High tidal volume upregulates intrapulmonary cytokines in an in vivo mouse model of ventilator-induced lung injury

Author:

Wilson Michael R.,Choudhury Sharmila,Goddard Michael E.,O'Dea Kieran P.,Nicholson Andrew G.,Takata Masao

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-α 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-α by WEHI bioassay. Low-Vt ventilation induced minimal changes in physiology and pathology with negligible TNF-α and MIP-2 proteins and TNF-α bioactivity. These results demonstrate that high-Vt ventilation in the absence of underlying injury induces intrapulmonary TNF-α and MIP-2 expression in mice. The apparently transient nature of TNF-α upregulation may help explain previous controversy regarding the involvement of cytokines in ventilator-induced lung injury.

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology

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