Faculty Bibliography

Acute lung injury remains a major cause of morbidity and mortality in paediatric intensive care units. Research over the past decade has altered our understanding of the pathophysiology of acute lung injury and the effects of mechanical ventilation on the lung. As a result, approaches to conventional mechanical ventilation of the injured lung are now largely centred around preservation of adequate gas exchange while protecting the lung from further ventilator-induced lung injury. Current techniques for accomplishing these goals include adjusting the ventilator based on the measurement and interpretation of pressure-volume curves, limitation of inspiratory tidal volumes, use of elevated levels of positive end-expiratory pressure, recruiting manoeuvres and prone positioning. The currently available data regarding the efficacy and appropriate use of these techniques are reviewed.

Endothelin (ET) may contribute to pulmonary edema formation, particularly under hypoxic conditions, and decreases in ET-B receptor expression can lead to reduced ET clearance. ET increases vascular endothelial cell growth factor (VEGF) production in vitro, and VEGF overexpression in the lung causes pulmonary edema in vivo. We hypothesized that pulmonary vascular ET-B receptor deficiency leads to increased lung ET, that excess ET increases lung VEGF levels, promoting pulmonary edema formation, and that hypoxia exaggerates these effects. We studied these hypotheses in ET-B receptor-deficient rats. In normoxia, homozygous ET-B-deficient animals had significantly more lung vascular leak than heterozygous or control animals. Hypoxia increased vascular leak regardless of genotype, and hypoxic ET-B-deficient animals leaked more than hypoxic control animals. ET-B-deficient animals had higher lung ET levels in both normoxia and hypoxia. Lung HIF-1alpha and VEGF content was greater in the ET-B-deficient animals in both normoxia and hypoxia, and both HIF-1alpha and VEGF levels were reduced by ET-A receptor antagonism. Both ET-A receptor blockade and VEGF antagonism reduced vascular leak in hypoxic ET-B-deficient animals. We conclude that ET-B receptor-deficient animals display an exaggerated lung vascular protein leak in normoxia, that hypoxia exacerbates that leak, and that this effect is in part attributable to an ET-mediated increase in lung VEGF content.