Three days after a single exposure to ozone, the mechanism of airway hyperreactivity is dependent on substance P and nerve growth factor

Abstract

Ozone causes persistent airway hyperreactivity in humans and animals. One day after ozone exposure, airway hyperreactivity is mediated by release of eosinophil major basic protein that inhibits neuronal M(2) muscarinic receptors, resulting in increased acetylcholine release and increased smooth muscle contraction in guinea pigs. Three days after ozone, IL-1β, not eosinophils, mediates ozone-induced airway hyperreactivity, but the mechanism at this time point is largely unknown. IL-1β increases NGF and the tachykinin substance P, both of which are involved in neural plasticity. These experiments were designed to test whether there is a role for NGF and tachykinins in sustained airway hyperreactivity following a single ozone exposure. Guinea pigs were exposed to filtered air or ozone (2 parts per million, 4 h). In anesthetized and vagotomized animals, ozone potentiated vagally mediated airway hyperreactivity 24 h later, an effect that was sustained over 3 days. Pretreatment with antibody to NGF completely prevented ozone-induced airway hyperreactivity 3 days, but not 1 day, after ozone and significantly reduced the number of substance P-positive airway nerve bundles. Three days after ozone, NK(1) and NK(2) receptor antagonists also blocked this sustained hyperreactivity. Although the effect of inhibiting NK(2) receptors was independent of ozone, the NK(1) receptor antagonist selectively blocked vagal hyperreactivity 3 days after ozone. These data confirm mechanisms of ozone-induced airway hyperreactivity change over time and demonstrate 3 days after ozone that there is an NGF-mediated role for substance P, or another NK(1) receptor agonist, that enhances acetylcholine release and was not present 1 day after ozone.

Ozone-induced eosinophil recruitment to airways is altered by antigen sensitization and tumor necrosis factor-αblockade

“…Restoring neuronal M 2 muscarinic receptor function on day 3, though, does not fully reverse airway hyperresponsiveness (Verhein et al. ). Unlike at 1 day, both neuronal and nonneuronal mechanisms account for ozone‐induced airway hyperresponsiveness 3 days later (Yost et al.…”

Airway smooth muscle in airway reactivity and remodeling: what have we learned?

“…On the other hand, prolonged dopaminergic signaling via a D2-like, Gi-coupled pathway leads to enhancement of the Gs-coupled ␤2-adrenoceptor (␤2AR) system, thus increasing cAMP and promoting bronchodilation. GRK3, G protein-coupled receptor kinase; RGS4, G-protein signaling 4. dence for TRPV1 in nonneuronal airway cells such as epithelium (298) and ASM (354) but considerable data on the expression of kinin receptors in ASM (173,200,252,322). Thus it would be interesting to determine whether OGR1 can indirectly influence these mechanisms.…”

“…However, the functional role of neurotrophins in the airway are still under investigation. Here, recent data suggest that NGF is released by airway nerves in response to irritants [e.g., ozone (120,322) or cigarette smoke (336)], allergens (346), and infectious agents (38) contributing to irritability and enhanced contractility. NGF can also be derived from airway epithelial cells, for example following viral or bacterial infections (38,222).…”

“…Finally, the effects of inflammation (321,332), infection (124), pollutants (252), and other stimuli on airway nerves are being explored, again with the intent of suppressing excessive bronchoconstriction, as well as cough reflexes. Here, an emerging theme is again neurotrophins such as NGF, BDNF, and glial-derived neurotrophic factor that serve to influence airway reactivity (175,176,200) as well as enhance immunity and reactivity in the airway following bacterial infections (38), exposure to house dust mite (and important aspect of allergic asthma) (346), allergen challenge (176), or ozone (322). Furthermore, it may be relevant to consider whether novel mechanisms such as TAS2R and OGR1 are present and functional in neural pathways involved in airway tone.…”

Eosinophil and airway nerve interactions in asthma

“…Neuropeptides, such as substance P, are small signaling molecules that are synthesized and secreted by sensory nerves. Nerves increase substance P expression in response to allergens, ozone, and respiratory viruses, and blocking the substance P receptor neurokinin‐1 (NK1) suppresses airway hyperreactivity . Eosinophils mediate an increase in neuronal substance P after allergens and consequently, changes in neuronal substance P after allergens are absent in eosinophil‐deficient mice (unpublished observation).…”