Nitric oxide, hypoxia, and superoxide: the good, the bad, and the ugly!

Nitric oxide (NO) is endogenously synthesised by nitric oxide synthases (NOS) which convert l-arginine to l-citrulline and NO. Three NOS isoforms (types I, II and III) have been identified and all of them are expressed in the human lung.^1–8 NOS I (nNOS) and III (eNOS) are constitutively expressed in tissues and are dependent on increases in intracellular calcium for enzyme activation while NOS II (iNOS) is an inducible form that is calcium independent (table 1).⁹ All NOS isoforms require oxygen, NADPH, FAD, FMN, tetrahydrobiopterin, and calmodulin for activity.^1,9 NO is recognised to have a key role in virtually all aspects of lung biology and has been implicated in the pathophysiology of lung diseases.^{1,4,6,10–15} It is involved in pulmonary neurotransmission, host defence and bacteriostasis, airway and vascular smooth muscle relaxation, pulmonary capillary leak, inflammation, mucociliary clearance, airway mucus secretion, and cytotoxicity.^4,6,14

Cellular sources of NO in the lung include epithelial cells, endothelial cells of pulmonary arteries and veins, inhibitory non-adrenergic non-cholinergic neurones, smooth muscle cells, mast cells, mesothelial cells, fibroblasts, neutrophils, lymphocytes, and macrophages.^4,6,14 Specifically, NOS I is located in inhibitory non-adrenergic non-cholinergic neurones in the lung while NOS III is found in endothelial cells and the brush border of ciliated epithelial cells.^1,5,7 NOS II is found in the epithelial cells of the airway. Although NOS II may be induced in several types of cells in response to cytokines, endotoxin, or reactive oxygen species, it is continuously expressed in normal human airway epithelium at basal airway conditions.^8,16

Once produced, NO is freely diffusible and enters target cells activating soluble guanylate cyclase to produce guanosine 3′,5′-cyclic monophosphate (cGMP) …