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Conventional bronchodilator treatments, such as \u03b22-adrenergic receptor (\u03b22-AR) agonists, often lose efficacy due to receptor desensitization, while corticosteroid-resistant neutrophilic airway inflammation remains a major challenge in severe asthma. To identify novel bronchodilators, we screened the Sigma LOPAC1280 compound library using \u03b22-agonist-desensitized precision-cut lung slices (PCLS) as an ex vivo model and identified pirfenidone (PFD), an FDA-approved drug for idiopathic pulmonary fibrosis, as a novel bronchodilator. We then developed CXN-8, a more potent PFD derivative. Both compounds produced rapid, concentration-dependent airway relaxation in human, mouse, and rat PCLS preconstricted with multiple bronchoconstrictors, and maintained efficacy under \u03b22-AR-insensitive conditions. CXN-8 was \u223c50-fold more potent than PFD while achieving comparable maximal relaxation, with EC50 values ranging from 0.8 to 4.7\u2009\u03bcM across the different bronchoconstrictors. Mechanistically, PFD and CXN-8 suppressed RhoA-mediated Ca2\u2009+\u2009sensitization by restoring myosin light chain phosphatase activity, which reduced phosphorylation of myosin regulatory light chain (MLC20) and promoted ASM relaxation. In vivo, acute oral administration of PFD (300\u2009mg\/kg) or CXN-8 (15\u2009mg\/kg) reduced airway resistance and AHR in house dust mite-sensitized mice. Chronic oral treatment (daily, Days 14\u201324) further attenuated airway inflammation and remodeling, decreasing eosinophil and neutrophil infiltration, Th2 and Th17 cytokines, ASM thickening, and peribronchial collagen deposition. Collectively, these findings identify PFD and CXN-8 as dual-acting bronchodilator and anti-inflammatory agents that also alleviate airway remodeling, offering a promising therapeutic strategy for \u03b22-agonist-insensitive and corticosteroid-resistant asthma.<\/jats:p>","DOI":"10.1093\/ajrcmb\/aanag047","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T12:33:16Z","timestamp":1772973196000},"page":"1189-1203","source":"Crossref","is-referenced-by-count":1,"title":["Pirfenidone and its derivative: novel bronchodilators and leukocyte airway inflammation inhibitors"],"prefix":"10.1093","volume":"74","author":[{"given":"Yan","family":"Xie","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Neuroscience, Creighton University School of Medicine , Omaha, NE,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter W","family":"Abel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, Creighton University School of Medicine , Omaha, NE,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianzhou","family":"Xing","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, Creighton University School of Medicine , Omaha, NE,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, Creighton University School of Medicine , Omaha, NE,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haihong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, Creighton University School of Medicine , Omaha, NE,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven S","family":"An","sequence":"additional","affiliation":[{"name":"Rutgers Institute for Translational Medicine and Science , New Brunswick, NJ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Reynold A","family":"Panettieri","sequence":"additional","affiliation":[{"name":"Rutgers Institute for Translational Medicine and Science , New Brunswick, NJ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas B","family":"Casale","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of South Florida School of Medicine , Tampa, FL,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Tu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Neuroscience, Creighton University School of Medicine , Omaha, NE,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,3,15]]},"reference":[{"key":"2026082703534187200_aanag047-B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/s40733-016-0029-3","article-title":"Asthma costs and social impact","volume":"3","author":"Nunes","year":"2017","journal-title":"Asthma Res Pract"},{"key":"2026082703534187200_aanag047-B2","author":"Global strategy for asthma management and prevention. 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