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.

Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury

“…6). The protection conferred by interfering with PDE2A expression was accompanied by a significant reduction in MIP2 and KC, key neutrophil chemoattractants in mouse models of LPS lung injury (1) and VILI (18,50). Moreover, MIP2 is known to be synergistically increased when these two injuries are combined (25,27).…”

Strategies to minimize lung injury in extremely low birth weight infants

“…Recentemente, tem sido demonstrado na literatura que mediadores inflamatórios, como o FNT-alfa e as interleucinas, aumentam durante a ventilação mecânica, principalmente quando se empregam volumes correntes elevados 13,14,[21][22][23][24][25] . Naik et al observaram que o início da ventilação mecânica em ovelhas prematuras desencadeou o aumento dos níveis de mediadores inflamatórios, sugerindo que bastam alguns ciclos de ventilação mecâ-nica no prematuro para causar a lesão pulmonar 15 .…”

Ventilator-Induced Lung Injury: Mechanisms and Future Therapeutic Interventions

“…In a randomized controlled trial, these authors observed elevated concentrations of IL-1β, TNF-α, IL-6 and IL-1 receptor antagonist in the bronchoalveolar lavage fluid (BALf) of ALI/ARDS patients when excessive tidal volumes were used for 36 hours (Ranieri et al, 1999). Based on experimental and clinical observations, it has been hypothesized that the ventilator-induced inflammatory response in the lung may lead to pulmonary injury (Haitsma et al, 2003;Wilson et al, 2003;Wilson et al, 2005). Most experimental models of VILI, however, applied excessively high tidal volumes and/or inspiratory pressures compared to those applied in the clinical setting (Copland et al, 2004;Haitsma et al, 2003;Wilson et al, 2003).…”

“…Based on experimental and clinical observations, it has been hypothesized that the ventilator-induced inflammatory response in the lung may lead to pulmonary injury (Haitsma et al, 2003;Wilson et al, 2003;Wilson et al, 2005). Most experimental models of VILI, however, applied excessively high tidal volumes and/or inspiratory pressures compared to those applied in the clinical setting (Copland et al, 2004;Haitsma et al, 2003;Wilson et al, 2003). In an attempt to better reflect the human situation, we used clinically more relevant ventilator settings in our animal studies (Hegeman et al, 2010).…”