{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T06:33:55Z","timestamp":1793428435394,"version":"4.5.0"},"reference-count":41,"publisher":"Radiation Research Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Radiation Research"],"published-print":{"date-parts":[[2023,3,15]]},"abstract":"<jats:p>Radiation models, such as whole thorax lung irradiation (WTLI) or partial-body irradiation (PBI) with bone-marrow sparing, have shown that affected lung tissue displays a continual progression of injury, often for months after the initial insult. Undoubtably, a variety of resident and infiltrating cell types either contribute to or fail to resolve this type of progressive injury, which in lung tissue, often develops into lethal and irreversible radiation-induced pulmonary fibrosis (RIPF), indicating a failure of the lung to return to a homeostatic state. Resident pulmonary epithelium, which are present at the time of irradiation and persist long after the initial insult, play a key role in the maintenance of homeostatic conditions in the lung and have often been described as contributing to the progression of radiation-induced lung injury (RILI). In this study, we took an unbiased approach through RNA sequencing to determine the in vivo response of the lung epithelium in the progression of RIPF. In our methodology, we isolated CD326+ epithelium from the lungs of 12.5 Gy WTLI C57BL\/6J female mice (aged 8\u201310 weeks and sacrificed at regular intervals) and compared irradiated and non-irradiated CD326+ cells and whole lung tissue. We subsequently verified our findings by qPCR and immunohistochemistry. Transcripts associated with epithelial regulation of immune responses and fibroblast activation were significantly reduced in irradiated animals at 4 weeks postirradiation. Additionally, alveolar type-2 epithelial cells (AEC2) appeared to be significantly reduced in number at 4 weeks and thereafter based on the diminished expression of pro-surfactant protein C (pro-SPC). This change is associated with a reduction of Cd200 and cyclooxygenase 2 (COX2), which are expressed within the CD326 populations of cells and function to suppress macrophage and fibroblast activation under steady-state conditions, respectively. These data indicate that either preventing epithelial cell loss that occurs after irradiation or replacing important mediators of immune and fibroblast activity produced by the epithelium are potentially important strategies for preventing or treating this unique injury.<\/jats:p>","DOI":"10.1667\/rade-22-00103.1","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T02:12:54Z","timestamp":1684462374000},"page":"439-451","source":"Crossref","is-referenced-by-count":8,"title":["Epithelial Responses in Radiation-Induced Lung Injury (RILI) Allow Chronic Inflammation and Fibrogenesis"],"prefix":"10.1667","volume":"199","author":[{"given":"Tyler A.","family":"Beach","sequence":"first","affiliation":[{"name":"SRI Biosciences, SRI International, Menlo Park, Calfornia 94025-3493"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob N.","family":"Finkelstein","sequence":"additional","affiliation":[{"name":"University of Rochester Medical Center, Departments of Pediatrics and Neonatology, and Environmental Medicine, Rochester, New York 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Polly Y.","family":"Chang","sequence":"additional","affiliation":[{"name":"SRI Biosciences, SRI International, Menlo Park, Calfornia 94025-3493"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1243","reference":[{"key":"38","doi-asserted-by":"crossref","unstructured":"Y He, D Thummuri, G Zheng, et al.  \"Transl Res.\"  209, \"Cellular senescence and radiation-induced pulmonary fibrosis.\" 14 (2019)","DOI":"10.1016\/j.trsl.2019.03.006"},{"key":"40","doi-asserted-by":"crossref","unstructured":"R Komaki, JS Lee, L Milas, et al.  \"Int J Radiat Oncol Biol Phys.\"  58, \"Effects of amifostine on acute toxicity from concurrent chemotherapy and radiotherapy for inoperable non-small-cell lung cancer: report of a randomized comparative trial.\" 1369 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radiation-induced lung fibrosis.\" 1474 (2013)","DOI":"10.1093\/jnci\/djt212"},{"key":"5","doi-asserted-by":"crossref","unstructured":"P Cheresh, SJ Kim, S Tulasiram, et al.  \"Biochim Biophys Acta.\"  1832, \"Oxidative stress and pulmonary fibrosis.\" 1028 (2013)","DOI":"10.1016\/j.bbadis.2012.11.021"},{"key":"10","doi-asserted-by":"crossref","unstructured":"AM Groves, CJ Johnston, RS Misra, et al.  \"Int J Radiat Biol.\"  92, \"Effects of IL-4 on pulmonary fibrosis and the accumulation and phenotype of macrophage subpopulations following thoracic irradiation.\" 754 (2016)","DOI":"10.1080\/09553002.2016.1222094"},{"key":"12","doi-asserted-by":"crossref","unstructured":"AM Groves, CJ Johnston, RS Misra, et al.  \"Radiat Res.\"  184, \"Whole-lung irradiation results in pulmonary macrophage alterations that are subpopulation and strain specific.\" 639 (2015)","DOI":"10.1667\/RR14178.1"},{"key":"34","doi-asserted-by":"crossref","unstructured":"CE Rube, D Uthe, KW Schmid, et al.  \"Int J Radiat Oncol Biol Phys.\"  47, \"Dose-dependent induction of transforming growth factor beta (TGF-beta) in the lung tissue of fibrosis-prone mice after thoracic irradiation.\" 1033 (2000)","DOI":"10.1016\/S0360-3016(00)00482-X"},{"key":"17","doi-asserted-by":"crossref","unstructured":"RJ Snelgrove, J Goulding, AM Didierlaurent, et al.  \"Nat Immunol.\"  9, \"A critical function for CD200 in lung immune homeostasis and the severity of influenza infection.\" 1074 (2008)","DOI":"10.1038\/ni.1637"},{"key":"27","doi-asserted-by":"crossref","unstructured":"CA Schneider, WS Rasband, KW Eliceiri,  \"Nat Methods.\"  9, \"NIH Image to ImageJ: 25 years of image analysis.\" 671 (2012)","DOI":"10.1038\/nmeth.2089"},{"key":"11","doi-asserted-by":"crossref","unstructured":"AM Groves, CJ Johnston, JP Williams, et al.  \"Radiat Res.\"  189, \"Role of infiltrating monocytes in the development of radiation-induced pulmonary fibrosis.\" 300 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(2009)","DOI":"10.1016\/j.biocel.2009.02.009"},{"key":"7","doi-asserted-by":"crossref","unstructured":"AK Perl, D Riethmacher, JA Whitsett,  \"Am J Respir Crit Care Med.\"  183, \"Conditional depletion of airway progenitor cells induces peribronchiolar fibrosis.\" 511 (2011)","DOI":"10.1164\/rccm.201005-0744OC"},{"key":"8","doi-asserted-by":"crossref","unstructured":"TA Beach, CJ Johnston, AM Groves, et al.  \"Exp Lung Res.\"  43, \"Radiation induced pulmonary fibrosis as a model of progressive fibrosis: Contributions of DNA damage, inflammatory response and cellular senescence genes.\" 134 (2017)","DOI":"10.1080\/01902148.2017.1318975"},{"key":"9","doi-asserted-by":"crossref","unstructured":"TA Beach, AM Groves, CJ Johnston, et al.  \"Int J Radiat Biol.\"  94, \"Recurrent DNA damage is associated with persistent injury in progressive radiation-induced pulmonary fibrosis.\" 1104 (2018)","DOI":"10.1080\/09553002.2018.1516907"},{"key":"13","doi-asserted-by":"crossref","unstructured":"BL 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Mason,  \"Respirology.\"  11, \"Biology of alveolar type II cells.\" S12 (2006)","DOI":"10.1111\/j.1440-1843.2006.00800.x"},{"key":"16","doi-asserted-by":"crossref","unstructured":"F Broeckaert  and A Bernard  \"Clin Exp Allergy.\"  30, \"Clara cell secretory protein (CC16): characteristics and perspectives as lung peripheral biomarker.\" 469 (2000)","DOI":"10.1046\/j.1365-2222.2000.00760.x"},{"key":"18","doi-asserted-by":"crossref","unstructured":"PD Bozyk  and BB Moore  \"Am J Respir Cell Mol Biol.\"  45, \"Prostaglandin E2 and the pathogenesis of pulmonary fibrosis.\" 445 (2011)","DOI":"10.1165\/rcmb.2011-0025RT"},{"key":"19","doi-asserted-by":"crossref","unstructured":"PG Holt  and DH Strickland  \"Nat Immunol.\"  9, \"The CD200-CD200R axis in local control of lung inflammation.\" 1011 (2008)","DOI":"10.1038\/ni0908-1011"},{"key":"20","doi-asserted-by":"crossref","unstructured":"V Lama, BB Moore, P Christensen, et al.  \"Am J Respir Cell Mol Biol.\"  27, \"Prostaglandin E2 synthesis and suppression of fibroblast proliferation by alveolar epithelial cells is cyclooxygenase-2-dependent.\" 752 (2002)","DOI":"10.1165\/rcmb.4857"},{"key":"21","doi-asserted-by":"crossref","unstructured":"T Kohyama, RF Ertl, V Valenti, et al.  \"Am J Physiol Lung Cell Mol Physiol.\"  281, \"Prostaglandin E2 inhibits fibroblast chemotaxis.\" L1257 (2001)","DOI":"10.1152\/ajplung.2001.281.5.L1257"},{"key":"22","doi-asserted-by":"crossref","unstructured":"PB Bitterman, MD Wewers, SI Rennard, et al.  \"J Clin Invest.\"  77, \"Modulation of alveolar macrophage-driven fibroblast proliferation by alternative macrophage mediators.\" 700 (1986)","DOI":"10.1172\/JCI112364"},{"key":"23","doi-asserted-by":"crossref","unstructured":"AP Epa, TH Thatcher, SJ Pollock, et al.  \"PLoS One.\"  10, \"Normal Human Lung Epithelial Cells Inhibit Transforming Growth Factor-beta Induced Myofibroblast Differentiation via Prostaglandin E2.\" e0135266 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(2008)","DOI":"10.2144\/000112729"},{"key":"31","doi-asserted-by":"crossref","unstructured":"EA Howe, R Sinha, D Schlauch, et al.  \"Bioinformatics.\"  27, \"RNA-Seq analysis in MeV.\" 3209 (2011)","DOI":"10.1093\/bioinformatics\/btr490"},{"key":"32","unstructured":"\"Place R Foundation for Statistical Computing.\"  2021"},{"key":"33","doi-asserted-by":"crossref","unstructured":"K Hasegawa, A Sato, K Tanimura, et al.  \"Respir Res.\"  18, \"Fraction of MHCII and EpCAM expression characterizes distal lung epithelial cells for alveolar type 2 cell isolation.\" 150 (2017)","DOI":"10.1186\/s12931-017-0635-5"},{"key":"35","doi-asserted-by":"crossref","unstructured":"CE Rube, D Uthe, F Wilfert, et al.  \"Int J Radiat Oncol Biol Phys.\"  61, \"The bronchiolar epithelium as a prominent source of pro-inflammatory cytokines after lung irradiation.\" 1482 (2005)","DOI":"10.1016\/j.ijrobp.2004.12.072"},{"key":"36","doi-asserted-by":"crossref","unstructured":"D Schaue  and WH McBride  \"Radiat Res.\"  173, \"Links between innate immunity and normal tissue radiobiology.\" 406 (2010)","DOI":"10.1667\/RR1931.1"},{"key":"37","doi-asserted-by":"crossref","unstructured":"D Shapiro, J Finkelstein, DP Penney, et al.  \"Int J Radiat Oncol Biol Phys.\"  8, \"Sequential Effects of Irriadiation on the Pulmonary System.\" 879 (1982)","DOI":"10.1016\/0360-3016(82)90092-X"},{"key":"39","doi-asserted-by":"crossref","unstructured":"MI Koukourakis, G Kyrias, S Kakolyris, et al.  \"J Clin Oncol.\"  18, \"Subcutaneous administration of amifostine during fractionated radiotherapy: a randomized phase II study.\" 2226 (2000)","DOI":"10.1200\/JCO.2000.18.11.2226"},{"key":"41","doi-asserted-by":"crossref","unstructured":"J Pan, D Li, Y Xu, et al.  \"Int J Radiat Oncol Biol Phys.\"  99, \"Inhibition of Bcl-2\/xl With ABT-263 Selectively Kills Senescent Type II Pneumocytes and Reverses Persistent Pulmonary Fibrosis Induced by Ionizing Radiation in Mice.\" 353 (2017)","DOI":"10.1016\/j.ijrobp.2017.02.216"}],"container-title":["Radiation Research"],"original-title":[],"deposited":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T06:10:07Z","timestamp":1793427007000},"score":1,"resource":{"primary":{"URL":"https:\/\/bioone.org\/journals\/radiation-research\/volume-199\/issue-5\/RADE-22-00103.1\/Epithelial-Responses-in-Radiation-Induced-Lung-Injury-RILI-Allow-Chronic\/10.1667\/RADE-22-00103.1.full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,15]]},"references-count":41,"aliases":["10.1667\/rade-22-00130.1"],"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5,1]]}},"URL":"https:\/\/doi.org\/10.1667\/rade-22-00103.1","relation":{},"ISSN":["0033-7587","1938-5404"],"issn-type":[{"value":"0033-7587","type":"print"},{"value":"1938-5404","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,15]]}}}