{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:19:18Z","timestamp":1792001958852,"version":"4.4.0"},"reference-count":45,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T00:00:00Z","timestamp":1639612800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["1R01DE031478, 1R01DE022975"],"award-info":[{"award-number":["1R01DE031478, 1R01DE022975"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82001065, 91649124, 81991504"],"award-info":[{"award-number":["82001065, 91649124, 81991504"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Beijing Municipality Government grants","award":["PXM2018_014226_000021; PXM2018_193312_000006_0028S643_FCG, PXM2017_014226_000023; Z181100001718208"],"award-info":[{"award-number":["PXM2018_014226_000021; PXM2018_193312_000006_0028S643_FCG, PXM2017_014226_000023; Z181100001718208"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Salivary gland function is commonly and irreversibly damaged by radiation therapy for head and neck cancer. This damage greatly decreases the patient\u2019s quality of life and is difficult to remedy. Previously, we found that the transient activation of Hedgehog signaling alleviated salivary hypofunction after radiation in both mouse and pig models through the inhibition of radiation-induced cellular senescence that is mediated by resident macrophages in mouse submandibular glands. Here we report that in swine parotid glands sharing many features with humans, the Hedgehog receptor PTCH1 is mainly expressed in macrophages, and levels of PTCH1 and multiple macrophage markers are significantly decreased by radiation but recovered by transient Hedgehog activation. These parotid macrophages mainly express the M2 macrophage marker ARG1, while radiation promotes expression of pro-inflammatory cytokine that is reversed by transient Hedgehog activation. Hedgehog activation likely preserves parotid macrophages after radiation through inhibition of P53 signaling and consequent cellular senescence. Consistently, VEGF, an essential anti-senescence cytokine downstream of Hedgehog signaling, is significantly decreased by radiation but recovered by transient Hedgehog activation. These findings indicate that in the clinically-relevant swine model, transient Hedgehog activation restores the function of irradiated salivary glands through the recovery of resident macrophages and the consequent inhibition of cellular senescence and inflammation.<\/jats:p>","DOI":"10.3390\/ijms222413493","type":"journal-article","created":{"date-parts":[[2021,12,16]],"date-time":"2021-12-16T11:27:36Z","timestamp":1639654056000},"page":"13493","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Transient Activation of Hedgehog Signaling Inhibits Cellular Senescence and Inflammation in Radiated Swine Salivary Glands through Preserving Resident Macrophages"],"prefix":"10.3390","volume":"22","author":[{"given":"Liang","family":"Hu","sequence":"first","affiliation":[{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health, School of Stomatology, Capital Medical University, Beijing 100050, China"},{"name":"Outpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Conglin","family":"Du","sequence":"additional","affiliation":[{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health, School of Stomatology, Capital Medical University, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi","family":"Yang","sequence":"additional","affiliation":[{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health, School of Stomatology, Capital Medical University, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health, School of Stomatology, Capital Medical University, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhao","family":"Zhu","sequence":"additional","affiliation":[{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health, School of Stomatology, Capital Medical University, Beijing 100050, China"},{"name":"Outpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaochen","family":"Shan","sequence":"additional","affiliation":[{"name":"Outpatient Department of Oral and Maxillofacial Surgery, School of Stomatology, Capital Medical University, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunmei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health, School of Stomatology, Capital Medical University, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songlin","family":"Wang","sequence":"additional","affiliation":[{"name":"Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, Beijing Laboratory of Oral Health, School of Stomatology, Capital Medical University, Beijing 100050, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Medicine, Institute for Regenerative Medicine, College of Medicine, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. 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