{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T17:06:59Z","timestamp":1778605619056,"version":"3.51.4"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T00:00:00Z","timestamp":1768780800000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Chronic cough hypersensitivity is common across respiratory diseases and often occurs without airway inflammation, yet effective treatments remain limited. Nitric oxide (NO), an important endogenous signaling molecule and environmental pollutant, has been implicated in respiratory pathophysiology, but its role in cough hypersensitivity remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>The aim of this study was to investigate whether long-term NO exposure induces cough hypersensitivity and to define the underlying mechanisms involved.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A guinea pig model of chronic NO exposure was established and compared with a cigarette smoke (CS) \u2013induced cough model. Cough sensitivity was assessed using capsaicin challenge tests. Airway pathology and inflammation were evaluated by histological staining and molecular analyses\n                      <jats:italic>in vivo<\/jats:italic>\n                      and in 16HBE epithelial cells. Expression of TRPV1 and HIF1\u03b1 was examined in tracheal tissues and ND7\/23 sensory neuron-like cells using immunofluorescence and qPCR.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Acute NO exposure did not trigger coughing. Notably, prolonged NO exposure significantly increased capsaicin-induced cough frequency and reduced cough latency. In contrast to CS, chronic NO exposure did not induce airway inflammation, epithelial remodeling, or cytokine upregulation. Instead, NO exposure markedly enhanced the expression of TRPV1 and HIF1\u03b1 in airway sensory fibers and ND7\/23 cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings demonstrate that prolonged NO exposure induces cough hypersensitivity via HIF1\u03b1\u2013TRPV1\u2013mediated neural sensitization, independent of airway inflammation. This study establishes a novel non-inflammatory model of chronic cough and identifies potential therapeutic targets for refractory cough.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1679727","type":"journal-article","created":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T09:35:11Z","timestamp":1768815311000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Long-term nitric oxide exposure induces cough hypersensitivity via non-inflammatory activation of the HIF1\u03b1\u2013TRPV1 pathway"],"prefix":"10.3389","volume":"17","author":[{"given":"Jingxin","family":"Zhao","sequence":"first","affiliation":[{"name":"Clinical Research Center, the First People\u2019s Hospital of Foshan (The Affiliated Foshan Hospital of Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology","place":["Foshan, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinjun","family":"Jiang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peifang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, the First People\u2019s Hospital of Foshan (The Affiliated Foshan Hospital of Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology","place":["Foshan, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Xiong","sequence":"additional","affiliation":[{"name":"The Eighth Affiliated Hospital, Sun Yat-sen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong","family":"Yan","sequence":"additional","affiliation":[{"name":"Clinical Research Center, the First People\u2019s Hospital of Foshan (The Affiliated Foshan Hospital of Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology","place":["Foshan, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Clinical Research Center, the First People\u2019s Hospital of Foshan (The Affiliated Foshan Hospital of Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology","place":["Foshan, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuan","family":"Zeng","sequence":"additional","affiliation":[{"name":"Clinical Research Center, the First People\u2019s Hospital of Foshan (The Affiliated Foshan Hospital of Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology","place":["Foshan, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenbin","family":"Deng","sequence":"additional","affiliation":[{"name":"School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-sen University","place":["Shenzhen, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yichu","family":"Nie","sequence":"additional","affiliation":[{"name":"Clinical Research Center, the First People\u2019s Hospital of Foshan (The Affiliated Foshan Hospital of Southern University of Science and Technology), School of Medicine, Southern University of Science and Technology","place":["Foshan, Guangdong, China"]},{"name":"State Key Laboratory of Neurology and Oncology Drug Development","place":["Nanjing, Jiangsu, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,1,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.1042\/cs20200394","article-title":"Back to the future: re-establishing guinea pig in vivo asthma models","volume":"134","author":"Adner","year":"2020","journal-title":"Clin. 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