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1 Department of Anaesthetics and Intensive Care, Imperial College London, London, United Kingdom
* To whom correspondence should be addressed. E-mail: m.takata{at}imperial.ac.uk.
Although high stretch mechanical ventilation has been demonstrated to induce lung inflammation, the roles of soluble mediators, in particular TNF, remain controversial. We have previously shown in mice that high stretch ventilation, in the absence of preceding lung injury, induces expression of bioactive TNF in lung lavage fluid early in the course of injury, but the biological significance of this, if any, has yet to be determined. We therefore investigated the pulmonary inflammatory response to a transient period of high stretch ventilation in anesthetised mice lacking TNF receptors, and mice treated with anti-TNF antibodies. A standardised stretchinduced lung injury (assessed by lung mechanics, blood gases and lavage protein content), followed by non-injurious low stretch ventilation for 3 hours produced significant alveolar neutrophil infiltration in wildtype mice. However, neutrophil recruitment was substantially attenuated in TNF receptor double knockout mice and in wildtype mice treated with intratracheal anti-TNF antibody. This attenuation was not associated with decreased concentrations of neutrophil attractant CXC chemokines (macrophage inflammatory protein-2 and keratinocytederived chemokine) in lavage fluid. In contrast to intratracheal antibody, intravenous anti-TNF antibody did not reduce neutrophil infiltration, suggesting that the role of TNF signalling is localised within the alveolar space, and does not require decompartmentalisation of TNF into the circulation. These findings provide the first direct evidence that pulmonary inflammation induced by high stretch ventilation without underlying lung injury possesses a significant TNF-dependent component. The results suggest a potential for regional anti-TNF treatment in attenuating stretch-induced pulmonary inflammation.
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