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Molecular Mechanisms and New Targets of Refractory Asthma
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Molecular Mechanisms and New Targets of Refractory Asthma

A special issue of Biology (ISSN 2079-7737). This special issue belongs to the section "Biochemistry and Molecular Biology".

Deadline for manuscript submissions: 30 June 2025 | Viewed by 8037

Special Issue Editors

Prof. Dr. Yaping Tu

E-Mail Website
Guest Editor
Department of Pharmacology and Neuroscience, Creighton University School of Medicine, Omaha, NE 68124, USA
Interests: pharmacology; asthma; cancer biology; signal transduction; G-protein coupled receptor
Prof. Dr. Steven S. An

E-Mail Website
Guest Editor
Department of Pharmacology, Rutgers-Robert Wood Johnson Medical School, The State University of New Jersey, New Brunswick, NJ 08091, USA
Interests: biophysics; airway smooth muscle; lung diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Asthma is a chronic obstructive inflammatory airway disease with substantial morbidity and mortality, affecting over 300 million people worldwide. Airway hyperresponsiveness and airway inflammation are hallmarks of asthma clinically managed with β2-agonist bronchodilators and corticosteroids. Refractory asthma manifests with persistent symptoms despite the use of high-dose corticosteroids and long-acting β2-agonists, leading to increased morbidity and costs associated with treatment. Understanding the mechanisms and developing strategies to overcome this therapeutic resistance pose a significant unmet need.

For this Special Issue, “Molecular Mechanisms and New Targets of Refractory Asthma”, we welcome the submission of original articles and reviews that explore all biological aspects of refractory asthma, with an emphasis on molecular mechanisms and new therapeutic targets. The goal of this Special Issue is to improve our understanding of the therapeutic resistance in asthma, and provide valuable insights to address the overarching challenge of refractory asthma.

Prof. Dr. Yaping Tu
Prof. Dr. Steven S. An
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biology is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • refractory asthma
  • airway hyperresponsiveness
  • T2 and non-T2 inflammation
  • steroid resistance
  • therapeutic targets

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Published Papers (3 papers)

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Research

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20 pages, 3496 KiB  
Article
Neutralizing Oxidized Phosphatidylcholine Reduces Airway Inflammation and Hyperreactivity in a Murine Model of Allergic Asthma
by Jignesh Vaghasiya, Aruni Jha, Sujata Basu, Alaina Bagan, Siwon K. Jengsuksavat, Amir Ravandi, Christopher D. Pascoe and Andrew J. Halayko
Biology 2024, 13(8), 627; https://doi.org/10.3390/biology13080627 - 17 Aug 2024
Viewed by 2018
Abstract
Oxidative stress is associated with asthma pathobiology. We reported that oxidized phosphatidylcholines (OxPCs) are mediators of oxidative stress and accumulate in the lung in response to allergen challenge. The current study begins to unravel mechanisms for OxPC accumulation in the lung, providing the [...] Read more.
Oxidative stress is associated with asthma pathobiology. We reported that oxidized phosphatidylcholines (OxPCs) are mediators of oxidative stress and accumulate in the lung in response to allergen challenge. The current study begins to unravel mechanisms for OxPC accumulation in the lung, providing the first insights about how OxPCs underpin allergic airway pathophysiology, and pre-clinical testing of selective neutralization of OxPCs in a murine model of allergic asthma. We hypothesized that intranasal delivery of E06, a natural IgM antibody that neutralizes the biological activity of OxPCs, can ameliorate allergen-induced airway inflammation and airway hyperresponsiveness. Adult BALB/c mice were intranasally (i.n.) challenged with house dust mite (HDM) (25 μg/mouse, 2 weeks). Some animals also received E06 monoclonal antibody (mAb) (10 µg) i.n. 1 hr before each HDM challenge. HDM challenge reduced mRNA for anti-oxidant genes (SOD1, SOD2, HO-1, and NFE2L2) in the lung by several orders of magnitude (p < 0.05). Concomitantly, total immune cell number in bronchoalveolar lavage fluid (BALF) increased significantly (p < 0.001). E06 mAb treatment prevented allergen-induced BALF immune cell number by 43% (p < 0.01). This included a significant blockade of eosinophils (by 48%, p < 0.001), neutrophils (by 80%, p < 0.001), macrophages (by 80%, p < 0.05), and CD4 (by 30%, p < 0.05) and CD8 (by 42%, p < 0.01) lymphocytes. E06 effects correlated with a significant reduction in TNF (by 64%, p < 0.001) and IL-1β (by 75%, p < 0.05) and a trend to diminish accumulation of other cytokines (e.g., IL-4, -10, and -33, and IFN-γ). E06 mAb treatment also inhibited HDM exposure-induced increases in total respiratory resistance and small airway resistance by 24% and 26%, respectively. In conclusion, prophylactic treatment with an OxPC-neutralizing antibody significantly limits allergen-induced airway inflammation and airway hyperresponsiveness, suggesting that OxPCs are important mediators of oxidative stress-associated allergic lung pathophysiology. Full article
(This article belongs to the Special Issue Molecular Mechanisms and New Targets of Refractory Asthma)
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Review

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15 pages, 916 KiB  
Review
Molecular Pathways and Potential Therapeutic Targets of Refractory Asthma
by Leah Ishmael, Thomas Casale and Juan Carlos Cardet
Biology 2024, 13(8), 583; https://doi.org/10.3390/biology13080583 - 1 Aug 2024
Cited by 3 | Viewed by 2869
Abstract
Asthma is a chronic inflammatory lung disease. Refractory asthma poses a significant challenge in management due to its resistance to standard therapies. Key molecular pathways of refractory asthma include T2 inflammation mediated by Th2 and ILC2 cells, eosinophils, and cytokines including IL-4, IL-5, [...] Read more.
Asthma is a chronic inflammatory lung disease. Refractory asthma poses a significant challenge in management due to its resistance to standard therapies. Key molecular pathways of refractory asthma include T2 inflammation mediated by Th2 and ILC2 cells, eosinophils, and cytokines including IL-4, IL-5, and IL-13. Additionally, non-T2 mechanisms involving neutrophils, macrophages, IL-1, IL-6, and IL-17 mediate a corticosteroid resistant phenotype. Mediators including alarmins (IL-25, IL-33, TSLP) and OX40L have overlap between T2 and non-T2 inflammation and may signify unique pathways of asthma inflammation. Therapies that target these pathways and mediators have proven to be effective in reducing exacerbations and improving lung function in subsets of severe asthma patients. However, there are patients with severe asthma who do not respond to approved therapies. Small molecule inhibitors, such as JAK-inhibitors, and monoclonal antibodies targeting mast cells, IL-1, IL-6, IL-33, TNFα, and OX40L are under investigation for their potential to modulate inflammation involved in refractory asthma. Understanding refractory asthma heterogeneity and identifying mediators involved are essential in developing therapeutic interventions for patients unresponsive to currently approved biologics. Further investigation is needed to develop personalized treatments based on these molecular insights to potentially offer more effective treatments for this complex disease. Full article
(This article belongs to the Special Issue Molecular Mechanisms and New Targets of Refractory Asthma)
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12 pages, 456 KiB  
Review
Rho-Kinase Inhibition of Active Force and Passive Tension in Airway Smooth Muscle: A Strategy for Treating Airway Hyperresponsiveness in Asthma
by Yuto Yasuda, Lu Wang, Pasquale Chitano and Chun Y. Seow
Biology 2024, 13(2), 115; https://doi.org/10.3390/biology13020115 - 11 Feb 2024
Cited by 4 | Viewed by 2554
Abstract
Rho-kinase inhibitors have been identified as a class of potential drugs for treating asthma because of their ability to reduce airway inflammation and active force in airway smooth muscle (ASM). Past research has revealed that, besides the effect on the ASM’s force generation, [...] Read more.
Rho-kinase inhibitors have been identified as a class of potential drugs for treating asthma because of their ability to reduce airway inflammation and active force in airway smooth muscle (ASM). Past research has revealed that, besides the effect on the ASM’s force generation, rho-kinase (ROCK) also regulates actin filament formation and filament network architecture and integrity, thus affecting ASM’s cytoskeletal stiffness. The present review is not a comprehensive examination of the roles played by ROCK in regulating ASM function but is specifically focused on passive tension, which is partially determined by the cytoskeletal stiffness of ASM. Understanding the molecular basis for maintaining active force and passive tension in ASM by ROCK will allow us to determine the suitability of ROCK inhibitors and its downstream enzymes as a class of drugs in treating airway hyperresponsiveness seen in asthma. Because clinical trials using ROCK inhibitors in the treatment of asthma have yet to be conducted, the present review focuses on the in vitro effects of ROCK inhibitors on ASM’s mechanical properties which include active force generation, relaxation, and passive stiffness. The review provides justification for future clinical trials in the treatment of asthma using ROCK inhibitors alone and in combination with other pharmacological and mechanical interventions. Full article
(This article belongs to the Special Issue Molecular Mechanisms and New Targets of Refractory Asthma)
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