{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:41:35Z","timestamp":1760150495495,"version":"build-2065373602"},"reference-count":47,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2023,11,25]],"date-time":"2023-11-25T00:00:00Z","timestamp":1700870400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ZonMW\u2013TopZorg St. Antonius Science Corner grant","award":["842002001","10070012010004"],"award-info":[{"award-number":["842002001","10070012010004"]}]},{"name":"ZonMW TZO vision grant","award":["842002001","10070012010004"],"award-info":[{"award-number":["842002001","10070012010004"]}]},{"name":"Prof. Dr. Jaap Swierenga foundation","award":["842002001","10070012010004"],"award-info":[{"award-number":["842002001","10070012010004"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>In sporadic idiopathic pulmonary fibrosis (sIPF) and pulmonary fibrosis caused by a mutation in telomere (TRG-PF) or surfactant related genes (SRG-PF), there are a number of aberrant cellular processes known that can lead to fibrogenesis. We investigated whether RNA expression of genes involved in these processes differed between sIPF, TRG-PF, and SRG-PF and whether expression levels were associated with survival. RNA expression of 28 genes was measured in lung biopsies of 26 sIPF, 17 TRG-PF, and 6 SRG-PF patients. Significant differences in RNA expression of TGFBR2 (p = 0.02) and SFTPA2 (p = 0.02) were found between sIPF, TRG-PF, and SRG-PF. Patients with low (&lt;median) expression of HSPA5 (p = 0.04), COL1A1 (p = 0.03), and ATF4 (0.005) had significantly longer survival rates than patients with high (\u2265median) expression of these genes. In addition, we scored for low (0) or high (1) expression of six endoplasmic reticulum (ER) stress genes (HSP90B1, DDIT3, EDEM1, HSPA5, ATF4, and XBP1) and found that patients with high expression in a low number of ER stress genes (total score 0\u20131) had longer survival rates than patients with high expression in a high number of ER stress genes (total score 2\u20136) (p = 0.03). In conclusion, there are minor differences between sIPF, TRG-PF, and SRG-PF and high expression in a high number of ER stress genes significantly associated with shorter survival time, suggesting that ER stress may be a target for therapy for PF.<\/jats:p>","DOI":"10.3390\/ijms242316748","type":"journal-article","created":{"date-parts":[[2023,11,27]],"date-time":"2023-11-27T03:32:03Z","timestamp":1701055923000},"page":"16748","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["New Insights via RNA Profiling of Formalin-Fixed Paraffin-Embedded Lung Tissue of Pulmonary Fibrosis Patients"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0519-1769","authenticated-orcid":false,"given":"Dymph","family":"Klay","sequence":"first","affiliation":[{"name":"Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karin M.","family":"Kazemier","sequence":"additional","affiliation":[{"name":"Center of Translational Immunology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"},{"name":"Division of Heart and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6727-8416","authenticated-orcid":false,"given":"Joanne J.","family":"van der Vis","sequence":"additional","affiliation":[{"name":"Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"},{"name":"Department of Clinical Chemistry, ILD Center of Excellence, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hidde M.","family":"Smits","sequence":"additional","affiliation":[{"name":"Center of Translational Immunology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan C.","family":"Grutters","sequence":"additional","affiliation":[{"name":"Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"},{"name":"Division of Heart and Lungs, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Coline H. M.","family":"van Moorsel","sequence":"additional","affiliation":[{"name":"Interstitial Lung Diseases Center of Excellence, Department of Pulmonology, St. Antonius Hospital, 3435 CM Nieuwegein, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1007\/s12325-018-0693-1","article-title":"Incidence, Prevalence, and Survival of Patients with Idiopathic Pulmonary Fibrosis in the UK","volume":"35","author":"Strongman","year":"2018","journal-title":"Adv. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"00170","DOI":"10.1183\/23120541.00170-2018","article-title":"Demographics and survival of patients with idiopathic pulmonary fibrosis in the FinnishIPF registry","volume":"5","author":"Kaunisto","year":"2019","journal-title":"ERJ Open Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"200085","DOI":"10.1183\/16000617.0085-2020","article-title":"Genetic disorders of the surfactant system: Focus on adult disease","volume":"30","author":"Grutters","year":"2021","journal-title":"Eur. Respir. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1378\/chest.14-3078","article-title":"Telomere length in interstitial lung diseases","volume":"148","author":"Snetselaar","year":"2015","journal-title":"Chest"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2200577","DOI":"10.1183\/13993003.00577-2022","article-title":"Utility of whole genome sequencing in assessing risk and clinically-relevant outcomes for pulmonary fibrosis","volume":"1","author":"Zhang","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1183\/09031936.00141013","article-title":"Serum lysyl oxidase-like 2 levels and idiopathic pulmonary fibrosis disease progression","volume":"43","author":"Chien","year":"2014","journal-title":"Eur. Respir. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1693","DOI":"10.1164\/ajrccm\/140.6.1693","article-title":"An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis","volume":"140","author":"Kuhn","year":"1989","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"L1119","DOI":"10.1152\/ajplung.00382.2007","article-title":"Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: Association with altered surfactant protein processing and herpesvirus infection","volume":"294","author":"Lawson","year":"2008","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1164\/rccm.200802-313OC","article-title":"Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis","volume":"178","author":"Korfei","year":"2008","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"L391","DOI":"10.1152\/ajplung.00097.2010","article-title":"Accelerated epithelial cell senescence in IPF and the inhibitory role of SIRT6 in TGF-\u03b2-induced senescence of human bronchial epithelial cells","volume":"300","author":"Minagawa","year":"2011","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Disayabutr, S., Kim, E.K., Cha, S.-I., Green, G., Naikawadi, R.P., Jones, K.D., Golden, J.A., Schroeder, A., Matthay, M.A., and Kukreja, J. (2016). miR-34 miRNAs Regulate Cellular Senescence in Type II Alveolar Epithelial Cells of Patients with Idiopathic Pulmonary Fibrosis. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0158367"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1186\/s12931-019-1100-4","article-title":"Dysregulated expression of hypoxia-inducible factors augments myofibroblasts differentiation in idiopathic pulmonary fibrosis","volume":"20","author":"Cisneros","year":"2019","journal-title":"Respir. Res."},{"key":"ref_13","first-page":"e90558","article-title":"Single-cell RNA sequencing identifies diverse roles of epithelial cells in idiopathic pulmonary fibrosis","volume":"1","author":"Xu","year":"2017","journal-title":"J. Clin. Investig. Insight."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Guiot, J., Henket, M., Corhay, J.L., Moermans, C., and Louis, R. (2017). Sputum biomarkers in IPF: Evidence for raised gene expression and protein level of IGFBP-2, IL-8 and MMP-7. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0171344"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1186\/s12931-014-0155-5","article-title":"Increased constitutive \u03b1SMA and Smad2\/3 expression in idiopathic pulmonary fibrosis myofibroblasts is KCa3.1-dependent","volume":"15","author":"Roach","year":"2014","journal-title":"Respir. Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1084\/jem.20102510","article-title":"Severe lung fibrosis requires an invasive fibroblast phenotype regulated by hyaluronan and CD44","volume":"208","author":"Li","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Shochet, G.E., Bardenstein-Wald, B., McElroy, M., Kukuy, A., Surber, M., Edelstein, E., Pertzov, B., Kramer, M.R., and Shitrit, D. (2021). Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22073331"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"17939","DOI":"10.1038\/s41598-018-36063-2","article-title":"HIF-1\u03b1 triggers ER stress and CHOP-mediated apoptosis in alveolar epithelial cells, a key event in pulmonary fibrosis","volume":"8","author":"Delbrel","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Patel, A.S., Lin, L., Geyer, A., Haspel, J.A., An, C.H., Cao, J., Rosas, I.O., and Morse, D. (2012). Autophagy in Idiopathic Pulmonary Fibrosis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0041394"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"L552","DOI":"10.1152\/ajplung.00079.2015","article-title":"Translational Research in Acute Lung Injury and Pulmonary Fibrosis: Reduced FoxO3a expression causes low autophagy in idiopathic pulmonary fibrosis fibroblasts on collagen matrices","volume":"309","author":"Im","year":"2015","journal-title":"Am. J. Physiol.-Lung Cell Mol. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2002806","DOI":"10.1183\/13993003.02806-2020","article-title":"Functional assessment and phenotypic heterogeneity of SFTPA1 and SFTPA2 mutations in interstitial lung diseases and lung cancer","volume":"56","author":"Legendre","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1056\/NEJM200102223440805","article-title":"A mutation in the surfactant protein C gene associated with familial interstitial lung disease","volume":"344","author":"Nogee","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"170135","DOI":"10.1183\/16000617.0135-2017","article-title":"Systematic review of drug effects in humans and models with surfactant-processing disease","volume":"27","author":"Klay","year":"2018","journal-title":"Eur. Respir. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1165\/rcmb.2009-0382OC","article-title":"Endoplasmic reticulum stress induced by surfactant protein C BRICHOS mutants promotes proinflammatory signaling by epithelial cells","volume":"44","author":"Maguire","year":"2011","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"22103","DOI":"10.1074\/jbc.M110.121467","article-title":"Surfactant protein A2 mutations associated with pulmonary fibrosis lead to protein instability and endoplasmic reticulum stress","volume":"285","author":"Maitra","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"L846","DOI":"10.1152\/ajplung.00449.2015","article-title":"The unfolded protein response controls ER stress-induced apoptosis of lung epithelial cells through angiotensin generation","volume":"311","author":"Nguyen","year":"2016","journal-title":"Am. J. Physiol.-Lung Cell Mol. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1073\/pnas.1504780112","article-title":"Telomere dysfunction causes alveolar stem cell failure","volume":"112","author":"Alder","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8861","DOI":"10.1074\/jbc.RA118.006615","article-title":"Telomerase reverse transcriptase ameliorates lung fibrosis by protecting alveolar epithelial cells against senescence","volume":"294","author":"Liu","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wang, Y., Yella, J., Chen, J., McCormack, F.X., Madala, S.K., and Jegga, A.G. (2017). Unsupervised gene expression analyses identify IPF-severity correlated signatures, associated genes and biomarkers. BMC Pulm. Med., 17.","DOI":"10.1186\/s12890-017-0472-9"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1164\/rccm.200601-062OC","article-title":"Gene Expression Profiling of Familial and Sporadic Interstitial Pneumonia","volume":"175","author":"Yang","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"26007","DOI":"10.1088\/1752-7155\/10\/2\/026007","article-title":"Comparative proteomic analysis of bronchoalveolar lavage of familial and sporadic cases of idiopathic pulmonary fibrosis","volume":"10","author":"Carleo","year":"2016","journal-title":"J. Breath Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1164\/ajrccm.162.3.9910080","article-title":"Serum surfactant proteins A and D as prognostic factors in idiopathic pulmonary fibrosis and their relationship to disease extent","volume":"162","author":"Takahashi","year":"2000","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1183\/09031936.02.00081102","article-title":"Serum surfactant proteins-A and -D as biomarkers in idiopathic pulmonary fibrosis","volume":"19","author":"Greene","year":"2002","journal-title":"Eur. Respir. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1016\/j.chest.2022.11.002","article-title":"Progressive Disease With Low Survival in Adult Patients With Pulmonary Fibrosis Carrying Surfactant-Related Gene Mutations: An Observational Study","volume":"163","author":"Klay","year":"2023","journal-title":"Chest"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"645548","DOI":"10.3389\/fimmu.2021.645548","article-title":"Collagen 1a1 Expression by Airway Macrophages Increases In Fibrotic ILDs and Is Associated With FVC Decline and Increased Mortality","volume":"12","author":"Tsitoura","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1164\/rccm.201902-0451OC","article-title":"Grp78 loss in epithelial progenitors reveals an age-linked role for endoplasmic reticulum stress in pulmonary fibrosis","volume":"201","author":"Borok","year":"2020","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1165\/rcmb.2011-0121OC","article-title":"Involvement of endoplasmic reticulum stress in myofibroblastic differentiation of lung fibroblasts","volume":"46","author":"Baek","year":"2012","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1152\/ajplung.00410.2011","article-title":"Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis","volume":"302","author":"Tanjore","year":"2012","journal-title":"Am. J. Physiol.-Lung Cell Mol. Physiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1172\/JCI93560","article-title":"Endoplasmic reticulum stress in the pathogenesis of fibrotic disease","volume":"128","author":"Kropski","year":"2018","journal-title":"J. Clin. Invest."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"107519","DOI":"10.1016\/j.intimp.2021.107519","article-title":"Inhibition of ER stress by targeting the IRE1\u03b1-TXNDC5 pathway alleviates crystalline silica-induced pulmonary fibrosis","volume":"95","author":"Chen","year":"2021","journal-title":"Int. Immunopharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2003198","DOI":"10.1183\/13993003.03198-2020","article-title":"Safety and efficacy of pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis and carrying a telomere-related gene mutation","volume":"57","author":"Justet","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2201383","DOI":"10.1183\/13993003.01383-2022","article-title":"European Respiratory Society Statement on Familial Pulmonary Fibrosis","volume":"61","author":"Borie","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1111\/resp.14303","article-title":"Genetic testing in interstitial lung disease: An international survey","volume":"27","author":"Terwiel","year":"2022","journal-title":"Respirology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1164\/rccm.2009-040GL","article-title":"An Official ATS\/ERS\/JRS\/ALAT Statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management","volume":"183","author":"Raghu","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"e21","DOI":"10.1093\/nar\/gkn1027","article-title":"Telomere length measurement by a novel monochrome multiplex quantitative PCR method","volume":"37","author":"Cawthon","year":"2009","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Snetselaar, R., Van Batenburg, A.A., Van Oosterhout, M.F.M., Kazemier, K.M., Roothaan, S.M., Peeters, T., Van Der Vis, J.J., Goldschmeding, R., Grutters, J.C., and Van Moorsel, C.H.M. (2017). Short telomere length in IPF lung associates with fibrotic lesions and predicts survival. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0189467"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"van Batenburg, A.A., Kazemier, K.M., van Oosterhout, M.F.M., van der Vis, J.J., van Es, H.W., Grutters, J.C., Goldschmeding, R., and van Moorsel, C.H.M. (2020). From organ to cell: Multi-level telomere length assessment in patients with idiopathic pulmonary fibrosis. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0226785"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16748\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:30:07Z","timestamp":1760131807000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/23\/16748"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,25]]},"references-count":47,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2023,12]]}},"alternative-id":["ijms242316748"],"URL":"https:\/\/doi.org\/10.3390\/ijms242316748","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2023,11,25]]}}}