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Neural-Immunologic Interactions in Asthma
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.
... 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. ...
Basic science and clinical models of the vertebral subluxation are reviewed. Neurobiological mechanisms associated with these models are described. Models reviewed include the subluxation com- plex model, subluxation degeneration, nerve compression, dysafferentation, the neurodystrophic model and segmental facilitation. Clinical models, including the segmental, postural, and tonal approaches are discussed.
... 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]. ...
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.
Concomitant involvement of the upper and lower respiratory tracts is an everyday clinical reality. However, the pathophysiological mechanisms are still poorly clucidated. Nasal polyposis and asthma are frequently associated. Nasal and sinus superinfections are factors of deterioration of polyposis, but are also responsible for decompensation of asthma. The clinical context also modifies the susceptibility and prognosis of patients in relation to upper and lower respiratory tract infections, arguing in favour of global ENT and bronchial diagnostic and therapeutic management ENT of these diseases which often affect the entire respiratory tract.
Galen was the first to notice a relationship between nasal pathology and asthma (1). Numerous studies have been done throughout the years which point to this rela tionship, but it is not routine for physicians to treat nasal inflammation with maintenance medications in patients with asthma. A recent article (2) in the New England Journal of Medicine reviewing the pathophysiology of asthma failed to mention the contributory role of inflammation in the nose and sinuses to hyperreactivity of the bronchi. Another review (3) of the relationship between asthma and sinusitis in the pediatric literature failed to mention the possibility that allergic rhinitis also might contribute to lung hyperreactivity. This review is undertaken to alert primary care physicians to the significance with which both allergic and perennial rhinitis and sinusitis contribute to the success or failure of a management program for certain patients with asthma.
The ability of neurotensin (NT) at nmolar levels to stimulate exocytosis of the mast cell suggested that it could play a role in neuro-immune-endocrine interactions. The inhibition by a specific receptor antagonist of NT's mast cell stimulation suggested the presence of a specific mast cell NT receptor. We have here employed several probes to determine if a specific neurotensin receptor was present on rat serosal mast cells.
Serosal mast cells were isolated from the peritoneal and pleural cavities of male Sprague-Dawley rats.
Immunocytochemistry with an antibody raised against the C-terminal peptide of the neurotensin receptor was utilized. The same antibody was employed in immunoblotting following SDS gel electrophoresis of mast cell extracts. An RNA probe for ribonuclease protection assays (RPA) was prepared using the rat brain neurotensin receptor cDNA and polymerase chain reaction was carried out using primers based on the rat brain neurotensin receptor sequence.
Mast cells showed specific staining with the anti-neurotensin receptor antibody and this same antibody revealed a protein on SDS gels migrating as a 70 kDa species. Ribonuclease protection assays revealed the predicted protected fragment at approximately 450 bp while PCR amplification gave a major product at 843 bp.
These results indicate that a specific neurotensin receptor is present on the rat mast cell.
The effects of vagotomy on the respiratory responses of guinea‐pigs to anaphylactic reactions and to intravenous injections of histamine acid phosphate are described.
In spontaneously breathing guinea‐pigs, vagotomy reduced by 50% or more the decreases in total lung conductance (bronchoconstriction) and the decreases in lung compliance, and almost abolished the rapid shallow breathing due to histamine.
In paralysed, artificially ventilated guinea‐pigs, vagotomy reduced by more than 33% the decreases in total lung conductance, but had little effect on the changes in lung compliance due to histamine.
In paralysed, artificially ventilated guinea‐pigs, vagotomy reduced by 75% the decrease in total lung conductance and halved the decrease in lung compliance due to anaphylaxis.
We conclude that a vagal reflex is mainly responsible for the rapid shallow breathing due to histamine, and partly responsible for the bronchoconstrictions due to histamine and to anaphylaxis in guinea‐pigs. We suggest that “lung irritant receptors” in the bronchial epithelium are the afferent end‐organs involved.
We have examined the effects of repeated exposure to antigen on airway responses to cholinergic stimulation in two inbred strains of mice that are similar in underlying cholinergic airway responsiveness, yet differ in their ability to produce IgE. Both BALB/c and SJL/J mice were repeatedly exposed to ovalbumin by inhalation for a 10-d period. While the BALB/c mice developed IgE antibody to this allergen, the SJL/J strain failed to mount an appreciable IgE response. In vitro assessments of the response of tracheal smooth muscle from saline exposed mice (controls) of both strains demonstrated responses to both methacholine and electrical field stimulation that were not significantly different between the strains. Following exposure to ovalbumin, the BALB/c strain developed a significant increase in their response to electrical field stimulation, while their response to methacholine was unaltered. In contrast, the in vitro responsiveness to these stimuli did not increase in SJL/J mice following similar exposure to inhaled nebulized ovalbumin. The passive transfer of cells from the peribronchial lymph nodes of ovalbumin-sensitized BALB/c mice into syngeneic nonimmune mice also led to increases in responsiveness of tracheal smooth muscle to electrical field stimulation. In contrast, transfer of cells from nonsensitized mice did not alter responsiveness. These results suggest that murine species capable of developing an IgE response to allergen also develop alterations in the neural control of their airways. Further, this alteration appears to be lymphocyte dependent, in that cells found within peribronchial lymph nodes following allergen exposure are capable of transferring this increase in responsiveness to nonimmune mice.
The effect of antigen challenge on the function of neuronal M2-muscarinic autoreceptors in the lungs was studied in anesthetized guinea pigs. Guinea pigs were injected intraperitoneally with saline (control group) or ovalbumin (10 mg/kg) on days 1, 3, and 5. One group of sensitized animals was challenged on days 20-25 with aerosolized ovalbumin for 5 min/day (challenged group), while another group of the sensitized animals was not challenged (sensitized group). On day 26 the animals were anesthetized, paralyzed, tracheostomized, and artificially ventilated. Pulmonary inflation pressure (Ppi), tidal volume, blood pressure, and heart rate were recorded. Both vagus nerves were cut, and electrical stimulation of the distal portions caused bronchoconstriction (measured as an increase in Ppi) and bradycardia. In the control group, pilocarpine (1-100 micrograms/kg iv) attenuated vagally induced bronchoconstriction by stimulating inhibitory M2-muscarinic receptors on parasympathetic nerves in the lungs. Conversely, blockade of these receptors with the antagonist gallamine (0.1-10 mg/kg iv) produced a marked potentiation of vagally induced bronchoconstriction. These results confirm previous findings. In the challenged guinea pigs, pilocarpine did not inhibit vagally induced bronchoconstriction. Furthermore, gallamine did not potentiate vagally induced bronchoconstriction to the same degree as in the controls. In the group of animals that was sensitized but not challenged, the potentiation of vagally induced bronchoconstriction by gallamine was identical to the controls. There was no increase in baseline Ppi in the sensitized or challenged animals compared with the controls.(ABSTRACT TRUNCATED AT 250 WORDS)
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.
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