title: High tidal volume upregulates intrapulmonary cytokines in an in vivo mouse model of ventilator-induced lung injury.
abstract: Mechanical ventilation has been demonstrated to exacerbate lung injury, and a sufficiently high tidal volume can induce injury in otherwise healthy lungs. However, it remains controversial whether injurious ventilation per se, without preceding lung injury, can initiate cytokine-mediated pulmonary inflammation. To address this, we developed an in vivo mouse model of acute lung injury produced by high tidal volume (Vt) ventilation. Anesthetized C57BL6 mice were ventilated at high Vt (34.5 +/- 2.9 ml/kg, mean +/- SD) for a duration of 156 +/- 17 min until mean blood pressure fell below 45 mmHg (series 1); high Vt for 120 min (series 2); or low Vt (8.8 +/- 0.5 ml/kg) for 120 or 180 min (series 3). High Vt produced progressive lung injury with a decrease in respiratory system compliance, increase in protein concentration in lung lavage fluid, and lung pathology showing hyaline membrane formation. High-Vt ventilation was associated with increased TNF-alpha in lung lavage fluid at the early stage of injury (series 2) but not the later stage (series 1). In contrast, lavage fluid macrophage inflammatory protein-2 (MIP-2) was increased in all high-Vt animals. Lavage fluid from high-Vt animals contained bioactive TNF-alpha by WEHI bioassay. Low-Vt ventilation induced minimal changes in physiology and pathology with negligible TNF-alpha and MIP-2 proteins and TNF-alpha bioactivity. These results demonstrate that high-Vt ventilation in the absence of underlying injury induces intrapulmonary TNF-alpha and MIP-2 expression in mice. The apparently transient nature of TNF-alpha upregulation may help explain previous controversy regarding the involvement of cytokines in ventilator-induced lung injury.
authors.affiliation: Dept. of Anaesthetics and Intensive Care, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, 369 Fulham Road, London SW10 9NH, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Wilson
authors.forename: Sharmila
authors.initials: S
authors.lastname: Choudhury
authors.forename: Michael E
authors.initials: ME
authors.lastname: Goddard
authors.forename: Kieran P
authors.initials: KP
authors.lastname: O'Dea
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Nicholson
authors.forename: Masao
authors.initials: M
authors.lastname: Takata
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008171:Lung Diseases / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011506:Proteins / Q000378:metabolism; D012121:Respiration, Artificial / Q000009:adverse effects*; D013990:Tidal Volume; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha