{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:47:05Z","timestamp":1761007625208,"version":"build-2065373602"},"reference-count":31,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T00:00:00Z","timestamp":1729641600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["aao-hnsfjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Otolaryngol.--head neck surg."],"published-print":{"date-parts":[[2025,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>Laryngotracheal stenosis (LTS) describes fibrotic airway obstruction that is life\u2010threatening without treatment. Targeted therapies are needed as an adjunct to surgical management. We have previously observed the upregulation of immune checkpoint programmed cell death (PD)\u20101 and its ligand, PD\u2010L1, in patients with LTS. This study aims to determine whether PD\u20101 and PD\u2010L1 play a role in the pathophysiology of LTS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Design<\/jats:title><jats:p>Basic science.<\/jats:p><\/jats:sec><jats:sec><jats:title>Setting<\/jats:title><jats:p>Laboratory.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Fibroblasts derived from the subglottic scar of 5 iSGS patients were cultured ex vivo with transforming growth factor \u03b2 (TGF\u03b2), PD\u2010L1 agonist (PD\u20101), and PD\u2010L1 blockade (anti\u2010PD\u2010L1). PD\u2010L1, TGF\u03b2 receptor II (TGF\u03b2RII), and Collagen\u20101 expression were quantified by flow cytometry. A validated chemomechanical injury model of subglottic stenosis was applied in PD\u20101 knockout and wild\u2010type (WT) mice, and subglottic thickening was assessed by histologic analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TGF\u03b2 significantly increased the expression of PD\u2010L1 and Collagen\u20101 in human airway scar fibroblasts (<jats:italic>P<\/jats:italic>\u2009&lt;\u2009.05). PD\u20101 knockout mice demonstrated no significant difference in subglottic airway fibrosis compared to WT mice. Ex vivo PD\u2010L1 modulation had no impact on fibroblast Collagen\u20101 expression. PD\u2010L1 high\u2010intensity fibroblasts expressed greater Collagen\u20101 and TGF\u03b2RII compared to PD\u2010L1 low\u2010intensity fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>PD\u20101 knockout does not protect mice from the development of laryngotracheal fibrosis. However, its ligand, PD\u2010L1 is highly expressed on pathologic fibroblasts unique to scar, characterized by high Collagen\u20101 and TGF\u03b2RII expression. PD\u2010L1 is also upregulated in conjunction with Collagen\u20101 by TGF\u03b2 stimulation. PD\u2010L1 may act independently of PD\u20101 to sensitize fibroblasts to TGF\u03b2, suggesting direct targeting of PD\u2010L1 may have therapeutic potential in LTS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ohn.1034","type":"journal-article","created":{"date-parts":[[2024,10,23]],"date-time":"2024-10-23T11:28:18Z","timestamp":1729682898000},"page":"563-570","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PD\u2010L1 Acts Independently of PD\u20101 as a Marker of Pathologic Fibroblasts in Laryngotracheal Stenosis"],"prefix":"10.1002","volume":"172","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9592-932X","authenticated-orcid":false,"given":"Ruth J.","family":"Davis","sequence":"first","affiliation":[{"name":"Division of Otolaryngology\u2013Head and Neck Surgery, Department of Surgery University of Wisconsin\u2013Madison Madison Wisconsin USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward Ryan R.","family":"Talatala","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongmei","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yueli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason S.","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Gelbard","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology\u2013Head and Neck Surgery Vanderbilt University Medical Center Nashville Tennessee USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,10,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.24956"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/mSphereDirect.00211-19"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.26097"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0221-9"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/0194599820978271"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.28840"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.28790"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1177\/0194599818803584"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2017.0977"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aar8356"},{"issue":"6","key":"e_1_2_9_12_1","article-title":"PD\u2010L1 on invasive fibroblasts drives fibrosis in a humanized model of idiopathic pulmonary fibrosis","volume":"4","author":"Geng Y","year":"2019","journal-title":"JCI Insight"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16466-4"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoto.2014.1663"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.23949"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/lary.25708"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/0194599815573708"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.7150\/thno.36276"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ohn.502"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.8.5064"},{"key":"e_1_2_9_21_1","doi-asserted-by":"crossref","unstructured":"GelbardA ShiltsMH StricklandB et al.Idiopathic subglottic stenosis arises at the epithelial interface of host and pathogen.Res Sq. 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