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Animal models of airway hyperresponsiveness

S. I. Said
European Respiratory Journal 2009 33: 217-218; DOI: 10.1183/09031936.00131008
S. I. Said
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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.

    • © ERS Journals Ltd

    References

    1. ↵
      Meurs H, Gosens R, Zaagsma J. Airway hyperresponsiveness in asthma: lessons from in vitro model systems and animal models. Eur Respir J 2008;32:487–502.
      OpenUrlAbstract/FREE Full Text
    2. ↵
      Matsuzaki Y, Hamasaki Y, Said SI. Vasoactive intestinal peptide: a possible transmitter of nonadrenergic relaxation of guinea pig airways. Science 1980;210:1252–1253.
      OpenUrlAbstract/FREE Full Text
    3. ↵
      Takahashi N, Tanaka H, Abdullah N, Jing L, Inoue R, Ito Y. Regional difference in the distribution of L-NAME-sensitive and -insensitive NANC relaxations in cat airway. J Physiol 1995;488:709–720.
      OpenUrlPubMedWeb of Science
    4. ↵
      Dey RD, Mayer B, Said SI. Colocalization of vasoactive intestinal peptide and nitric oxide synthase in neurons of the ferret trachea. Neuroscience 1993;54:839–843.
      OpenUrlCrossRefPubMedWeb of Science
    5. ↵
      Fischer A, Hoffmann B. Nitric oxide synthase in neurons and nerve fibers of lower airways and in vagal sensory ganglia of man. Correlation with neuropeptides. Am J Respir Crit Care Med 1996;154:209–216.
      OpenUrlPubMedWeb of Science
    6. ↵
      Anastasiadis PZ, Bezin L, Gordon LJ, et al. Vasoactive intestinal peptide induces both tyrosine hydroxylase activity and tetrahydrobiopterin biosynthesis in PC12 cells. Neuroscience 1998;86:179–189.
      OpenUrlCrossRefPubMedWeb of Science
    7. ↵
      Grider JR, Jin JG. Vasoactive intestinal peptide release and L-citrulline production from isolated ganglia of the myenteric plexus: evidence for regulation of vasoactive intestinal peptide release by nitric oxide. Neuroscience 1993;54:521–526.
      OpenUrlCrossRefPubMedWeb of Science
    8. ↵
      Canning BJ, Fischer A. Localization of heme oxygenase-2 immunoreactivity to parasympathetic ganglia of human and guinea-pig airways. Am J Respir Cell Mol Biol 1998;18:279–285.
      OpenUrlPubMedWeb of Science
    9. ↵
      Said SI, Rattan S. The multiple mediators of neurogenic smooth muscle relaxation. Trends Endocrinol Metab 2004;15:189–191.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      Szema AM, Hamidi SA, Lyubsky S, et al. Mice lacking the VIP gene show airway hyperresponsiveness and airway inflammation, partially reversible by VIP. Am J Physiol Lung Cell Mol Physiol 2006;291:L880–L886.
      OpenUrlAbstract/FREE Full Text
    11. ↵
      Hamidi SA, Prabhakar S, Said SI. Enhancement of pulmonary vascular remodelling and inflammatory genes with VIP gene deletion. Eur Respir J 2008;31:135–139.
      OpenUrlAbstract/FREE Full Text
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    Animal models of airway hyperresponsiveness
    S. I. Said
    European Respiratory Journal Jan 2009, 33 (1) 217-218; DOI: 10.1183/09031936.00131008

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    Animal models of airway hyperresponsiveness
    S. I. Said
    European Respiratory Journal Jan 2009, 33 (1) 217-218; DOI: 10.1183/09031936.00131008
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