{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T18:20:53Z","timestamp":1788805253610,"version":"build-2803163510"},"reference-count":93,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"FOCUS: Training and Guidance for UMFST Researchers in Health","award":["100455\/29.08.2025"],"award-info":[{"award-number":["100455\/29.08.2025"]}]},{"name":"Health Programme of the Ministry of Investments and European Projects","award":["PS\/688\/PS_P3\/OP4\/ESO4.7\/PS_P3_ESO4.7_A6"],"award-info":[{"award-number":["PS\/688\/PS_P3\/OP4\/ESO4.7\/PS_P3_ESO4.7_A6"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Asthma is increasingly recognized as a heterogeneous syndrome where traditional management fails, particularly given spirometry\u2019s limitations in assessing small airway dysfunction. This review synthesizes the transition from clinical phenotyping to deep molecular endotyping, establishing a framework for precision medicine. We highlight the insufficiency of absolute eosinophil counts, proposing eosinophil cationic protein (ECP) and eosinophil-derived neurotoxin (EDN) as superior activation metrics. Furthermore, we explore Type 2 drivers (IL-4\/IL-13, periostin) and epithelial alarmins like TSLP. Beyond classical immunology, the text describes metabolic dysregulation, specifically asymmetric dimethylarginine (ADMA) in obese-asthma phenotypes where nitric oxide synthase uncoupling promotes oxidative stress. We also analyze YKL-40 and surfactant protein D (SP-D) as markers of remodeling and barrier permeability, alongside microRNAs\u2014specifically miR-21\u2014in corticosteroid resistance. We conclude that managing refractory asthma requires shifting from reactive symptom control to an integrated analysis of multi-omic biomarkers. Establishing this comprehensive molecular profile via specialized centers is fundamental for addressing current diagnostic limitations, selecting biological therapies, and modifying the disease trajectory through an endotype-driven strategy addressing inflammatory, metabolic, and structural pathologies.<\/jats:p>","DOI":"10.3390\/ijms27062545","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T14:45:39Z","timestamp":1773153939000},"page":"2545","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The Architecture of Deep Phenotyping in Asthma: Integrating Molecular, Metabolic, and Neuro-Hormonal Endotypes"],"prefix":"10.3390","volume":"27","author":[{"given":"Nicolae","family":"Demenciuc","sequence":"first","affiliation":[{"name":"Department of Allergology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of T\u00e2rgu Mure\u0219, 540142 T\u00e2rgu Mure\u0219, Romania"},{"name":"Doctoral School, George Emil Palade University of Medicine, Pharmacy, Science and Technology of T\u00e2rgu Mure\u0219, 540142 T\u00e2rgu Mure\u0219, Romania"},{"name":"Intensive Care Unit, Emergency County Hospital T\u00e2rgu Mure\u0219, 540136 T\u00e2rgu Mure\u0219, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1235-9331","authenticated-orcid":false,"given":"Corina","family":"Ureche","sequence":"additional","affiliation":[{"name":"Department of Allergology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of T\u00e2rgu Mure\u0219, 540142 T\u00e2rgu Mure\u0219, Romania"},{"name":"Department of Allergology, Emergency County Hospital T\u00e2rgu Mure\u0219, 540136 T\u00e2rgu Mure\u0219, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7785-0121","authenticated-orcid":false,"given":"Corina Eugenia","family":"Budin","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Mure\u0219 Clinical County Hospital, 540003 T\u00e2rgu Mure\u0219, Romania"},{"name":"Department of Pathophysiology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of T\u00e2rgu Mure\u0219, 540142 T\u00e2rgu Mure\u0219, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-6297-0378","authenticated-orcid":false,"given":"Mircea","family":"Stoian","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Intensive Care, George Emil Palade University of Medicine, Pharmacy, Science and Technology of T\u00e2rgu Mure\u0219, 540142 T\u00e2rgu Mure\u0219, Romania"},{"name":"Intensive Care Unit, Mures Clinical Country Hospital, Street Gheorghe Marinescu No.1, 540103 T\u00e2rgu Mure\u0219, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teodora","family":"Nicola-Varo","sequence":"additional","affiliation":[{"name":"Department of Allergology, George Emil Palade University of Medicine, Pharmacy, Science and Technology of T\u00e2rgu Mure\u0219, 540142 T\u00e2rgu Mure\u0219, Romania"},{"name":"Doctoral School, George Emil Palade University of Medicine, Pharmacy, Science and Technology of T\u00e2rgu Mure\u0219, 540142 T\u00e2rgu Mure\u0219, Romania"},{"name":"Department of Allergology, Emergency County Hospital T\u00e2rgu Mure\u0219, 540136 T\u00e2rgu Mure\u0219, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3558-2856","authenticated-orcid":false,"given":"Edith Simona","family":"Ianosi","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Mure\u0219 Clinical County Hospital, 540003 T\u00e2rgu Mure\u0219, Romania"},{"name":"Department of Pulmonology, University of Medicine, Pharmacy, Science and Technology \u201cGeorge Emil Palade\u201d of T\u00e2rgu Mure\u0219, 540139 T\u00e2rgu Mure\u0219, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-8111-2980","authenticated-orcid":false,"given":"Dariana-Elena","family":"P\u0103tr\u00eenta\u0219u","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Mure\u0219 Clinical County Hospital, 540003 T\u00e2rgu Mure\u0219, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca","family":"Goman","sequence":"additional","affiliation":[{"name":"Department of Pulmonology, Doctoral School of Biomedical Sciences, University of Oradea, 410073 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4343-4397","authenticated-orcid":false,"given":"Lavinia","family":"Davidescu","sequence":"additional","affiliation":[{"name":"Department of Pneumology, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Deleanu","sequence":"additional","affiliation":[{"name":"Doctoral School, George Emil Palade University of Medicine, Pharmacy, Science and Technology of T\u00e2rgu Mure\u0219, 540142 T\u00e2rgu Mure\u0219, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e41","DOI":"10.1016\/S2213-2600(25)00242-5","article-title":"2025 GINA Report for Asthma","volume":"13","author":"Venkatesan","year":"2025","journal-title":"Lancet Respir. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/nm.2678","article-title":"Asthma Phenotypes: The Evolution from Clinical to Molecular Approaches","volume":"18","author":"Wenzel","year":"2012","journal-title":"Nat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1183\/09059180.00010410","article-title":"The Role of Small Airways in Obstructive Airway Diseases","volume":"20","author":"Burgel","year":"2011","journal-title":"Eur. Respir. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2686","DOI":"10.1016\/j.jaip.2025.07.002","article-title":"Small Airway Dysfunction Is an Independent Exacerbation Risk Biomarker in the Mild, Well-Controlled Patient With Asthma: A Frequently Unrecognized High-Risk Phenotype","volume":"13","author":"Galant","year":"2025","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/S2213-2600(21)00536-1","article-title":"The Role of Small Airway Dysfunction in Asthma Control and Exacerbations: A Longitudinal, Observational Analysis Using Data from the ATLANTIS Study","volume":"10","author":"Kraft","year":"2022","journal-title":"Lancet Respir. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s12948-021-00147-8","article-title":"Small Airway Dysfunction and Poor Asthma Control: A Dangerous Liaison","volume":"19","author":"Cottini","year":"2021","journal-title":"Clin. Mol. Allergy"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.jaci.2010.11.037","article-title":"Asthma Endotypes: A New Approach to Classification of Disease Entities within the Asthma Syndrome","volume":"127","author":"Akdis","year":"2011","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s12016-018-8712-1","article-title":"Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease","volume":"56","author":"Kuruvilla","year":"2019","journal-title":"Clin. Rev. Allerg. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/all.14425","article-title":"EAACI Biologicals Guidelines-Recommendations for Severe Asthma","volume":"76","author":"Agache","year":"2021","journal-title":"Allergy"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2000260","DOI":"10.1183\/13993003.00260-2020","article-title":"Anti-Alarmins in Asthma: Targeting the Airway Epithelium with next-Generation Biologics","volume":"56","author":"Porsbjerg","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/S0140-6736(17)30879-6","article-title":"After Asthma: Redefining Airways Diseases","volume":"391","author":"Pavord","year":"2018","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1159\/000330840","article-title":"Sputum YKL-40 Levels and Pathophysiology of Asthma and Chronic Obstructive Pulmonary Disease","volume":"83","author":"Otsuka","year":"2012","journal-title":"Respiration"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.pccm.2023.07.002","article-title":"Small Airways in Asthma: Pathophysiology, Identification and Management","volume":"1","author":"Toumpanakis","year":"2023","journal-title":"Chin. Med. J. Pulm. Crit. Care Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1164\/rccm.202009-3631CI","article-title":"Severe Adult Asthmas: Integrating Clinical Features, Biology, and Therapeutics to Improve Outcomes","volume":"203","author":"Wenzel","year":"2021","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1016\/j.cell.2021.02.016","article-title":"The Basic Immunology of Asthma","volume":"184","author":"Hammad","year":"2021","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1056\/NEJMra1608969","article-title":"Severe and Difficult-to-Treat Asthma in Adults","volume":"377","author":"Israel","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1016\/S2213-2600(20)30053-9","article-title":"Predictive Value of Blood Eosinophils and Exhaled Nitric Oxide in Adults with Mild Asthma: A Prespecified Subgroup Analysis of an Open-Label, Parallel-Group, Randomised Controlled Trial","volume":"8","author":"Pavord","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/S2213-2600(25)00174-2","article-title":"Eosinophils in Asthma Phenotypes: Perpetrators or Guilty by Association?","volume":"13","author":"Lommatzsch","year":"2025","journal-title":"Lancet Respir. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1183\/09031936.00201813","article-title":"Importance of Concomitant Local and Systemic Eosinophilia in Uncontrolled Asthma","volume":"44","author":"Schleich","year":"2014","journal-title":"Eur. Respir. J."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Budin, C.E., Cocuz, I.G., Enache, L.S., Ren\u021ba, I.A., Cazacu, C., P\u0103tr\u00eenta\u0219u, D.E., Olteanu, M., R\u00e2jnoveanu, R.-M., Iano\u0219i, E.S., and R\u00e2jnoveanu, A. (2024). Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratio: Side by Side with Molecular Mutations in Patients with Non-Small Cell Lung Cancer-The INOLUNG Study. Cancers, 16.","DOI":"10.20944\/preprints202407.0487.v1"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"39","DOI":"10.5578\/tt.20219905","article-title":"The Significance of Eosinophil and Eosinophil Lymphocyte Ratio (ELR) in Predicting Response to Omalizumab Treatment in Patients with Severe Allergic Asthma","volume":"69","author":"Tepetam","year":"2021","journal-title":"Tuberk. Toraks"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"de Groot, J.C., Ten Brinke, A., and Bel, E.H.D. (2015). Management of the Patient with Eosinophilic Asthma: A New Era Begins. ERJ Open Res., 1.","DOI":"10.1183\/23120541.00024-2015"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1016\/j.jaip.2022.11.046","article-title":"Clinical Potential of Eosinophil-Derived Neurotoxin in Asthma Management","volume":"11","author":"Malinovschi","year":"2023","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1080\/02770903.2024.2441885","article-title":"The Role of Periostin, Eosinophil Cationic Protein (ECP), Nesfatin-1, and NUCB2 in Asthma and Obesity","volume":"62","author":"Sarioglu","year":"2025","journal-title":"J. Asthma"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"244","DOI":"10.2500\/aap.2023.44.230016","article-title":"Association of EDN Levels in Patients with Asthma and Correlation with FEV1%: A Meta-Analysis","volume":"44","author":"Kuai","year":"2023","journal-title":"Allergy Asthma Proc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0954-6111(05)80010-1","article-title":"Serum Eosinophil Cationic Protein (ECP) in Chronic Asthma. Relationship to Spirometry, Flow-Volume Curves, PC20, and Exacerbations","volume":"88","author":"Wever","year":"1994","journal-title":"Respir. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"8","DOI":"10.3345\/kjp.2013.56.1.8","article-title":"Eosinophil-Derived Neurotoxin: A Novel Biomarker for Diagnosis and Monitoring of Asthma","volume":"56","author":"Kim","year":"2013","journal-title":"Korean J. Pediatr."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"66","DOI":"10.5415\/apallergy.0000000000000104","article-title":"Eosinophil Granule Proteins as a Biomarker in Managing Asthma and Allergies","volume":"13","author":"Kim","year":"2023","journal-title":"Asia Pac. Allergy"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"100990","DOI":"10.1016\/j.waojou.2024.100990","article-title":"Serum and Urine Eosinophil-Derived Neurotoxin (EDN) Levels Predict Biologic Response in Severe Asthma","volume":"18","author":"Kang","year":"2025","journal-title":"World Allergy Organ. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1136\/thoraxjnl-2021-217343","article-title":"Blood Eosinophil Cationic Protein and Eosinophil-Derived Neurotoxin Are Associated with Different Asthma Expression and Evolution in Adults","volume":"77","author":"Granger","year":"2022","journal-title":"Thorax"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Pollock, J., Huang, J.T.J., Shuttleworth, M., Long, M.B., Richardson, H., de Lima, D.A., Kuzmanova, E., Clarke, C., Shteinberg, M., and Aliberti, S. (2026). Clinical, Molecular and Microbial Characterisation of the Eosinophilic Endotype of Bronchiectasis: Data from the EMBARC-BRIDGE Study. Thorax, thorax-2025-223305.","DOI":"10.1136\/thorax-2025-223305"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1038\/nm.2755","article-title":"IgE and Mast Cells in Allergic Disease","volume":"18","author":"Galli","year":"2012","journal-title":"Nat. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4678","DOI":"10.1172\/JCI78891","article-title":"Mechanisms of Immune Tolerance to Allergens: Role of IL-10 and Tregs","volume":"124","author":"Akdis","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1097\/01.WOX.0000411961.02158.51","article-title":"204 IGE\/IGG4 Ratio as a Possible Surrogate Marker of Clinical Efficacy During Allergen-Specific Immunotherapy with House Dust Mite Vaccines","volume":"5","author":"Labrada","year":"2012","journal-title":"World Allergy Organ. J."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1038\/s41423-025-01261-2","article-title":"Type 2 Immunity in Allergic Diseases","volume":"22","author":"Ogulur","year":"2025","journal-title":"Cell. Mol. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nri3341","article-title":"Eosinophils: Changing Perspectives in Health and Disease","volume":"13","author":"Rosenberg","year":"2013","journal-title":"Nat. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nri3786","article-title":"Type 2 Inflammation in Asthma--Present in Most, Absent in Many","volume":"15","author":"Fahy","year":"2015","journal-title":"Nat. Rev. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.jaci.2024.01.024","article-title":"Update on Asthma Biology","volume":"153","author":"Georas","year":"2024","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.1056\/NEJMoa1804092","article-title":"Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma","volume":"378","author":"Castro","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2101499","DOI":"10.1183\/13993003.01499-2021","article-title":"ERS\/ATS Technical Standard on Interpretive Strategies for Routine Lung Function Tests","volume":"60","author":"Stanojevic","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.jaci.2012.06.025","article-title":"Periostin Is a Systemic Biomarker of Eosinophilic Airway Inflammation in Asthmatic Patients","volume":"130","author":"Jia","year":"2012","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nri.2015.17","article-title":"Mucosal Immunity to Pathogenic Intestinal Bacteria","volume":"16","author":"Behnsen","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1016\/j.jaip.2024.02.007","article-title":"Lebrikizumab in Uncontrolled Asthma: Reanalysis in a Well-Defined Type 2 Population","volume":"12","author":"Corren","year":"2024","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.immuni.2015.07.007","article-title":"Barrier Epithelial Cells and the Control of Type 2 Immunity","volume":"43","author":"Hammad","year":"2015","journal-title":"Immunity"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1038\/s41577-021-00538-7","article-title":"Does the Epithelial Barrier Hypothesis Explain the Increase in Allergy, Autoimmunity and Other Chronic Conditions?","volume":"21","author":"Akdis","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1016\/j.jaci.2012.07.010","article-title":"Thymic Stromal Lymphopoietin and Allergic Disease","volume":"130","author":"Ziegler","year":"2012","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nri.2016.95","article-title":"Interleukin-33 in Health and Disease","volume":"16","author":"Liew","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1800","DOI":"10.1056\/NEJMoa2034975","article-title":"Tezepelumab in Adults and Adolescents with Severe, Uncontrolled Asthma","volume":"384","author":"Corren","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s11882-015-0528-y","article-title":"Asthma Is Different in Women","volume":"15","author":"Zein","year":"2015","journal-title":"Curr. Allergy Asthma Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2487","DOI":"10.1016\/j.celrep.2017.10.110","article-title":"Testosterone Attenuates Group 2 Innate Lymphoid Cell-Mediated Airway Inflammation","volume":"21","author":"Cephus","year":"2017","journal-title":"Cell Rep."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"237","DOI":"10.2147\/JAA.S208823","article-title":"Metabolic Dysfunction and Asthma: Current Perspectives","volume":"13","author":"Pite","year":"2020","journal-title":"J. Asthma Allergy"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"S28","DOI":"10.1164\/ajrccm\/143.3_Pt_2.S28","article-title":"Neuropeptides and Asthma","volume":"143","author":"Barnes","year":"1991","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.immuni.2020.10.001","article-title":"Substance P Release by Sensory Neurons Triggers Dendritic Cell Migration and Initiates the Type-2 Immune Response to Allergens","volume":"53","author":"Perner","year":"2020","journal-title":"Immunity"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.jaci.2025.05.017","article-title":"Neural Control of the Pathophysiology of Allergic Airway Disease and Its Clinical Implications: A Focus on Allergic Rhinitis and Asthma","volume":"156","author":"Fang","year":"2025","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1164\/ajrccm\/151.3_Pt_1.613","article-title":"Elevated Substance P Content in Induced Sputum from Patients with Asthma and Patients with Chronic Bronchitis","volume":"151","author":"Tomaki","year":"1995","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1080\/15384101.2022.2092166","article-title":"Substance P Promotes the Progression of Bronchial Asthma through Activating the PI3K\/AKT\/NF-\u03baB Pathway Mediated Cellular Inflammation and Pyroptotic Cell Death in Bronchial Epithelial Cells","volume":"21","author":"Li","year":"2022","journal-title":"Cell Cycle"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"187","DOI":"10.4168\/aair.2018.10.3.187","article-title":"The Emerging Role of TRPV1 in Airway Inflammation","volume":"10","author":"Kim","year":"2018","journal-title":"Allergy Asthma Immunol. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.cytogfr.2017.09.002","article-title":"Neuroendocrine Cells Derived Chemokine Vasoactive Intestinal Polypeptide (VIP) in Allergic Diseases","volume":"38","author":"Verma","year":"2017","journal-title":"Cytokine Growth Factor. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e131733","DOI":"10.1172\/jci.insight.131733","article-title":"L-Citrulline Increases Nitric Oxide and Improves Control in Obese Asthmatics","volume":"4","author":"Holguin","year":"2019","journal-title":"JCI Insight"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"785835","DOI":"10.1155\/2013\/785835","article-title":"Adiponectin, Leptin, and Resistin in Asthma: Basic Mechanisms through Population Studies","volume":"2013","author":"Sood","year":"2013","journal-title":"J. Allergy"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1164\/rccm.201011-1810OC","article-title":"Asymmetric Dimethylarginine Is Increased in Asthma","volume":"184","author":"Scott","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Zhou, B., Jiang, G.T., Liu, H., Guo, M., Liu, J., and She, J. (2021). Dysregulated Arginine Metabolism in Young Patients with Chronic Persistent Asthma and in Human Bronchial Epithelial Cells. Nutrients, 13.","DOI":"10.21203\/rs.3.rs-567567\/v1"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1016\/j.jaci.2018.02.004","article-title":"Obesity and Asthma","volume":"141","author":"Peters","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1164\/rccm.201207-1270OC","article-title":"An Association between L-Arginine\/Asymmetric Dimethyl Arginine Balance, Obesity, and the Age of Asthma Onset Phenotype","volume":"187","author":"Holguin","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"To, M., and To, Y. (2025). Corticosteroid Insensitivity in Obese Asthma: Potential Mechanisms and Therapeutic Perspectives. Front Allergy, 6.","DOI":"10.3389\/falgy.2025.1719900"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1080\/17476348.2018.1506331","article-title":"The Effect of Obesity on Lung Function","volume":"12","author":"Dixon","year":"2018","journal-title":"Expert. Rev. Respir. Med."},{"key":"ref_67","first-page":"82","article-title":"Role of Epigenetics in the Pathogenesis of Asthma","volume":"16","author":"Alizadeh","year":"2017","journal-title":"Iran. J. Allergy Asthma Immunol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1016\/j.jaci.2016.04.038","article-title":"MicroRNA-21 Drives Severe, Steroid-Insensitive Experimental Asthma by Amplifying Phosphoinositide 3-Kinase-Mediated Suppression of Histone Deacetylase 2","volume":"139","author":"Kim","year":"2017","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Vorobeva, E.V., Kyyaly, M.A., Sones, C.L., He, P.J.W., Arshad, S.H., Sanchez-Elsner, T., and Kurukulaaratchy, R.J. (2025). Circulating microRNAs as Potential Diagnostic Tools for Asthma and for Indicating Severe Asthma Risk. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26146676"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1186\/s12931-022-02304-2","article-title":"Gene Network Analysis for Identification of microRNA Biomarkers for Asthma","volume":"23","author":"Cay","year":"2022","journal-title":"Respir. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1165\/rcmb.2016-0231TR","article-title":"MicroRNA Profiling in Asthma: Potential Biomarkers and Therapeutic Targets","volume":"57","author":"Heffler","year":"2017","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1177\/1753425920901563","article-title":"Role of microRNA-21 and microRNA-155 as Biomarkers for Bronchial Asthma","volume":"27","author":"ElKashef","year":"2021","journal-title":"Innate Immun."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1111\/sji.12535","article-title":"Altered miR-155 Expression in Allergic Asthmatic Airways","volume":"85","author":"Johansson","year":"2017","journal-title":"Scand. J. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Zimbru, R.-I., Zimbru, E.-L., Bojin, F.-M., Haidar, L., Andor, M., Harich, O.O., T\u0103nasie, G., Tatu, C., Mailat, D.-E., and Zb\u00eercea, I.-M. (2025). Connecting the Dots: How MicroRNAs Link Asthma and Atherosclerosis. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26083570"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1016\/j.jaci.2016.01.029","article-title":"Circulating microRNAs as Biomarkers in Patients with Allergic Rhinitis and Asthma","volume":"137","author":"Panganiban","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Gil-Mart\u00ednez, M., Lorente-Sorolla, C., Naharro, S., Rodrigo-Mu\u00f1oz, J.M., and Del Pozo, V. (2023). Advances and Highlights of miRNAs in Asthma: Biomarkers for Diagnosis and Treatment. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021628"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Hern\u00e1ndez-D\u00edazcouder, A., Romero-Nava, R., Del-R\u00edo-Navarro, B.E., S\u00e1nchez-Mu\u00f1oz, F., Guzm\u00e1n-Mart\u00edn, C.A., Reyes-Noriega, N., Rodr\u00edguez-Cort\u00e9s, O., Leija-Mart\u00ednez, J.J., V\u00e9lez-Res\u00e9ndiz, J.M., and Villafa\u00f1a, S. (2024). The Roles of MicroRNAs in Asthma and Emerging Insights into the Effects of Vitamin D3 Supplementation. Nutrients, 16.","DOI":"10.3390\/nu16030341"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.1111\/all.14646","article-title":"Spotlight on microRNAs in Allergy and Asthma","volume":"76","author":"Weidner","year":"2021","journal-title":"Allergy"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.jaci.2013.03.003","article-title":"The Chitinase-like Protein YKL-40: A Possible Biomarker of Inflammation and Airway Remodeling in Severe Pediatric Asthma","volume":"132","author":"Konradsen","year":"2013","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_80","first-page":"247","article-title":"The Relationship between Serum YKL-40 Levels and Severity of Asthma","volume":"12","author":"Duru","year":"2013","journal-title":"Iran. J. Allergy Asthma Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1183\/09031936.00034409","article-title":"YKL-40 in Asthmatic Patients, and Its Correlations with Exacerbation, Eosinophils and Immunoglobulin E","volume":"35","author":"Tang","year":"2010","journal-title":"Eur. Respir. J."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Specjalski, K., Romantowski, J., and Niedoszytko, M. (2023). YKL-40 as a Possible Marker of Neutrophilic Asthma. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1115938"},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Watson, A., Madsen, J., and Clark, H.W. (2020). SP-A and SP-D: Dual Functioning Immune Molecules With Antiviral and Immunomodulatory Properties. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.622598"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"12878","DOI":"10.1021\/bi8010175","article-title":"Pulmonary Surfactant Protein D Binds MD-2 through the Carbohydrate Recognition Domain","volume":"47","author":"Nie","year":"2008","journal-title":"Biochemistry"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1111\/resp.13193","article-title":"Surfactant Protein D Multimerization and Gene Polymorphism in COPD and Asthma","volume":"23","author":"Fakih","year":"2018","journal-title":"Respirology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1016\/j.chest.2015.12.038","article-title":"Surfactant Protein-D and Asthma","volume":"149","author":"Mitchell","year":"2016","journal-title":"Chest"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.chest.2016.05.032","article-title":"Serum Surfactant Protein D as a Marker of Asthma Severity","volume":"150","author":"Benfante","year":"2016","journal-title":"Chest"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1203\/00006450-200206000-00006","article-title":"Surfactant Protein D Gene Polymorphism Associated with Severe Respiratory Syncytial Virus Infection","volume":"51","author":"Lahti","year":"2002","journal-title":"Pediatr. Res."},{"key":"ref_89","doi-asserted-by":"crossref","unstructured":"Mohamed, S.O.O., Mohammed, A., Mohamed, T., Fadil, H., Salih, M.S.K., Mohamed, A.H., Alhassan, A., Saeed, S.G.A., Salih, F.S.K., and Mustafa, H.M.A. (2025). Surfactant Proteins Levels in Asthmatic Patients and Their Correlation with Severity of Asthma: A Systematic Review. BMC Pulm. Med., 25.","DOI":"10.1186\/s12890-025-03654-5"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1111\/pai.13403","article-title":"Blood Eosinophil Count as Predictor of Asthma Exacerbation. A Meta-Analysis","volume":"32","author":"Mallah","year":"2021","journal-title":"Pediatr. Allergy Immunol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"33","DOI":"10.2147\/JAA.S496630","article-title":"Asthma Biologics Across the T2 Spectrum of Inflammation in Severe Asthma: Biomarkers and Mechanism of Action","volume":"18","author":"Lindsley","year":"2025","journal-title":"J. Asthma Allergy"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Bara\u0144ski, K., and Kocot, K. (2022). The Effect of Obesity on Fractional Exhaled Nitric Oxide in School-Aged Children. Children, 9.","DOI":"10.3390\/children9091406"},{"key":"ref_93","doi-asserted-by":"crossref","unstructured":"Ravindran, S., Ullah, M.K., Karnik, M., Greeshma, M.V., Bansal, N., Kulkarni, S., ShankaraSetty, R.V., Madhunapantula, S.V., Siddaiah, J.B., and Chaya, S.K. (2025). Unsupervised Phenotyping of Asthma: Integrating Serum Periostin with Clinical and Inflammatory Profiles. Diagnostics, 15.","DOI":"10.3390\/diagnostics15233028"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2545\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,12]],"date-time":"2026-03-12T05:18:45Z","timestamp":1773292725000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/6\/2545"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,10]]},"references-count":93,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,3]]}},"alternative-id":["ijms27062545"],"URL":"https:\/\/doi.org\/10.3390\/ijms27062545","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,10]]}}}