Comprehensive Physiology Wiley Online Library

Ventilation‐Induced Lung Injury

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Abstract

Mechanical ventilation (MV) is, by definition, the application of external forces to the lungs. Depending on their magnitude, these forces can cause a continuum of pathophysiological alterations ranging from the stimulation of inflammation to the disruption of cell‐cell contacts and cell membranes. These side effects of MV are particularly relevant for patients with inhomogeneously injured lungs such as in acute lung injury (ALI). These patients require supraphysiological ventilation pressures to guarantee even the most modest gas exchange. In this situation, ventilation causes additional strain by overdistension of the yet non‐injured region, and additional stress that forms because of the interdependence between intact and atelectatic areas. Cells are equipped with elaborate mechanotransduction machineries that respond to strain and stress by the activation of inflammation and repair mechanisms. Inflammation is the fundamental response of the host to external assaults, be they of mechanical or of microbial origin and can, if excessive, injure the parenchymal tissue leading to ALI. Here, we will discuss the forces generated by MV and how they may injure the lungs mechanically and through inflammation. We will give an overview of the mechanotransduction and how it leads to inflammation and review studies demonstrating that ventilator‐induced lung injury can be prevented by blocking pathways of mechanotransduction or inflammation. © 2011 American Physiological Society. Compr Physiol 1:635‐661, 2011.

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Figure 1. Figure 1.

Possible mechanisms of air filling of distal airways during ventilation. (A) Recruitment, (B) expansion of alveolar ducts, (C) unfolding of interfolded structures, and (D) expansion of alveoli.

Figure 2. Figure 2.

Consequences of increasing mechanical load in lungs. The indicated pressures provide only rough estimates. For further details see the text.

Figure 3. Figure 3.

Mechanosensing (left) and injury‐sensing (right) mechanisms leading to inflammation. For further details see the text. LMWH, low‐molecular‐weight hyaluronan.

Figure 4. Figure 4.

Activation of transcription factors by mechanical ventilation. (A) Examples of cell‐type specific upregulation of transcription factors in response to mechanical ventilation or stretch. (B) Activation of NF‐κB in alveolar macrophages in isolated perfused mouse lungs ventilated with 10 or 25 cm H2O. The blue stain indicates the nucleus, and the brown stain NF‐κB. Ventilation with 25 cm H2O caused translocation of NF‐κB to the nucleus. Taken with permission from .

Figure 5. Figure 5.

Effect of exogenous surfactant on tidal volume (TV) and TNF production in isolated perfused mouse lungs. Initially, lungs were ventilated for 60 min at 10 cm H2O end‐inspiratory pressure before they were continued to be ventilated for 150 min at 10 cm H2O (black circles) or 25 cm H2O in the absence (green circles) or presence (orange symbols) of exogenous surfactant. The end‐expiratory pressure was always 2 cm H2O. All data are shown as mean ± SEM from four to six independent experiments. Similar results were obtained for IL‐6. The data are taken with permission from .

Figure 6. Figure 6.

Comparison of lipopolysaccharide (LPS)‐ and ventilation‐induced gene expression in isolated perfused mouse lungs. Shown is the upregulation of genes in lungs perfused with LPS (1 μg/ml) or ventilated with 25 cm H2O (OV, overventilation) for 3 h in comparison to control lungs (C) ventilated with 10 cm H2O. The data are taken with permission from . up, upregulation.

Figure 7. Figure 7.

Bronchoalveolar lavage (BAL) fluid characteristics of patients without major complications. The time interval between intubation and the first BAL was less than 36 h (mean = 16 h, range = 6‐36 h). Patients were then subjected to BAL at the end of the first and second weeks. PAF, platelet‐activating factor. *, p < 0.05 vs Week 0. Data were taken with permission from .

Figure 8. Figure 8.

Plasma cytokines levels in ARDS patients. Patients were routinely ventilated with a lung‐protective ventilation strategy (Vt 5 ml/kg predicted body weight, PEEP 15 cm H2O) and then switched for 6 h to a more conventional ventilatory setting (Vt 12 ml/kg predicted body weight, PEEP of 5 cm H2O). The data are taken with permission from .

Figure 9. Figure 9.

Proposed mechanisms of VILI in different conceptualized regions of lungs from ARDS patients. Please note that in real lungs, the regions a to c may coexist next to each other. For further details see the text. The figure has been adopted from .



Figure 1.

Possible mechanisms of air filling of distal airways during ventilation. (A) Recruitment, (B) expansion of alveolar ducts, (C) unfolding of interfolded structures, and (D) expansion of alveoli.



Figure 2.

Consequences of increasing mechanical load in lungs. The indicated pressures provide only rough estimates. For further details see the text.



Figure 3.

Mechanosensing (left) and injury‐sensing (right) mechanisms leading to inflammation. For further details see the text. LMWH, low‐molecular‐weight hyaluronan.



Figure 4.

Activation of transcription factors by mechanical ventilation. (A) Examples of cell‐type specific upregulation of transcription factors in response to mechanical ventilation or stretch. (B) Activation of NF‐κB in alveolar macrophages in isolated perfused mouse lungs ventilated with 10 or 25 cm H2O. The blue stain indicates the nucleus, and the brown stain NF‐κB. Ventilation with 25 cm H2O caused translocation of NF‐κB to the nucleus. Taken with permission from .



Figure 5.

Effect of exogenous surfactant on tidal volume (TV) and TNF production in isolated perfused mouse lungs. Initially, lungs were ventilated for 60 min at 10 cm H2O end‐inspiratory pressure before they were continued to be ventilated for 150 min at 10 cm H2O (black circles) or 25 cm H2O in the absence (green circles) or presence (orange symbols) of exogenous surfactant. The end‐expiratory pressure was always 2 cm H2O. All data are shown as mean ± SEM from four to six independent experiments. Similar results were obtained for IL‐6. The data are taken with permission from .



Figure 6.

Comparison of lipopolysaccharide (LPS)‐ and ventilation‐induced gene expression in isolated perfused mouse lungs. Shown is the upregulation of genes in lungs perfused with LPS (1 μg/ml) or ventilated with 25 cm H2O (OV, overventilation) for 3 h in comparison to control lungs (C) ventilated with 10 cm H2O. The data are taken with permission from . up, upregulation.



Figure 7.

Bronchoalveolar lavage (BAL) fluid characteristics of patients without major complications. The time interval between intubation and the first BAL was less than 36 h (mean = 16 h, range = 6‐36 h). Patients were then subjected to BAL at the end of the first and second weeks. PAF, platelet‐activating factor. *, p < 0.05 vs Week 0. Data were taken with permission from .



Figure 8.

Plasma cytokines levels in ARDS patients. Patients were routinely ventilated with a lung‐protective ventilation strategy (Vt 5 ml/kg predicted body weight, PEEP 15 cm H2O) and then switched for 6 h to a more conventional ventilatory setting (Vt 12 ml/kg predicted body weight, PEEP of 5 cm H2O). The data are taken with permission from .



Figure 9.

Proposed mechanisms of VILI in different conceptualized regions of lungs from ARDS patients. Please note that in real lungs, the regions a to c may coexist next to each other. For further details see the text. The figure has been adopted from .

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Ulrike Uhlig, Stefan Uhlig. Ventilation‐Induced Lung Injury. Compr Physiol 2011, 1: 635-661. doi: 10.1002/cphy.c100004