{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:42:15Z","timestamp":1793295735436,"version":"4.5.0"},"reference-count":40,"publisher":"European Respiratory Society (ERS)","issue":"3","license":[{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018493","name":"Taipei Medical University-Shuang Ho Hospital, Ministry of Health and Welfare","doi-asserted-by":"publisher","award":["113TMU-SHH-03"],"award-info":[{"award-number":["113TMU-SHH-03"]}],"id":[{"id":"10.13039\/100018493","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["108-2314-B-038-111-MY3"],"award-info":[{"award-number":["108-2314-B-038-111-MY3"]}],"id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["111-2314-B-038-150-MY3"],"award-info":[{"award-number":["111-2314-B-038-150-MY3"]}],"id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100020950","name":"National Science and Technology Council","doi-asserted-by":"publisher","award":["111-2314-B-038-152-MY3"],"award-info":[{"award-number":["111-2314-B-038-152-MY3"]}],"id":[{"id":"10.13039\/501100020950","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["Eur Respir J"],"accepted":{"date-parts":[[2025,5,10]]},"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Prolonged exposure to airborne particulate matter (PM) is associated with emphysema and COPD; however, the precise underlying mechanism remains unclear. In a previous high-throughput screen, we identified inter-\u03b1-trypsin inhibitor heavy chain 4 (ITIH4) as a biomarker of long-term PM exposure. We hypothesised that ITIH4 is implicated in PM-related emphysema.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated the association between ITIH4 expression and ambient PM exposure through a clinical cohort analysis (220 patients with COPD and 61 healthy participants) and\n                      <jats:italic>in vitro<\/jats:italic>\n                      studies.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The COPD cohort studies revealed significant correlations between emphysema severity, ambient PM exposure and serum ITIH4 levels. In primary small airway epithelial cells from COPD patients with low basal levels of ITIH4, exposure to PM and oxidative stress led to increased apoptosis. However, ITIH4 overexpression significantly inhibited oxidative-stress-induced apoptosis in normal and COPD airway epithelial cells. Acute exposure to hydrogen peroxide resulted in the rapid degradation of ITIH4 protein with no effect on transcriptional level, although\n                      <jats:italic>ITIH4<\/jats:italic>\n                      gene expression is downregulated in the lung tissue of patients with COPD. A human apoptosis antibody array revealed that ITIH4 overexpression attenuated hydrogen-peroxide-induced apoptotic signalling. Furthermore, extracellular ITIH4 protein confers cytoprotective functions in cells exposed to PM or oxidative stress. Mechanistically, ITIH4 attenuated oxidative-stress-induced c-Jun N-terminal kinase (JNK) activation and \u03b2-catenin decrease. A deficiency of ITIH4 exacerbated the effects of oxidative stress.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We identified a novel pathogenetic mechanism involving ITIH4, where chronic exposure to air pollution induces or promotes emphysema.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1183\/13993003.01610-2024","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T10:00:26Z","timestamp":1747908026000},"page":"2401610","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Particulate matter-related ITIH4 deficiency is associated with an emphysema phenotype of COPD through JNK-dependent and JNK-independent signalling"],"prefix":"10.1183","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1746-5771","authenticated-orcid":false,"given":"Sheng-Ming","family":"Wu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuan-Yuan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4651-5192","authenticated-orcid":false,"given":"Hsiao-Chi","family":"Chuang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1616-8647","authenticated-orcid":false,"given":"Shu-Chuan","family":"Ho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4622-2680","authenticated-orcid":false,"given":"Cheng-Wei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4644-5892","authenticated-orcid":false,"given":"Chia-Li","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7086-4873","authenticated-orcid":false,"given":"Wei-Lun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3569-3746","authenticated-orcid":false,"given":"Po-Hao","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7198-7234","authenticated-orcid":false,"given":"Shiou-Fu","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueh-Hsi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzu-Tao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7020-1180","authenticated-orcid":false,"given":"Chien-Hua","family":"Tseng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1281-8718","authenticated-orcid":false,"given":"Wen-Te","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4705-5802","authenticated-orcid":false,"given":"Kang-Yun","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"2025091702550817000_66.3.2401610.1","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(22)00470-6"},{"key":"2025091702550817000_66.3.2401610.2","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0059-2022"},{"key":"2025091702550817000_66.3.2401610.3","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201410-1875OC"},{"key":"2025091702550817000_66.3.2401610.4","doi-asserted-by":"crossref","first-page":"e114","DOI":"10.1016\/S2542-5196(18)30028-7","article-title":"Effect of long-term exposure to fine particulate matter on lung function decline and risk of chronic obstructive pulmonary disease in Taiwan: a longitudinal, cohort study","volume":"2","author":"Guo","year":"2018","journal-title":"Lancet Planet Health"},{"key":"2025091702550817000_66.3.2401610.5","doi-asserted-by":"publisher","DOI":"10.1183\/23120541.00324-2021"},{"key":"2025091702550817000_66.3.2401610.6","doi-asserted-by":"crossref","first-page":"4260204","DOI":"10.1155\/2020\/4260204","article-title":"Exposure to air pollution exacerbates inflammation in rats with preexisting COPD","volume":"2020","author":"Wang","year":"2020","journal-title":"Mediators Inflamm"},{"key":"2025091702550817000_66.3.2401610.7","doi-asserted-by":"crossref","first-page":"101","DOI":"10.2131\/jts.43.101","article-title":"Mitochondrial damage mediated by ROS incurs bronchial epithelial cell apoptosis upon ambient PM2.5 exposure","volume":"43","author":"Jin","year":"2018","journal-title":"J Toxicol Sci"},{"key":"2025091702550817000_66.3.2401610.8","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.06.00053805"},{"key":"2025091702550817000_66.3.2401610.9","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0126-2020"},{"key":"2025091702550817000_66.3.2401610.10","doi-asserted-by":"crossref","first-page":"5730395","DOI":"10.1155\/2018\/5730395","article-title":"Reactive oxygen species in chronic obstructive pulmonary disease","volume":"2018","author":"Boukhenouna","year":"2018","journal-title":"Oxid Med Cell Longev"},{"key":"2025091702550817000_66.3.2401610.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-021-00233-1"},{"key":"2025091702550817000_66.3.2401610.12","doi-asserted-by":"publisher","DOI":"10.1080\/03008200802325458"},{"key":"2025091702550817000_66.3.2401610.13","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aba7381"},{"key":"2025091702550817000_66.3.2401610.14","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1007\/s11845-021-02837-3","article-title":"Serum inter-alpha-trypsin inhibitor heavy chain 4 in patients with inflammatory bowel disease: correlation with disease risk, inflammation, activity, and its variation after treatment","volume":"191","author":"Wen","year":"2022","journal-title":"Ir J Med Sci"},{"key":"2025091702550817000_66.3.2401610.15","doi-asserted-by":"crossref","first-page":"e24231","DOI":"10.1002\/jcla.24231","article-title":"Inter-alpha-trypsin inhibitor heavy chain 4: a serologic marker relating to disease risk, activity, and treatment outcomes of rheumatoid arthritis","volume":"36","author":"He","year":"2022","journal-title":"J Clin Lab Anal"},{"key":"2025091702550817000_66.3.2401610.16","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1186\/1471-2164-15-839","article-title":"iTRAQ-proteomics and bioinformatics analyses of mammary tissue from cows with clinical mastitis due to natural infection with Staphylococci aureus","volume":"15","author":"Huang","year":"2014","journal-title":"BMC Genomics"},{"key":"2025091702550817000_66.3.2401610.17","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.1235"},{"key":"2025091702550817000_66.3.2401610.18","first-page":"831","article-title":"Inter-alpha-trypsin inhibitor heavy chain 4: a novel biomarker for environmental exposure to particulate air pollution in patients with chronic obstructive pulmonary disease","volume":"10","author":"Lee","year":"2015","journal-title":"Int J Chron Obstruct Pulmon Dis"},{"key":"2025091702550817000_66.3.2401610.19","doi-asserted-by":"crossref","first-page":"116863","DOI":"10.1016\/j.envpol.2021.116863","article-title":"Alveolar epithelial inter-alpha-trypsin inhibitor heavy chain 4 deficiency associated with senescence-regulated apoptosis by air pollution","volume":"278","author":"Chen","year":"2021","journal-title":"Environ Pollut"},{"key":"2025091702550817000_66.3.2401610.20","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.ebiom.2018.02.008","article-title":"Association of air pollution exposure and interleukin-13 haplotype with the risk of aggregate bronchitic symptoms in children","volume":"29","author":"Lee","year":"2018","journal-title":"EBioMedicine"},{"key":"2025091702550817000_66.3.2401610.21","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1016\/j.scitotenv.2018.07.073","article-title":"A hybrid kriging\/land-use regression model to assess PM2.5 spatial-temporal variability","volume":"645","author":"Wu","year":"2018","journal-title":"Sci Total Environ"},{"key":"2025091702550817000_66.3.2401610.22","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1186\/s12931-024-02836-9","article-title":"Cigarette smoke-induced dysbiosis: comparative analysis of lung and intestinal microbiomes in COPD mice and patients","volume":"25","author":"Laiman","year":"2024","journal-title":"Respir Res"},{"key":"2025091702550817000_66.3.2401610.23","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-7-53"},{"key":"2025091702550817000_66.3.2401610.24","doi-asserted-by":"publisher","DOI":"10.1007\/s10565-022-09709-1"},{"key":"2025091702550817000_66.3.2401610.25","doi-asserted-by":"crossref","first-page":"101544","DOI":"10.1016\/j.redox.2020.101544","article-title":"Oxidative stress-based therapeutics in COPD","volume":"33","author":"Barnes","year":"2020","journal-title":"Redox Biol"},{"key":"2025091702550817000_66.3.2401610.26","doi-asserted-by":"crossref","first-page":"2977","DOI":"10.1016\/j.bbamcr.2016.09.012","article-title":"Activation of apoptosis signalling pathways by reactive oxygen species","volume":"1863","author":"Redza-Dutordoir","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"2025091702550817000_66.3.2401610.27","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.116.5.1071"},{"key":"2025091702550817000_66.3.2401610.28","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200910-1560OC"},{"key":"2025091702550817000_66.3.2401610.29","doi-asserted-by":"publisher","DOI":"10.1016\/j.etap.2018.03.020"},{"key":"2025091702550817000_66.3.2401610.30","doi-asserted-by":"publisher","DOI":"10.1096\/fj.08-117804"},{"key":"2025091702550817000_66.3.2401610.31","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1106955"},{"key":"2025091702550817000_66.3.2401610.32","doi-asserted-by":"publisher","DOI":"10.1378\/chest.12-1766"},{"key":"2025091702550817000_66.3.2401610.33","doi-asserted-by":"crossref","first-page":"244","DOI":"10.3390\/jcm7090244","article-title":"Proteases and their inhibitors in chronic obstructive pulmonary disease","volume":"7","author":"Dey","year":"2018","journal-title":"J Clin Med"},{"key":"2025091702550817000_66.3.2401610.34","doi-asserted-by":"publisher","DOI":"10.1084\/jem.192.11.1587"},{"key":"2025091702550817000_66.3.2401610.35","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1164\/rccm.201807-1380LE","article-title":"Lectin complement pathway in emphysema","volume":"199","author":"Serban","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"2025091702550817000_66.3.2401610.36","first-page":"S146","article-title":"Alpha-1 antitrypsin and lung cell apoptosis","volume":"13","author":"Serban","year":"2016","journal-title":"Ann Am Thorac Soc"},{"key":"2025091702550817000_66.3.2401610.37","doi-asserted-by":"publisher","DOI":"10.1093\/ntr\/ntn010"},{"key":"2025091702550817000_66.3.2401610.38","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.jhep.2012.10.008","article-title":"From lung to liver: how does airborne particulate matter trigger NASH and systemic insulin resistance?","volume":"58","author":"Conklin","year":"2013","journal-title":"J Hepatol"},{"key":"2025091702550817000_66.3.2401610.39","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1111\/cei.13556","article-title":"Citrullinated inter-alpha-trypsin inhibitor heavy chain 4 in arthritic joints and its potential effect in the neutrophil migration","volume":"203","author":"Osada","year":"2021","journal-title":"Clin Exp Immunol"},{"key":"2025091702550817000_66.3.2401610.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114437"}],"container-title":["European Respiratory Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/13993003.01610-2024","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T09:55:15Z","timestamp":1758102915000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/13993003.01610-2024"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,22]]},"references-count":40,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,9,17]]},"published-print":{"date-parts":[[2025,9]]}},"alternative-id":["10.1183\/13993003.01610-2024"],"URL":"https:\/\/doi.org\/10.1183\/13993003.01610-2024","relation":{},"ISSN":["0903-1936","1399-3003"],"issn-type":[{"value":"0903-1936","type":"print"},{"value":"1399-3003","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,22]]}}}