Therapeutic modalities are necessary which will increase the efficiency of oxygen uptake by the lung during periods of acute lung injury. Inhalational vasodilators which depend on ventilation for distribution might be of great benefit in reducing arterial hypoxemia occurring during such lung injury. These agents would be preferentially active in non-injured lung regions with intact ventilation. By causing vasodilation and augmented perfusion in well ventilated lung regions only, such agents would optimize matching of ventilation and perfusion and improve arterial oxygenation. Total systemic oxygen delivery would also be improved by reductions in PVR resulting in increased right and left ventricular function and improved cardiac output. Inhaled nitric oxide is one such potential selective pulmonary vasodilator. Use of inhaled nitric oxide in patients with acute lung injury is rapidly gaining acceptance in Europe and is being introduced in the US. Controlled clinical studies evaluating the effectiveness of inhaled NO during acute lung injury have not been done however. In a canine model of lobar and diffuse bacterial pneumonia which closely simulates the acute lung injury and cardiopulmonary changes which occurs in humans with pneumonia, we have shown that short term administration of inhaled NO does result in improved pulmonary hemodynamics and gas exchange. Improvements with this agent are modest however and of unclear clinical importance. No animal data is presently available to support the belief that prolonged inhaled nitric oxide will improve overall outcome during acute lung injury. Inhaled nitric oxide has a number of potential toxicities which should be of great concern in patients presenting with acute pneumonia. Inhaled NO has the capacity to aggravate oxidant lung injury via the formation of peroxynitrite and hydroxyl radical. This potential would be even greater in patients with inflammatory lung injury on oxygen therapy. Nitric oxide also, by down- regulating endothelial receptors for neutrophil adhesion, has the capacity to limit neutrophil migration out of the intravascular space. This effect might very well limit host defense during acute lung injury associated with intrapulmonary bacterial infection. Studies evaluating the potential toxic long term effects of inhaled nitric oxide during inflammatory lung injury associated with infection have not been conducted. In order to address effectiveness and potential toxicity of prolonged inhaled nitric oxide during acute lung injury. we have designed a rat model of intrapulmonary infection which is associated with inflammatory lung injury. We have also developed techniques for the long term monitoring and administration of inhaled nitric oxide at varying levels of oxygen exposure to small animals. We intend to combine these techniques to evaluate the potential effectiveness or toxicity of prolonged NO inhalation during intrapulmonary infection and inflammation in the presence of oxygen therapy.
