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 important physiologic role in the regulation of pulmonary vasomotor tone by several known mechanisms. Nitric oxide stimulates soluble guanylyl cyclase, resulting in increased levels of cyclic GMP in lung smooth muscle cells. The gating of K+ and Ca2+ channels by cyclic GMP binding is thought to play a role in nitric oxide-mediated vasodilation. Nitric oxide may also regulate pulmonary vasodilation by direct activation of K+ channels or by modulating the expression and activity of angiotensin II receptors. Administration of nitric oxide by inhalation has been shown to acutely improve hypoxemia associated with pulmonary hypertension in humans and animals. This is presumably due to its ability to induce pulmonary vasodilation. Inhaled nitric oxide improves oxygenation and reduces the need for extracorporeal membrane oxygenation in term and near-term infants with persistent pulmonary hypertension. However, long-term benefits to these infants have been difficult to demonstrate. In other pathologic conditions, such as prematurity and acute respiratory distress syndrome, short-term benefits have not been shown conclusively 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 oxidative damage to lung epithelial cells. Conversely, protective effects of nitric oxide have been described in a number of pathological states, including hyperoxic and ischemia/reperfusion injury. Nitric oxide has also been reported to protect against oxidative damage induced by other reactive intermediates, 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.
Weinberger
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Department of Pediatrics-Neonatology, UMDNJ-Robert Wood Johnson Medical School, St. Peter's University Hospital, New Brunswick, NJ 08903, USA. barryw@pol.net
Heck
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Laskin
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Laskin
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D000280:Administration, Inhalation; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008168:Lung / Q000187:drug effects*; D008171:Lung Diseases / Q000188:drug therapy; D009504:Neutrophils / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology* / Q000627:therapeutic use; D010547:Persistent Fetal Circulation Syndrome / Q000188:drug therapy; D011945:Receptors, Angiotensin / Q000502:physiology; D012128:Respiratory Distress Syndrome / Q000188:drug therapy; D014664:Vasodilation / Q000187:drug effects
D000975:Antioxidants; D011945:Receptors, Angiotensin; D009569:Nitric Oxide