Possible Mechanisms of VILI

It is now clear that ventilation-induced pulmonary edema is essentially the result of severe changes in the permeability of the alveolar-capillary barrier. Small increases in microvascular transmural pressure may add their effects to those of altered permeability to enhance edema severity.

Depending on the duration of the aggression, two different kinds of injury probably occur. Small animals very rapidly develop a severe permeability pulmonary edema as a consequence of acute extreme lung stretching. This edema probably does not involve inflammatory cell recruitment or secretion of mediators. Edema develops more slowly in larger animals, in particular in response to moderately high airway pressures, rendering the situation more complex. A low lung volume injury probably adds its own effects to the direct mechanical aggression at high end-inspiratory volume. Indeed, high Vt mechanical ventilation without PEEP may reduce the aerated volume and gradually cause mechanical non-uniformity. This lung inhomogeneity will in turn promote overinflation of the more distensible and probably healthier zones, leading to positive feed-back aggravation. In addition, lung injury develops slowly enough in large animals for inflammatory pathways to become involved.

Mechanisms of Increased Vascular Transmural Pressure

Increased fluid filtration by this mechanism may occur at both extra-alveolar [48, 49] and alveolar [50-52] sites during mechanical ventilation. Increased transmural pressure in extra-alveolar vessels may result from the increase in lung volume, a consequence of lung interdependence [45, 53, 54], whereas increased filtration across alveolar microvessels maybe the consequence of surfactant inactivation [8, 52].

Mechanisms of Altered Permeability

While permeability alterations are obvious and severe during ventilator-induced edema, the underlying mechanisms are not fully understood, and there are prob ably several. In particular, as previously stressed, the mechanisms of lung injury may well vary according to the extent and duration of lung overdistension.

Effects of surfactant inactivation

In addition to its effects on fluid filtration, surfactant inactivation and elevated alveolar surface tension may increase alveolar epithelial permeability to small solutes. DTPA clearance in rabbits [55] and dogs [56] was increased following surfactant inactivation by detergent aerosolization. This effect was ascribed to the uneven distribution of lung mechanical properties resulting in ventilation inhomo-geneities and regional overexpansion, rather than to the elimination of peculiar barrier properties of surfactant [56]. The effects of surfactant inactivation and large VT ventilation on alveolocapillar permeability (as assessed by pulmonary DTPA clearance) are additive [57]. Increased surface tension may also alter endothelial permeability as a result of increased radial traction on pulmonary microvessels [52].

Participation of inflammatory cells and mediators

Role of inflammatory cells: The endothelial cell disruptions that have been observed during overinflation edema in small animals may allow direct contact between polymorphonuclear cells and basement membrane. This contact may promote leukocyte activation. As previously mentioned, the short duration of experiments conducted in small animals did not allow massive leukocyte recruitment. A striking feature of the VILI that occurs after several hours in larger animals is the infiltration of inflammatory cells into the interstitial and alveolar spaces. In one of the earliest studies on this subject, Woo and Hedley-White [58] observed that overinflation produced edema in open-chest dogs, and that leukocytes accumulated in the vasculature and macrophages in the alveoli. Further studies have confirmed these results [59] and shown that high transpulmonary pressure increased the transit time of leukocytes in the lungs of rabbits [60]. Conversely, when animals are depleted in neutrophils, high volume pulmonary edema is less severe than in non-depleted animals [61].

Role of inflammatory mediators: The participation of inflammatory cytokines in the course of VILI has been the subject of recent studies and is a matter of debate [62]. Tremblay and colleagues [63] examined the effects of different ventilatory strategies on the level of several cytokines in bronchoalveolar lavage (BAL) fluid of isolated rat lungs ventilated with different end-expiratory pressures and VT. High Vt ventilation (40 ml/kgbw) with ZEEP resulted in considerable increases in tumor necrosis factor (TNF)-a, interleukin (IL)-1fi and IL-6 and in macrophage inhibitory protein (MIP)-2. Unfortunately, results from this study have not been replicated by another group using the same ex vivo lung model [64]. It is worth noting that stretching in vitro human alveolar macrophages [65] or A549 epithelial cells [66] led to no TNF-a release, but to IL-8 release. In vivo studies of intact animals show that high volume mechanical ventilation that produces a very severe pulmonary edema does not induce the release of TNF-a [64,67]. Studies on TNF-a mRNA also yield conflicting results since Takata and coworkers [68] showed large increases in TNF-a mRNA in the intraalveolar cells of surfactant-depleted rabbits after one hour of conventional mechanical ventilation with peak inspiratory and end-expiratory pressures of 28 and 5 cmH20 (resulting in a mean airway pressure of 13 cmH2O) whereas Imanaka and colleagues showed no increase in lung tissue TNF-a mRNA of rats ventilated by high pressure (45 cmH2O of peak inspiratory pressure [69].

The only mediator which is constantly found in the different experimental studies is MIP-2 (or IL-8, pending on the experimental model). The presence of this neutrophil chemoattractant mediator in lungs subjected to high volume ventilation is in agreement with the well documented recruitment of neutrophils that occurs after long term ventilation [59, 70-72].

In addition to increasing the amount of cytokines in the lung, it has been suspected that overinflation during mechanical ventilation may promote the release of cytokines [73,74] or bacteria [75,76] into the blood, thus giving a causative role for mechanical ventilation in multiorgan dysfunction [77, 78]. However, this hypothesis remains to be proven [79].

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