title: Selective inhibition of intra-alveolar p55 TNF receptor attenuates ventilator-induced lung injury.
abstract: BACKGROUND
  Tumour necrosis factor (TNF) is upregulated in the alveolar space early in the course of ventilator-induced lung injury (VILI). Studies in genetically modified mice indicate that the two TNF receptors play opposing roles during injurious high-stretch mechanical ventilation, with p55 promoting but p75 preventing pulmonary oedema.
  
  
  OBJECTIVE
  To investigate the effects of selective inhibition of intra-alveolar p55 TNF receptor on pulmonary oedema and inflammation during ventilator-induced lung injury using a newly developed domain antibody.
  
  
  METHODS
  Anaesthetised mice were ventilated with high tidal volume and given an intratracheal bolus of p55-specific domain antibody or anti-TNF monoclonal antibody ('pure' VILI model). As a model of enhanced inflammation, a subclinical dose of lipopolysaccharide (LPS) was included in the intratracheal antibody bolus (LPS+VILI model). Development of lung injury was assessed by respiratory mechanics and blood gases and protein levels in lavage fluid. Flow cytometry was used to determine leucocyte recruitment and alveolar macrophage activation, while lavage fluid cytokines were assessed by ELISA.
  
  
  RESULTS
  The ventilation protocol produced deteriorations in respiratory mechanics and gas exchange with increased lavage fluid protein levels in the two models. The p55-specific domain antibody substantially attenuated all of these changes in the 'pure' VILI model, while anti-TNF antibody was ineffective. In the LPS+VILI model, p55 blockade prevented deteriorations in respiratory mechanics and oxygenation and significantly decreased neutrophil recruitment, expression of intercellular adhesion molecule 1 on alveolar macrophages, and interleukin 6 and monocyte chemotactic protein 1 levels in lavage fluid.
  
  
  CONCLUSIONS
  Selective inhibition of intra-alveolar p55 TNF receptor signalling by domain antibodies may open new therapeutic approaches for ventilated patients with acute lung injury.
authors.affiliation: Section of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Bertok
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wilson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Morley
authors.forename: Ruud
authors.initials: R
authors.lastname: de Wildt
authors.forename: Andrew
authors.initials: A
authors.lastname: Bayliffe
authors.forename: Masao
authors.initials: M
authors.lastname: Takata
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000276:immunology / Q000627:therapeutic use*; D002245:Carbon Dioxide / Q000097:blood; D004353:Drug Evaluation, Preclinical / Q000379:methods; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011654:Pulmonary Edema / Q000209:etiology / Q000517:prevention & control; D011659:Pulmonary Gas Exchange / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000037:antagonists & inhibitors* / Q000276:immunology; D016896:Treatment Outcome; D053319:Tumor Necrosis Factor Decoy Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D055397:Ventilator-Induced Lung Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D008070:Lipopolysaccharides; D047888:Receptors, Tumor Necrosis Factor, Type I; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; D002245:Carbon Dioxide; C069521:recombinant human tumor necrosis factor-binding protein-1; D010100:Oxygen