Microvessel damage in acute respiratory distress syndrome: the answer may not be NO.

Acute lung injury and acute respiratory distress syndrome (ARDS) arise from a wide variety of causes, but the common clinical manifestations are refractory hypoxaemia and increased pulmonary vascular resistance. A major pathological feature of acute lung injury and ARDS is damage to the pulmonary vascular endothelium, secondary to the activation and adhesion of platelets, neutrophils and monocytes. 45 This may result in loss of endotheliumderived vasodilators, such as nitric oxide and prostacyclin. Loss of these factors may contribute to the widespread and indiscriminate pulmonary vasoconstriction seen in ARDS, detected clinically as an increase in pulmonary vascular resistance. The clinical consequence is hypoxaemia, since blood ̄ow to ventilated alveoli is limited by vasoconstriction and local thrombus formation. As well as inducing vasodilation, nitric oxide inhibits the release of cytokines and prevents the expression of adhesion molecules in endothelial cells, smooth muscle cells, leucocytes and platelets. 39 Thus a simple paradigm might be that damage to the pulmonary vascular endothelium enhances basal tone and the tendency towards vasoconstriction, abolishes endothelium-dependent relaxation and promotes adhesion of platelets and leucocytes, leading to in ̄ammation and pulmonary hypertension. The vascular endothelium is a complex piece of anatomical and biochemical machinery, especially in the lung, where large and small vessels have a completely different embryonic origin. In in vitro studies of the pulmonary circulation, much confusion has arisen because of the use of different generations of vessels, which have different functions, i.e. conduit as opposed to resistance arteries. The true seat of pulmonary vascular resistance in large animals is the pulmonary microvasculature (vessels of <400 mm in diameter), yet the endothelial responses of these small vessels have hardly been studied. In general terms, in the systemic circulation at least, nitric oxide is a feature of large vessels, whereas a different mediator, endothelium-derived hyperpolarizing factor (EDHF), characterizes microvessels. It would not be unreasonable to speculate that a similar situation occurs in the pulmonary circulation. This article reviews the pathophysiology of ARDS and how the various endothelium-derived relaxing factors (EDRFs) may be affected by the condition. It is suggested that, if the pulmonary microcirculation is the principal source of pulmonary vascular resistance, pulmonary hypertension in ARDS may be linked to loss of EDHF activity, not nitric oxide. If so, inhaled nitric oxide may not be the most appropriate therapy.