metabolism; D005333:Fetus / Q000187:drug effects* / Q000503:physiopathology*; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018384:Oxidative Stress / Q000187:drug effects; D011247:Pregnancy; D047928:Premature Birth / Q000097:blood / Q000503:physiopathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034561:Sheep, Domestic
chemical_list: D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger