Ventilator - Induced Lung Injury

By Neil R. MacIntyre, MD, FCCP

Mechanisms of Lung Injury and the Development of Systemic Inflammation

The mechanisms of stretch injury are incompletely understood. Cyclical strain may have effects on a number of lung cells through alterations in membrane ion channels, changes in membrane-associated molecules, and physical membrane disruption.⁵ Once the stretch signal has been sensed by the cell, a wide variety of intracellular signaling mechanisms (eg, nuclear factor kB) appear to be activated that are responsible for increased gene expression and production of cytokines and other pro- and anti-inflammatory molecules that regulate VILI.^5,37,38

These processes have been studied in a number of lung cells including alveolar epithelial cells, alveolar macrophages, and pulmonary endothelial cells. For example, cultured alveolar epithelial cells subjected to > 130% stretch vs baseline have been shown to release interleukin 8.⁶ Other studies have shown that injured alveolar epithelial cells can produce a number of other inflammatory modulators such as tumor necrosis factor a (TNF-a).^6,39,40 Alveolar macrophages subjected to mechanical stretch are also known to be a source of a variety of proinflammatory modulators (eg, interleukin 8) as well as substances involved in lung remodeling (eg, matrix metalloproteinase-9).⁴¹ Pulmonary vascular endothelial cells have been shown to possess a number of stretch-inducible enzyme systems and pathways responsible for cytokine release.^42,43

Once stretch-induced lung injury has been initiated, the neutrophil plays an important role in the subsequent inflammatory response. This was first demonstrated by the observation that neutrophil-depleted animals receiving mechanical ventilation had markedly reduced VILI compared with control animals.⁴⁴ Other observations have shown marked neutrophil recruitment in VILI.⁴⁵ Moreover, BAL fluid from ARDS patients who underwent high-stretch ventilation produced significant neutrophil activation as compared with BAL fluid from those who received ventilation with a low-stretch strategy.⁴⁶

Both animal and clinical studies have validated the concept that VILI is accompanied by a systemic inflammatory process.^5,9,13,15 As noted above, the NIH ARDS Network trial demonstrated higher interleukin 6 levels and more distal organ failures in patients who received ventilation with the high-stretch strategy than in those with the low-stretch strategy.²⁷ Several animal studies^9,11,12 have clearly shown that inflammatory mediators in both BAL fluid and blood are associated with ventilator strategies designed to produce VILI (although controversy exists on the relative importance of the various substances¹⁴). More recently, Ranieri and others¹³ have shown that a wide array of inflammatory mediators appear in the blood and BAL fluid of patients who undergo ventilation with a high-stretch strategy. Another factor that may potentiate the systemic inflammatory process in VILI is the translocation of bacteria across an injured alveolar-capillary interface into the systemic circulation.^47,48

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