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Inhibition of TNF receptor p55 by a domain antibody attenuates the initial phase of acid-induced lung injury in mice

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Title: Inhibition of TNF receptor p55 by a domain antibody attenuates the initial phase of acid-induced lung injury in mice
Authors: Wilson, MR
Wakabayashi, K
Bertok, S
Oakley, C
Patel, BV
O'Dea, KP
Cordy, JC
Morley, PJ
Bayliffe, AI
Takata, M
Item Type: Journal Article
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 ventilator36 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 hours 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 hours. Together with our previous data, the current study lends support towards the clinical targeting of p55 for patients with, or at risk of ARDS.
Issue Date: 13-Feb-2017
Date of Acceptance: 25-Jan-2017
URI: http://hdl.handle.net/10044/1/44245
DOI: https://dx.doi.org/10.3389/fimmu.2017.00128
ISSN: 1664-3224
Publisher: Frontiers Media
Journal / Book Title: Frontiers in Immunology
Volume: 8
Copyright Statement: © 2017 Wilson, Wakabayashi, Bertok, Oakley, Patel, O’Dea, Cordy, Morley, Bayliffe and Takata. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Sponsor/Funder: GlaxoSmithKline Services Unlimited
Wellcome Trust
Funder's Grant Number: L100018639
Keywords: Science & Technology
Life Sciences & Biomedicine
acid aspiration
respiratory mechanics
Publication Status: Published
Article Number: 128
Appears in Collections:Department of Surgery and Cancer