ArticleLiterature Review

Neural-Immunologic Interactions in Asthma

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Abstract

Recent investigations offer insights into the possible cause of asthma: Rather than being due to either neural or immunologic events, the fault may lie in concurrent malfunctioning of two interacting systems. Antigenic stimulation, for example, can affect neural depolarization and firing; by the same token, nerve stimulation can affect the growth and function of inflammatory cells.

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... The mechanisms by which NTs can influence airway structure or function are still under investigation. NTs can modulate neural influences, thus indirectly increasing airway contractility [36,37]. However, as shown in previous studies, BDNF can also directly influence ASM [Ca 2+ ] i [14]. ...
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Neurotrophins (NTs), which play an integral role in neuronal development and function, have been found in non-neuronal tissue (including lung), but their role is still under investigation. Recent reports show that NTs such as brain-derived neurotrophic factor (BDNF) as well as NT receptors are expressed in human airway smooth muscle (ASM). However, their function is still under investigation. We hypothesized that NTs regulate ASM intracellular Ca(2+) ([Ca(2+)](i)) by altered expression of Ca(2+) regulatory proteins. Human ASM cells isolated from lung samples incidental to patient surgery were incubated for 24 h (overnight) in medium (control) or 1 nM BDNF in the presence vs. absence of inhibitors of signaling cascades (MAP kinases; PI3/Akt; NFκB). Measurement of [Ca(2+)](i) responses to acetylcholine (ACh) and histamine using the Ca(2+) indicator fluo-4 showed significantly greater responses following BDNF exposure: effects that were blunted by pathway inhibitors. Western analysis of whole cell lysates showed significantly higher expression of CD38, Orai1, STIM1, IP(3) and RyR receptors, and SERCA following BDNF exposure, effects inhibited by inhibitors of the above cascades. The functional significance of BDNF effects were verified by siRNA or pharmacological inhibition of proteins that were altered by this NT. Overall, these data demonstrate that NTs activate signaling pathways in human ASM that lead to enhanced [Ca(2+)](i) responses via increased regulatory protein expression, thus enhancing airway contractility.
... The New York Times author was describing the findings of a paper written by Hossi et al. 73 Inflammatory disease is influenced by the nervous system. Undem 74 noted that nerve stimulation can affect the growth and function of inflammatory cells. Sternberg et al. 75 stated, "The central nervous system may coordinate both behavioral and immunologic adaptation during stressful situations. ...
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We have addressed the hypothesis that the excitability of peripheral neurons is affected during immediate hypersensitivity reactions. Guinea pigs were actively sensitized to ovalbumin. The electrical membrane properties of neurons within the superior cervical ganglion, bronchial parasympathetic ganglion and nodose ganglion were evaluated before, during and after antigen challenge. In all preparations, antigen stimulation induced the release of histamine and arachidonic acid metabolites. Our results support the hypothesis that the excitability of sympathetic, parasympathetic and sensory C-type neurons may be increased during immediate hypersensitivity reactions.
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In asthma, damage to airway epithelium, possibly caused by eosinophil products, exposes C-fibre afferent nerve endings. Stimulation of these endings by inflammatory mediators such as bradykinin may result in an axon (local) reflex with antidromic conduction down afferent nerve collaterals and release of sensory neuropeptides such as substance P, neurokinin A, and calcitonin gene-related peptide. These peptides are potent inducers of airway smooth muscle contraction, bronchial oedema, extravasation of plasma, mucus hypersecretion, and possibly inflammatory cell infiltration and secretion. Thus, axon reflexes could account for at least some of the pathophysiology of asthma and this concept might lead to new strategies for treatment.
Asthma: Physiology, Immunopharmacology, and Treatment
  • Bj Undem