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Comparative Study
. 2009;13(1):R1.
doi: 10.1186/cc7688. Epub 2009 Jan 19.

Mechanical ventilation using non-injurious ventilation settings causes lung injury in the absence of pre-existing lung injury in healthy mice

Affiliations
Comparative Study

Mechanical ventilation using non-injurious ventilation settings causes lung injury in the absence of pre-existing lung injury in healthy mice

Esther K Wolthuis et al. Crit Care. 2009.

Abstract

Introduction: Mechanical ventilation (MV) may cause ventilator-induced lung injury (VILI). Present models of VILI use exceptionally large tidal volumes, causing gross lung injury and haemodynamic shock. In addition, animals are ventilated for a relative short period of time and only after a 'priming' pulmonary insult. Finally, it is uncertain whether metabolic acidosis, which frequently develops in models of VILI, should be prevented. To study VILI in healthy mice, the authors used a MV model with clinically relevant ventilator settings, avoiding massive damage of lung structures and shock, and preventing metabolic acidosis.

Methods: Healthy C57Bl/6 mice (n = 66) or BALB/c mice (n = 66) were ventilated (tidal volume = 7.5 ml/kg or 15 ml/kg; positive end-expiratory pressure = 2 cmH2O; fraction of inspired oxygen = 0.5) for five hours. Normal saline or sodium bicarbonate were used to correct for hypovolaemia. Lung histopathology, lung wet-to-dry ratio, bronchoalveolar lavage fluid protein content, neutrophil influx and levels of proinflammatory cytokines and coagulation factors were measured.

Results: Animals remained haemodynamically stable throughout the whole experiment. Lung histopathological changes were minor, although significantly more histopathological changes were found after five hours of MV with a larger tidal volume. Lung histopathological changes were no different between the strains. In both strains and with both ventilator settings, MV caused higher wet-to-dry ratios, higher bronchoalveolar lavage fluid protein levels and more influx of neutrophils, and higher levels of proinflammatory cytokines and coagulation factors. Also, with MV higher systemic levels of cytokines were measured. All parameters were higher with larger tidal volumes. Correcting for metabolic acidosis did not alter endpoints.

Conclusions: MV induces VILI, in the absence of a priming pulmonary insult and even with use of relevant (least injurious) ventilator settings. This model offers opportunities to study the pathophysiological mechanisms behind VILI and the contribution of MV to lung injury in the absence of pre-existing lung injury.

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Figures

Figure 1
Figure 1
Histological specimens from the lungs of spontaneously breathing mice and mice ventilated with low/high tidal volumes. (a to c) Images of histological specimens from the lungs of spontaneously breathing C57Bl/6 mice (control) or ventilated with low tidal volumes (LVT) and high VT (HVT) for five hours. H&E stain; magnification 200×. (a) Control mice; (b) LVT mice; (c) HVT mice. (d to e) Images of citospin preparations of BALF of C57Bl/6 mice stained with Diff-Quick. (d) control mice; (e) LVT mice; (f) HVT mice.
Figure 2
Figure 2
Total protein level in control mice and mice ventilated with low/high tidal volumes. Total protein level in control mice, and in mice ventilated with low tidal volumes (LVT) and high VT (HVT) for five hours. Two fluid strategies (normal saline (white boxes) and sodium bicarbonate (grey boxes)) were compared. Data represent median and interquartile range of six mice. *p < 0.05 (HVT vs. LVT); ‡p < 0.001 (HVT vs. LVT).
Figure 3
Figure 3
Pulmonary levels of tumour necrosis factor (TNF)-α, interleukin (IL)-6, keratincyte-derived cytokine (KC) and macrophage inflammatory protein (MIP)-2 in lung tissue homogenate. Pulmonary levels of TNF-α, IL-6, KC and MIP-2 and in lung tissue homogenate in control mice, and in mice ventilated with low tidal volumes (LVT) and high VT (HVT) for five hours. Two fluid strategies (normal saline (white boxes) and sodium bicarbonate (grey boxes)) were compared. Data represent median and interquartile range of six mice. *p < 0.05 (LVT vs. control or sodium bicarbonate vs. saline, IL-6 and MIP-2 in C57Bl/6 mice); †p < 0.01 (HVT vs. LVT or LVT vs. control); ‡p < 0.001 (HVT vs. LVT or LVT vs. control).
Figure 4
Figure 4
Plasma levels of interleukin (IL)-6 and keratinocyte-derived chemokine (KC). Plasma levels of IL-6 and KC in control mice, and in mice ventilated with low tidal volumes (LVT) and high VT (HVT) for five hours. Data of the two fluid strategies are pooled. Data represent median and interquartile range of six mice. Levels of IL-6 and KC in control mice were below the detection limit of the assay. *p < 0.05 vs. control; †p < 0.01 vs. LVT; ‡p < 0.001 vs. LVT.
Figure 5
Figure 5
Thrombin-antithrombin complexes (TATc) levels and plasminogen activator inhibitor (PAI)-1 levels in bronchoalveolar lavage fluid. TATc levels and PAI-1 levels in bronchoalveolar lavage fluid in control mice, and in mice ventilated with low tidal volumes (LVT) and high VT(HVT) for five hours. Two fluid strategies (normal saline (white boxes) and sodium bicarbonate (grey boxes)) were compared. Data represent median and interquartile range of six mice. ‡p < 0.001 (HVT vs. LVT).

Comment in

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