title: Inhibition of TNF Receptor p55 By a Domain Antibody Attenuates the Initial Phase of Acid-Induced Lung Injury in Mice.
abstract: BACKGROUND
  Tumor necrosis factor-α (TNF) is strongly implicated in the development of acute respiratory distress syndrome (ARDS), but its potential as a therapeutic target has been hampered by its complex biology. TNF signals through two receptors, p55 and p75, which play differential roles in pulmonary edema formation during ARDS. We have recently shown that inhibition of p55 by a novel domain antibody (dAb™) attenuated ventilator-induced lung injury. In the current study, we explored the efficacy of this antibody in mouse models of acid-induced lung injury to investigate the longer consequences of treatment.
  
  
  METHODS
  We employed two acid-induced injury models, an acute ventilated model and a resolving spontaneously breathing model. C57BL/6 mice were pretreated intratracheally or intranasally with p55-targeting dAb or non-targeting "dummy" dAb, 1 or 4 h before acid instillation.
  
  
  RESULTS
  Acid instillation in the dummy dAb group caused hypoxemia, increased respiratory system elastance, pulmonary inflammation, and edema in both the ventilated and resolving models. Pretreatment with p55-targeting dAb significantly attenuated physiological markers of ARDS in both models. p55-targeting dAb also attenuated pulmonary inflammation in the ventilated model, with signs that altered cytokine production and leukocyte recruitment persisted beyond the very acute phase.
  
  
  CONCLUSIONS
  These results demonstrate that the p55-targeting dAb attenuates lung injury and edema formation in models of ARDS induced by acid aspiration, with protection from a single dose lasting up to 24 h. Together with our previous data, the current study lends support toward the clinical targeting of p55 for patients with, or at risk of ARDS.
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital , London , UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wilson
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London, UK; Department of Intensive Care Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Wakabayashi
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital , London , UK.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Bertok
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital , London , UK.
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Oakley
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital , London , UK.
authors.forename: Brijesh V
authors.initials: BV
authors.lastname: Patel
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital , London , UK.
authors.forename: Kieran P
authors.initials: KP
authors.lastname: O'Dea
authors.affiliation: Biopharm Molecular Discovery, GlaxoSmithKline R&D , Stevenage , UK.
authors.forename: Joanna C
authors.initials: JC
authors.lastname: Cordy
authors.affiliation: Biopharm Molecular Discovery, GlaxoSmithKline R&D , Stevenage , UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Morley
authors.affiliation: Biopharm Molecular Discovery, GlaxoSmithKline R&D , Stevenage , UK.
authors.forename: Andrew I
authors.initials: AI
authors.lastname: Bayliffe
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital , London , UK.
authors.forename: Masao
authors.initials: M
authors.lastname: Takata
keywords: CD120a; TNFRSF1a; acid aspiration; inflammation; respiratory mechanics