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This review introduces and elaborates on the paradigm of the \u201cEpithelial Immunopharmacological Rheostat,\u201d a conceptual framework that posits the epithelium as a dynamic, multidimensional signal processor that continuously calibrates the threshold of immune activation. Distinct from static models of barrier dysfunction or isolated alarmin biology, this rheostat operates through four hierarchically interacting axes: barrier integrity, alarmin\/type 2, senescence\/repair, and tolerogenic programming. We critically dissect how dysregulation of specific axes\u2014alone or in combination\u2014initiates and perpetuates the pathology of chronic respiratory diseases, including asthma, COPD, and idiopathic pulmonary fibrosis. A rigorous, pharmacology\u2010centric analysis deconstructs the molecular circuitry of epithelial\u2013immune crosstalk, evaluating the druggability of targets from tight junction complexes and pattern recognition receptors to the alarmin (TSLP, IL\u201033, IL\u201025) signaling cascades and their downstream JAK\u2010STAT, NF\u2010\u03baB, and MAPK effectors. Beyond cataloguing mechanisms, this review provides a comparative and critical appraisal of emerging therapeutic strategies, including alarmin\u2010targeted biologics, barrier\u2010restorative agents (e.g., postbiotics, short\u2010chain fatty acids), kinase inhibitors, senotherapeutics, and frontier cell\u2010based therapies. A dedicated synthesis addresses pivotal pharmacokinetic hurdles, biomarker\u2010driven stratification, and the imperative of precision endotyping. Finally, we forecast how advanced human organoid models are catalyzing the shift toward personalized interventions designed to reset the defective rheostat. This comprehensive synthesis maps the intricate landscape of epithelial immunopharmacology and identifies critical barriers that must be overcome to translate these insights into transformative clinical outcomes.<\/jats:p>","DOI":"10.1002\/eji.70249","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T06:18:26Z","timestamp":1785392306000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Respiratory Epithelial Barrier as an Immunopharmacological Rheostat: From Homeostatic Sentinel to Therapeutic Target in Chronic Lung Disease"],"prefix":"10.1002","volume":"56","author":[{"given":"Feng\u2010Xian","family":"Ni","sequence":"first","affiliation":[{"name":"Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine  Zhuhai Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Hu","sequence":"additional","affiliation":[{"name":"Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine  Zhuhai Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui\u2010Hui","family":"Chen","sequence":"additional","affiliation":[{"name":"Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine  Zhuhai Guangdong China"},{"name":"Zhuhai Hospital Affiliated to Faculty of Chinese Medicine Macau University of Science and Technology  Zhuhai Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong\u2010Hui","family":"Huang","sequence":"additional","affiliation":[{"name":"Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine  Zhuhai Guangdong China"},{"name":"Zhuhai Hospital Affiliated to Faculty of Chinese Medicine Macau University of Science and Technology  Zhuhai Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze\u2010Bo","family":"Jiang","sequence":"additional","affiliation":[{"name":"Zhuhai Hospital of Integrated Traditional Chinese and Western Medicine  Zhuhai Guangdong China"},{"name":"Zhuhai Hospital Affiliated to Faculty of Chinese Medicine Macau University of Science and Technology  Zhuhai Guangdong China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pccm.2025.05.005"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1159\/000503328"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12026\u2010025\u201009606\u20109"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph18060812"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14228186"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gde.2022.101910"},{"key":"e_1_2_12_8_1","first-page":"507","article-title":"Benvitimod Inhibits IL\u20104\u2013 and IL\u201013\u2013Induced Tight Junction Impairment by Activating AHR\/ARNT Pathway and Inhibiting STAT6 Phosphorylation in Human Keratinocytes","volume":"144","author":"Wang X.","year":"2024","journal-title":"Journal of Investigative Dermatology"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.531012"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/prot.26646"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/alr.21298"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/all.13395"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00292\u201023"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476\u20107961\u20104\u20105"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2024.116985"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s43188\u2010023\u201000223\u2010y"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416\u2010025\u201002999\u20102"},{"key":"e_1_2_12_18_1","first-page":"3213","article-title":"Potential Hazardous Effects of Printing Room PM2.5 Exposure Include Promotion of Lung Inflammation and Subsequent Injury","volume":"22","author":"Zou C.","year":"2020","journal-title":"Molecular Medicine Reports"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2019.105939"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2025.110179"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577\u2010024\u201001014\u20108"},{"key":"e_1_2_12_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42255\u2010024\u201001191\u20109"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.aninu.2021.09.012"},{"key":"e_1_2_12_24_1","article-title":"Targeting Interleukin\u201033 and Thymic Stromal Lymphopoietin Pathways for Novel Pulmonary Therapeutics in Asthma and COPD","volume":"32","author":"Calderon A. 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