Neuropeptides like substance P, VIP, and CGRP play opposing roles in asthma — some drive inflammation and bronchoconstriction while others protect against it — opening new drug target possibilities.
6+ neuropeptides involvedAt least six distinct neuropeptides are released in asthmatic airways after allergen exposure, with opposing pro- and anti-inflammatory effects
What the researchers found
Neuropeptides play a significant and underappreciated role in asthma beyond traditional inflammatory mechanisms. The airway epithelium contains pulmonary neuroendocrine cells that release neuropeptides including substance P (SP), neurokinin A (NKA), vasoactive intestinal peptide (VIP), CGRP, neuropeptide Y (NPY), and orphanin FQ (N/OFQ) after allergen exposure.
These neuropeptides have opposing effects: SP, NKA, and serotonin drive inflammation (promoting chemokine synthesis in eosinophils, mast cells, and neutrophils), while VIP and N/OFQ provide anti-inflammatory and bronchodilatory effects. CGRP and acetylcholine have dual roles depending on which receptor pathway is activated — for example, ACh acting on M3 receptors causes bronchoconstriction and mucus overproduction, while ACh acting on α7nAChR receptors on ILC2 cells actually reduces inflammation.
Experimental NK1R/NK2R antagonists and exogenous VIP administration have decreased inflammatory mediators in studies, suggesting that targeting neuropeptide pathways could be a novel therapeutic approach for asthma.
Why it matters
Most asthma research focuses on immune cells and inflammatory pathways, but the nervous system's contribution through neuropeptides is often overlooked. This review shows that neuropeptides are not just bystanders — they actively drive bronchoconstriction, mucus production, and immune cell recruitment. Understanding these pathways opens up entirely new drug targets for asthma, particularly for patients who don't respond well to conventional corticosteroid therapy.
The numbers in context
6+ neuropeptides involved · SP-NK1R axis promotes eosinophil/mast cell chemokines · VIP-VPAC1 axis = bronchodilation · CGRP-RAMP1 enhances Th2/Th9 responses · ACh-α7nAChR reduces TNF-α, IL-1, IL-6
How the study worked
Narrative review published in Frontiers in Cell and Developmental Biology, synthesizing evidence on the roles of neurotransmitters and neuropeptides in asthma pathophysiology, their receptor pathways, and potential therapeutic applications.
Who was studied
Not applicable (review covering asthma patients and relevant preclinical models)
What this study cannot tell us
Narrative review without systematic search methodology. Much of the neuropeptide research in asthma comes from animal models, with limited human clinical trial data for neuropeptide-targeted therapies. The therapeutic potential of NK1R/NK2R antagonists and VIP is based largely on preclinical and early-phase studies.
How to read the evidence
Published in Frontiers in Cell and Developmental Biology, a peer-reviewed open-access journal. The review provides a comprehensive overview of neuropeptide pathways in asthma but much of the therapeutic evidence cited is preclinical rather than from human trials.
When this study was published
Published in 2021. The neuropeptide pathways described remain relevant, though the therapeutic landscape continues to evolve with newer peptide-based approaches.
The bigger picture
The neuroimmune connection in asthma represents a frontier where peptide biology meets respiratory medicine. While current asthma drugs target inflammation (corticosteroids) or airway constriction (bronchodilators), neuropeptide-targeted therapies could address both simultaneously. This is part of a broader recognition that neuropeptides are key regulators of immune responses throughout the body, not just in the brain.
Questions still open
- Could VIP inhalation therapy provide bronchodilation and anti-inflammatory effects simultaneously for treatment-resistant asthma?
- Would NK1R antagonists (substance P blockers) reduce asthma exacerbations in patients with neurogenic inflammation?
- How do neuropeptide profiles differ between asthma phenotypes, and could they be used for precision treatment selection?
Common questions
How do neuropeptides affect asthma?
Could neuropeptide-targeting drugs treat asthma?
Read the original research
Neuroimmune Pathophysiology in Asthma.
Frontiers in cell and developmental biology, 9, 663535
Citation
Pavón-Romero, Gandhi F; Serrano-Pérez, Nancy Haydée; García-Sánchez, Lizbeth; Ramírez-Jiménez, Fernando; Terán, Luis M. (2021). Neuroimmune Pathophysiology in Asthma.. Frontiers in cell and developmental biology, 9, 663535. https://doi.org/10.3389/fcell.2021.663535