Neuroimmune Pathophysiology in Asthma

Abstract

Asthma is a chronic inflammation of lower airway disease, characterized by bronchial hyperresponsiveness. Type I hypersensitivity underlies all atopic diseases including allergic asthma. However, the role of neurotransmitters (NT) and neuropeptides (NP) in this disease has been less explored in comparison with inflammatory mechanisms. Indeed, the airway epithelium contains pulmonary neuroendocrine cells filled with neurotransmitters (serotonin and GABA) and neuropeptides (substance P[SP], neurokinin A [NKA], vasoactive intestinal peptide [VIP], Calcitonin-gene related peptide [CGRP], and orphanins-[N/OFQ]), which are released after allergen exposure. Likewise, the autonomic airway fibers produce acetylcholine (ACh) and the neuropeptide Y(NPY). These NT/NP differ in their effects; SP, NKA, and serotonin exert pro-inflammatory effects, whereas VIP, N/OFQ, and GABA show anti-inflammatory activity. However, CGPR and ACh have dual effects. For example, the ACh-M3 axis induces goblet cell metaplasia, extracellular matrix deposition, and bronchoconstriction; the CGRP-RAMP1 axis enhances Th2 and Th9 responses; and the SP-NK1R axis promotes the synthesis of chemokines in eosinophils, mast cells, and neutrophils. In contrast, the ACh-α7nAChR axis in ILC2 diminishes the synthesis of TNF-α, IL-1, and IL-6, attenuating lung inflammation whereas, VIP-VPAC1, N/OFQ-NOP axes cause bronchodilation and anti-inflammatory effects. Some NT/NP as 5-HT and NKA could be used as biomarkers to monitor asthma patients. In fact, the asthma treatment based on inhaled corticosteroids and anticholinergics blocks M3 and TRPV1 receptors. Moreover, the administration of experimental agents such as NK1R/NK2R antagonists and exogenous VIP decrease inflammatory mediators, suggesting that regulating the effects of NT/NP represents a potential novel approach for the treatment of asthma.

Curcumin supplementation in pediatric patients: A systematic review of current clinical evidence

“…Dyspnea, cough, and wheezing are the classic signs and symptoms of asthma due to airway hyper‐responsiveness and airway inflammation. Disease pathophysiology is predominantly related to lung infiltration and activation of immune cells (macrophages, eosinophils, basophils, T‐helper 1 [Th1], Th2, Th17, mast cells, neutrophils, dendritic cells), dysfunction of regulatory T cells (Treg), mucus hypersecretion, nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) activation, and excessive production of inflammatory mediators (interleukin [IL]‐4, IL‐5, IL‐8, IL‐13, IL‐17, IL‐25, IL‐33, leukotrienes, histamine, and nitric oxide) (Abidi, Gupta, Agarwal, Bhalla, & Saluja, 2014; Pavón‐Romero, Serrano‐Pérez, García‐Sánchez, Ramírez‐Jiménez, & Terán, 2021).…”

Regulatory Peptides in Asthma

“…On the other hand, there is also a less optimistic study showing that chronic administration of an NK1 receptor antagonist, maropitant, was ineffective in reducing signs of neurogenic airway inflammation, eosinophilia and AHR in an experimental feline model of asthma [125]. The more detailed information on the role of tachykinins in asthma was described in the latest review by Pavon-Romero et al [5] 2.9. CGRP Although the calcitonin gene-related peptide (CGRP) has been described quite thoroughly in the context of its role in asthma in the article by Pavon-Romeiro et al [5], it is impossible not to mention it in this review.…”

“…The more detailed information on the role of tachykinins in asthma was described in the latest review by Pavon-Romero et al [5] 2.9. CGRP Although the calcitonin gene-related peptide (CGRP) has been described quite thoroughly in the context of its role in asthma in the article by Pavon-Romeiro et al [5], it is impossible not to mention it in this review. CGRP is synthesized in the airway epithelium, in neuroepithelial bodies and together with SP in the sensory nerve endings of the vagus C-fiber and released into the airway when an allergic stimulus is acted upon (Figure 2) [126,127].…”

“…Interestingly, many other endogenous mediators, such as regulatory peptides not necessarily directly related to respiratory tract functioning, have been implicated in mediation of asthma related inflammatory process and airway hyperreactivity (AHR) [4,5].…”

“…They are produced by pulmonary neuroendocrine cells (bombesin-like peptides and serotonin), the only innervated airway epithelial cells [6]; and autonomic airway fibers innervating airway muscles, blood vessels and lungs (substance P (SP), neurokinin A (NKA) and vasoactive intestinal polypeptide (VIP)) [5]. Neuropeptides can act directly through their receptors and regulate airway smooth muscle tone, bronchial blood flow and airway secretion or act on inflammatory cells, contributing in this way to inflammatory process and ventilation in asthma pathology (Figure 1) [5,[7][8][9]. Their impact on asthma symptoms can be either soothing, as for neurotensin [10], or aggravating, as for neuropeptide Y [11].…”