{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T10:20:42Z","timestamp":1787653242846,"version":"build-2736575974"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Airway remodeling represents a key pathological feature of severe asthma. Although the interleukin-13 (IL-13) R130Q variant is associated with increased disease severity, its specific contribution to airway remodeling remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This study used an ovalbumin (OVA)-induced asthma model in which mice were sensitized intraperitoneally with OVA\/alum and subsequently challenged intranasally with OVA; human IL-13 130R or IL-13 130Q was administered intranasally before each challenge. Primary human bronchial smooth muscle cells (hBSMCs) from a single healthy donor were treated with both variants to assess CCK-8-derived proliferative\/metabolic activity, migration, acetylcholine (ACh)-induced intracellular calcium responses, and IL-4 and IL-5 concentrations in culture supernatants. JAK2 and STAT6 phosphorylation was evaluated separately as a downstream signaling readout. Structural modeling and independent triplicate 100-ns molecular dynamics simulations of the IL-13\/IL-13 receptor alpha 2 (IL-13R\u03b12) complex were performed using GROMACS 2025.4 with the AMBER ff19SB force field, and molecular mechanics\/generalized Born surface area analysis was used for relative comparison of binding free energies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>IL-13 130Q produced limited airway changes in mice without OVA sensitization, but exacerbated airway wall thickening, luminal narrowing, smooth-muscle expansion, and pulmonary inflammation in OVA-sensitized and intranasally challenged mice. In hBSMCs, IL-13 130Q induced greater CCK-8-derived proliferative\/metabolic activity, migration, ACh-induced intracellular calcium responses, and IL-4 and IL-5 concentrations than IL-13 130R at 10 -100 ng\/mL. Molecular dynamics analyses suggested the reduced binding stability of IL-13 130Q\/IL-13R\u03b12 complex, as reflected by fewer interfacial hydrogen bonds, altered intermolecular contacts, and a less favorable relative binding free energy. Elevated JAK2\/STAT6 phosphorylation indicated the amplification of downstream signaling, mechanistically tied to potential reduced decoy-receptor affinity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These preclinical data support a contextdependent potentiating function of IL13 130Q in airway smoothmuscle phenotypic modulation and airway remodeling. Further investigation may rationalize genotype-based stratification in the therapy of severe asthma.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphys.2026.1906184","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T09:37:56Z","timestamp":1787650676000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Interleukin-13 R130Q aggravates airway smooth-muscle phenotypic switching and promotes airway remodeling in severe asthma"],"prefix":"10.3389","volume":"17","author":[{"given":"Yafang","family":"He","sequence":"first","affiliation":[{"name":"Department of Pediatric Pulmonology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luanluan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Developmental and Behavioral Pediatrics, Shanghai Children\u2019s Medical Center, Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shasha","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojia","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Pan","sequence":"additional","affiliation":[{"name":"Shanghai Institute of Pediatric Research, Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Xin Hua Hospital, Shanghai Jiao Tong University, School of Medicine","place":["Shanghai, China"]},{"name":"School of Health Science and Engineering, University of Shanghai for Science and Technology","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixiao","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Integrative Medicine for Allergy, Shanghai Tonxin Pediatric Clinic","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guodong","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology, Xinhua Hospital affiliated to Shanghai Jiao Tong University School of Medicine","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1038\/s41586-024-07487-w","article-title":"Accurate structure prediction of biomolecular interactions with AlphaFold 3","volume":"630","author":"Abramson","year":"2024","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"H757","DOI":"10.1152\/ajpheart.00142.2011","article-title":"PKCalpha mediates acetylcholine-induced activation of TRPV4-dependent calcium influx in endothelial cells","volume":"301","author":"Adapala","year":"2011","journal-title":"Am. 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