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.
Aim 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.
- cytokine biology
- innate immunity
- lung physiology
- pulmonary oedema
- respiratory measurement
- airway epithelium
- macrophage biology
- neutrophil biology
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Funding This study was supported by grants from GlaxoSmithKline (GSK) (COL028224) and the Wellcome Trust (#081208). GSK have a financial interest in the use of domain antibodies, including those targeting p55 TNF receptor, in the treatment of pulmonary and other diseases. GSK were involved in the initial design of the study and contributed to the study report. However, GSK had no involvement in collection, analysis and interpretation of data or in the decision to submit the report for publication. GSK provided salary funds for one of the authors (SB) and three others (PJM, RdeW and AB) are employees of GSK. GSK also provided funds for animal and consumable costs. The Wellcome Trust provided support of infrastructure for the animal experiments.
Competing interests PJM, RdW and AB are employed by and hold stock in GSK. SB, MW and MT have no competing interests.
Ethics approval All protocols were approved by the ethical review board of Imperial College London as well as the GSK Policy on the Care, Welfare and Treatment of Laboratory Animals and carried out under the authority of the UK Home Office in accordance with the Animals (Scientific Procedures) Act 1986.
Provenance and peer review Not commissioned; externally peer reviewed.
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