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Molecular Advance on the Pathogenesis and Treatment of Asthma
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Molecular Advance on the Pathogenesis and Treatment of Asthma

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 June 2024) | Viewed by 7913

Special Issue Editor

Dr. Diego Bagnasco

E-Mail Website
Guest Editor
1. DIMI, Università degli Studi di Genova, Genoa, Italy
2. IRCCS Ospedale Policlinico San Martino, Genoa, Italy
Interests: asthma

Special Issue Information

Dear Colleagues,

I encourage you to participate in the Special Issue “Molecular Advance on the Pathogenesis and Treatment of Asthma” of this prestigious journal.

It is well known that asthma is a heterogeneous disease characterized by inflammation of the airways. Over the years, research has allowed first phenotypes and then endotypes to be highlighted so that patients can be clustered.

The increasingly in-depth study of inflammatory mechanisms has made it possible to highlight some common pathways related to the presence of certain cells, cytokines and inflammation factors. The increasingly precise search for mechanisms and related markers of predictive response to a therapy makes it possible to increasingly personalize therapy.

The aim of this Special Issue is to gather articles, of a high scientific level, that can provide a clear and modern picture on the topic of molecular research in the field of asthma, with an orientation toward the mechanisms of the disease to personalized therapeutic target, moving from drugs already on the market, to innovative molecules still under study.

Dr. Diego Bagnasco
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • severe asthma
  • type 2 and not type 2 inflammation
  • antibodies
  • comorbidities
  • omic science

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Published Papers (4 papers)

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Research

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14 pages, 695 KiB  
Article
Impact of CYP3A5 Polymorphisms on Pediatric Asthma Outcomes
by Flory L. Nkoy, Bryan L. Stone, Cassandra E. Deering-Rice, Angela Zhu, John G. Lamb, Joseph E. Rower and Christopher A. Reilly
Int. J. Mol. Sci. 2024, 25(12), 6548; https://doi.org/10.3390/ijms25126548 - 14 Jun 2024
Viewed by 681
Abstract
Genetic variation among inhaled corticosteroid (ICS)-metabolizing enzymes may affect asthma control, but evidence is limited. This study tested the hypothesis that single-nucleotide polymorphisms (SNPs) in Cytochrome P450 3A5 (CYP3A5) would affect asthma outcomes. Patients aged 2–18 years with persistent asthma were recruited to [...] Read more.
Genetic variation among inhaled corticosteroid (ICS)-metabolizing enzymes may affect asthma control, but evidence is limited. This study tested the hypothesis that single-nucleotide polymorphisms (SNPs) in Cytochrome P450 3A5 (CYP3A5) would affect asthma outcomes. Patients aged 2–18 years with persistent asthma were recruited to use the electronic AsthmaTracker (e-AT), a self-monitoring tool that records weekly asthma control, medication use, and asthma outcomes. A subset of patients provided saliva samples for SNP analysis and participated in a pharmacokinetic study. Multivariable regression analysis adjusted for age, sex, race, and ethnicity was used to evaluate the impact of CYP3A5 SNPs on asthma outcomes, including asthma control (measured using the asthma symptom tracker, a modified version of the asthma control test or ACT), exacerbations, and hospital admissions. Plasma corticosteroid and cortisol concentrations post-ICS dosing were also assayed using liquid chromatography–tandem mass spectrometry. Of the 751 patients using the e-AT, 166 (22.1%) provided saliva samples and 16 completed the PK study. The e-AT cohort was 65.1% male, and 89.6% White, 6.0% Native Hawaiian, 1.2% Black, 1.2% Native American, 1.8% of unknown race, and 15.7% Hispanic/Latino; the median age was 8.35 (IQR: 5.51–11.3) years. CYP3A5*3/*3 frequency was 75.8% in White subjects, 50% in Native Hawaiians and 76.9% in Hispanic/Latino subjects. Compared with CYP3A5*3/*3, the CYP3A5*1/*x genotype was associated with reduced weekly asthma control (OR: 0.98; 95% CI: 0.97–0.98; p < 0.001), increased exacerbations (OR: 6.43; 95% CI: 4.56–9.07; p < 0.001), and increased asthma hospitalizations (OR: 1.66; 95% CI: 1.43–1.93; p < 0.001); analysis of 3/*3, *1/*1 and *1/*3 separately showed an allelic copy effect. Finally, PK analysis post-ICS dosing suggested muted changes in cortisol concentrations for patients with the CYP3A5*3/*3 genotype, as opposed to an effect on ICS PK. Detection of CYP3A5*3/3, CYPA35*1/*3, and CYP3A5*1/*1 could impact inhaled steroid treatment strategies for asthma in the future. Full article
(This article belongs to the Special Issue Molecular Advance on the Pathogenesis and Treatment of Asthma)
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18 pages, 4186 KiB  
Article
Thymic Stromal Lymphopoietin (TSLP) Is Cleaved by Human Mast Cell Tryptase and Chymase
by Luisa Canè, Remo Poto, Francesco Palestra, Ilaria Iacobucci, Marinella Pirozzi, Seetharaman Parashuraman, Anne Lise Ferrara, Amalia Illiano, Antonello La Rocca, Edoardo Mercadante, Piero Pucci, Gianni Marone, Giuseppe Spadaro, Stefania Loffredo, Maria Monti and Gilda Varricchi
Int. J. Mol. Sci. 2024, 25(7), 4049; https://doi.org/10.3390/ijms25074049 - 5 Apr 2024
Viewed by 1371
Abstract
Thymic stromal lymphopoietin (TSLP), mainly expressed by epithelial cells, plays a central role in asthma. In humans, TSLP exists in two variants: the long form TSLP (lfTSLP) and a shorter TSLP isoform (sfTSLP). Macrophages (HLMs) and mast cells (HLMCs) are in close proximity [...] Read more.
Thymic stromal lymphopoietin (TSLP), mainly expressed by epithelial cells, plays a central role in asthma. In humans, TSLP exists in two variants: the long form TSLP (lfTSLP) and a shorter TSLP isoform (sfTSLP). Macrophages (HLMs) and mast cells (HLMCs) are in close proximity in the human lung and play key roles in asthma. We evaluated the early proteolytic effects of tryptase and chymase released by HLMCs on TSLP by mass spectrometry. We also investigated whether TSLP and its fragments generated by these enzymes induce angiogenic factor release from HLMs. Mass spectrometry (MS) allowed the identification of TSLP cleavage sites caused by tryptase and chymase. Recombinant human TSLP treated with recombinant tryptase showed the production of 1-97 and 98-132 fragments. Recombinant chymase treatment of TSLP generated two peptides, 1-36 and 37-132. lfTSLP induced the release of VEGF-A, the most potent angiogenic factor, from HLMs. By contrast, the four TSLP fragments generated by tryptase and chymase failed to activate HLMs. Long-term TSLP incubation with furin generated two peptides devoid of activating property on HLMs. These results unveil an intricate interplay between mast cell-derived proteases and TSLP. These findings have potential relevance in understanding novel aspects of asthma pathobiology. Full article
(This article belongs to the Special Issue Molecular Advance on the Pathogenesis and Treatment of Asthma)
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Review

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13 pages, 877 KiB  
Review
Thymic Stromal Lymphopoietin and Tezepelumab in Airway Diseases: From Physiological Role to Target Therapy
by Diego Bagnasco, Laura De Ferrari, Benedetta Bondi, Maria Giulia Candeliere, Marcello Mincarini, Anna Maria Riccio and Fulvio Braido
Int. J. Mol. Sci. 2024, 25(11), 5972; https://doi.org/10.3390/ijms25115972 - 29 May 2024
Viewed by 1161
Abstract
Thymic stromal lymphopoietin (TSLP), is a protein belonging to a class of epithelial cytokines commonly called alarmins, which also includes IL-25 and IL-33. Functionally, TSLP is a key player in the immune response to environmental insults, initiating a number of downstream inflammatory pathways. [...] Read more.
Thymic stromal lymphopoietin (TSLP), is a protein belonging to a class of epithelial cytokines commonly called alarmins, which also includes IL-25 and IL-33. Functionally, TSLP is a key player in the immune response to environmental insults, initiating a number of downstream inflammatory pathways. TSLP performs its role by binding to a high-affinity heteromeric complex composed of the thymic stromal lymphopoietin receptor (TSLPR) chain and IL-7Rα. In recent years, the important role of proinflammatory cytokines in the etiopathogenesis of various chronic diseases such as asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP), chronic obstructive pulmonary diseases (COPDs), and chronic spontaneous urticaria has been studied. Although alarmins have been found to be mainly implicated in the mechanisms of type 2 inflammation, studies on monoclonal antibodies against TSLP demonstrate partial efficacy even in patients whose inflammation is not definable as T2 and the so-called low T2. Tezepelumab is a human anti-TSLP antibody that prevents TSLP-TSLPR interactions. Several clinical trials are evaluating the safety and efficacy of Tezepelumab in various inflammatory disorders. In this review, we will highlight major recent advances in understanding the functional role of TSLP, its involvement in Th2-related diseases, and its suitability as a target for biological therapies. Full article
(This article belongs to the Special Issue Molecular Advance on the Pathogenesis and Treatment of Asthma)
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32 pages, 3964 KiB  
Review
Subsets of Eosinophils in Asthma, a Challenge for Precise Treatment
by Jakub Novosad, Irena Krčmová, Ondřej Souček, Marcela Drahošová, Vratislav Sedlák, Martina Kulířová and Pavlína Králíčková
Int. J. Mol. Sci. 2023, 24(6), 5716; https://doi.org/10.3390/ijms24065716 - 16 Mar 2023
Cited by 6 | Viewed by 4074
Abstract
The existence of eosinophils was documented histopathologically in the first half of the 19th century. However, the term “eosinophils” was first used by Paul Ehrlich in 1878. Since their discovery and description, their existence has been associated with asthma, allergies, and antihelminthic immunity. [...] Read more.
The existence of eosinophils was documented histopathologically in the first half of the 19th century. However, the term “eosinophils” was first used by Paul Ehrlich in 1878. Since their discovery and description, their existence has been associated with asthma, allergies, and antihelminthic immunity. Eosinophils may also be responsible for various possible tissue pathologies in many eosinophil-associated diseases. Since the beginning of the 21st century, the understanding of the nature of this cell population has undergone a fundamental reassessment, and in 2010, J. J. Lee proposed the concept of “LIAR” (Local Immunity And/or Remodeling/Repair), underlining the extensive immunoregulatory functions of eosinophils in the context of health and disease. It soon became apparent that mature eosinophils (in line with previous morphological studies) are not structurally, functionally, or immunologically homogeneous cell populations. On the contrary, these cells form subtypes characterized by their further development, immunophenotype, sensitivity to growth factors, localization, role and fate in tissues, and contribution to the pathogenesis of various diseases, including asthma. The eosinophil subsets were recently characterized as resident (rEos) and inflammatory (iEos) eosinophils. During the last 20 years, the biological therapy of eosinophil diseases, including asthma, has been significantly revolutionized. Treatment management has been improved through the enhancement of treatment effectiveness and a decrease in the adverse events associated with the formerly ultimately used systemic corticosteroids. However, as we observed from real-life data, the global treatment efficacy is still far from optimal. A fundamental condition, “sine qua non”, for correct treatment management is a thorough evaluation of the inflammatory phenotype of the disease. We believe that a better understanding of eosinophils would lead to more precise diagnostics and classification of asthma subtypes, which could further improve treatment outcomes. The currently validated asthma biomarkers (eosinophil count, production of NO in exhaled breath, and IgE synthesis) are insufficient to unveil super-responders among all severe asthma patients and thus give only a blurred picture of the adepts for treatment. We propose an emerging approach consisting of a more precise characterization of pathogenic eosinophils in terms of the definition of their functional status or subset affiliation by flow cytometry. We believe that the effort to find new eosinophil-associated biomarkers and their rational use in treatment algorithms may ameliorate the response rate to biological therapy in patients with severe asthma. Full article
(This article belongs to the Special Issue Molecular Advance on the Pathogenesis and Treatment of Asthma)
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