To the Editors:
I read with much interest the review by Meurs et al. 1, in which they examined the relative merits of several animal models of airway hyperresponsiveness (AHR), and the insights these models provide into the mechanisms of airway physiology and pathophysiology. The study appropriately focused on the role of nitric oxide (NO) as a transmitter of the inhibitory (i.e. relaxant) nonadrenergic, noncholinergic (NANC) system, the principal defence against excessive airway smooth muscle contraction. I propose adding two more NANC transmitters and another model of AHR to this excellent discussion.
The first additional NANC transmitter is the smooth muscle relaxant neuropeptide vasoactive intestinal peptide (VIP). VIP acts as an NANC transmitter in a variety of mammalian airways including human airways. VIP is released during relaxation of guinea pig trachea induced by electrical field stimulation; the release is proportional to the degree of relaxation, and blocked by the neurotoxin tetrodotoxin. The relaxation is reduced by prior incubation with VIP antiserum 2, by a VIP antagonist, α-chymotrypsin 3 or a VIP catalytic antibody. VIP and NO synthase (NOS) have been co-localised in neurons innervating ferret and human airways 4, 5. Beyond their presence together in the same neurons, VIP and NO have the following close functional interactions. 1) VIP promotes the normal synthesis and functioning of endothelial NOS, by stimulation of tetrahydrobiopterin, which plays a pivotal role in NOS function 6. 2) VIP activates a constitutive form of neuronal NOS and NO mediates a significant proportion of VIP-induced tracheal relaxation. 3) NO also stimulates VIP release from certain neurons 7.
Carbon monoxide (CO) is the latest entry into the field of NANC transmitters of smooth muscle relaxation. Previously thought of only as a highly toxic gas, CO is now known to be generated endogenously by the action of heme oxygenase, typically expressed in neurons that often also express NOS and VIP 8. Similar to NO, CO stimulates soluble guanylyl cyclase activity.
In summary, it appears likely that NANC relaxation of airway smooth muscle is mediated by at least two and probably all three transmitters, pharmacologically coupled, or otherwise working in concert. There are several benefits to having multiple transmitters, including: 1) VIP and CO are both more stable than NO in biological systems and, therefore, they induce longer-lasting relaxation; and 2) the presence of three transmitters of smooth muscle relaxation offers the distinct advantage of redundancy. Failure of relaxation is less likely with multiple transmitters than with only one, and the potential for more efficacious relaxation is enhanced, with these transmitters activating both the adenylyl cyclase-cyclic AMP and guanylyl cyclase-cyclic GMP pathways. Thus working together and cooperatively, VIP, NO and CO could improve the chances of preventing or correcting such life-threatening situations as severe airway constriction 9.
The additional model of airway hyperresponsiveness worth considering in this context is that recently reported in mice lacking the vasoactive intestinal peptide gene 10. In addition to spontaneously expressing airway hyperresponsiveness, these mice also show airway inflammation, evidenced by lung inflammatory cell infiltrates, increased cytokine and chemokine levels in bronchoalveolar lavage fluid, and upregulation of pro-inflammatory genes in lung tissue 11. The existence of this asthma-like phenotype is proof that vasoative intestinal peptide plays an essential role in maintaining normal airway function.
Statement of interest
None declared.
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