Nitric oxide in the lung: therapeutic and cellular mechanisms of action

Nitric oxide is produced by many cell types in the lung and plays an import ant physiologic role in the regulation of pulmonary vasomotor tone by sever al known mechanisms. Nitric oxide stimulates soluble guanylyl cyclase, resu lting in increased levels of cyclic GMP in lung smooth muscle cells. The ga ting of K+ and Ca2+ channels by cyclic GMP binding is thought to play a rol e in nitric oxide-mediated vasodilation: Nitric oxide may also regulate pul monary vasodilation by direct activation of K+ channels or by modulating th e expression and activity of angiotensin II receptors. Administration of ni tric oxide by inhalation has been shown to acutely improve hypoxemia associ ated with pulmonary hypertension in humans and animals. This is presumably due to its ability to induce pulmonary vasodilation. Inhaled nitric oxide i mproves oxygenation and reduces the need for extracorporeal membrane oxygen ation in term and near-term infants with persistent pulmonary hypertension. However, long-term benefits to these infants have been difficult to demons trate. In other pathologic conditions, such as prematurity and acute respir atory distress syndrome, short-term benefits have not been shown conclusive ly to outweigh potential toxicities. For example, high-dose inhaled nitric oxide decreases surfactant function in the lung. Inhaled nitric oxide also acts as a pulmonary irritant, causing priming of lung macrophages and oxida tive damage to lung epithelial cells. Conversely, protective effects of nit ric oxide have been described in a number of pathological states, including hyperoxic and ischemia/reperfusion injury. Nitric oxide has also been repo rted to protect against oxidative damage induced by other reactive intermed iates, including superoxide anion and hydroxyl radical. The dose and timing of nitric oxide administration needs to be ascertained in clinical trials before recommendations can be made regarding its optimal use in patients. ( C) 1999 Elsevier Science Inc. All rights reserved.