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Airway hypersensitivity (AHS), arising from sensitization of capsaicin\u2010sensitive lung vagal (CSLV) afferents, is a hallmark of these airway diseases. Although the immunoregulatory roles of TGF\u2010\u03b21 in airway diseases are well documented, its effects on pulmonary sensory neurons remain unexplored. Since TGF\u2010\u03b21 sensitizes dorsal root ganglion neurons, a somatic counterpart of CSLV neurons, we investigated whether TGF\u2010\u03b21 could sensitize CSLV afferents, thereby promoting AHS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Male Brown\u2010Norway rats were used to examine the effects of TGF\u2010\u03b21 on airway reflexes and the excitability of CSLV afferents in\u00a0vivo using breathing pattern and single\u2010fiber recordings, and its direct action on isolated CSLV neurons in\u00a0vitro using Ca\n                      <jats:sup>2+<\/jats:sup>\n                      imaging and immunofluorescence.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Intratracheal instillation of TGF\u2010\u03b21 enhanced the apneic responses and fiber activities of CSLV afferents elicited by capsaicin injections in\u00a0vivo. The sensitizing effect emerged at 20\u2009min and returned toward baseline by 90\u2009min after TGF\u2010\u03b21 instillation. In isolated CSLV neurons, perfusion with TGF\u2010\u03b21 increased capsaicin\u2010 and \u237a,\u03b2\u2010methylene ATP\u2010evoked Ca\n                      <jats:sup>2+<\/jats:sup>\n                      transients, indicating a direct sensitizing effect. Immunofluorescence demonstrated the expression of TGF\u2010\u03b2 receptors in these neurons. Pharmacological inhibition of TGF\u2010\u03b2 receptor I (TGF\u2010\u03b2RI), Smad3, or transient receptor potential ankyrin 1 (TRPA1), scavenging of reactive oxygen species (ROS), and TRPA1\u2010targeting small interfering RNA attenuated TGF\u2010\u03b21\u2010induced enhancement of capsaicin\u2010evoked responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>TGF\u2010\u03b21 enhances CSLV\u2010afferent excitability and directly sensitizes CSLV neurons, thereby promoting AHS. The cellular sensitizing effect involves TGF\u2010\u03b2RI, Smad3, ROS, and TRPA1\u2010associated mechanisms.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70311","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:23:31Z","timestamp":1789377811000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["<scp>TGF<\/scp>\n                    \u2010\u03b21 Directly Sensitizes Capsaicin\u2010Sensitive Lung Vagal Neurons to Promote Airway Hypersensitivity"],"prefix":"10.1111","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9739-0022","authenticated-orcid":false,"given":"Yueh\u2010Yin","family":"Chen","sequence":"first","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University  Taipei Taiwan"},{"name":"School of Respiratory Therapy, College of Medicine Taipei Medical University  Taipei 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