{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T21:57:03Z","timestamp":1774043823614,"version":"3.50.1"},"reference-count":57,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2022,1,30]],"date-time":"2022-01-30T00:00:00Z","timestamp":1643500800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Fonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["AG65143"],"award-info":[{"award-number":["AG65143"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2022,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few effective treatment options. We found a highly significant correlation between pregnancy\u2010associated plasma protein (PAPP)\u2010A expression in IPF lung tissue and disease severity as measured by various pulmonary and physical function tests. PAPP\u2010A is a metalloproteinase that enhances local insulin\u2010like growth factor (IGF) activity. We used primary cultures of normal adult human lung fibroblasts (NHLF) to test the hypothesis that PAPP\u2010A plays an important role in the development of pulmonary fibrosis.\u00a0Treatment of NHLF with pro\u2010fibrotic transforming growth factor (TGF)\u2010\u03b2 stimulated marked increases in IGF\u2010I mRNA expression (&gt;20\u2010fold) and measurable IGF\u2010I levels in 72\u2010h\u00a0conditioned medium (CM). TGF\u2010\u03b2 treatment also increased PAPP\u2010A levels in CM fourfold (<jats:italic>p<\/jats:italic>\u2009=\u20090.004) and proteolytic activity ~2\u2010fold. There was an indirect effect of TGF\u2010\u03b2 to stimulate signaling through the PI3K\/Akt pathway, which was significantly inhibited by both IGF\u2010I\u2010inactivating and PAPP\u2010A inhibitory antibodies.\u00a0Induction of senescence in NHLF increased PAPP\u2010A levels in CM 10\u2010fold (<jats:italic>p<\/jats:italic>\u2009=\u20090.006) with attendant increased proteolytic activity. Thus, PAPP\u2010A is a novel component of the senescent lung fibroblast secretome. In addition, NHLF secreted extracellular vehicles (EVs) with surface\u2010bound active PAPP\u2010A that were increased fivefold with senescence.\u00a0Regulation of PAPP\u2010A and IGF signaling by TGF\u2010\u03b2 and cell senescence suggests an interactive cellular mechanism underlying the resistance to apoptosis and the progression of fibrosis in IPF. Furthermore, PAPP\u2010A\u2010associated EVs may be a means of pro\u2010fibrotic, pro\u2010senescent communication with other cells in the lung and, thus, a potential therapeutic target for IPF.<\/jats:p>","DOI":"10.1002\/jcp.30687","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T06:26:31Z","timestamp":1643610391000},"page":"2220-2229","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Pregnancy\u2010associated plasma protein\u2010A (PAPP\u2010A) is a key component of an interactive cellular mechanism promoting pulmonary fibrosis"],"prefix":"10.1002","volume":"237","author":[{"given":"Laurie K.","family":"Bale","sequence":"first","affiliation":[{"name":"Division of Endocrinology Metabolism and Nutrition, Endocrine Research Unit  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marissa J.","family":"Schafer","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth J.","family":"Atkinson","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan K.","family":"Le Brasseur","sequence":"additional","affiliation":[{"name":"Department of Physical Medicine and Rehabilitation  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew J.","family":"Haak","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biomedical Engineering  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claus","family":"Oxvig","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology and Genetics University of Aarhus  Aarhus Denmark"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4550-6633","authenticated-orcid":false,"given":"Cheryl A.","family":"Conover","sequence":"additional","affiliation":[{"name":"Division of Endocrinology Metabolism and Nutrition, Endocrine Research Unit  Rochester Minnesota USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,1,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00220.2017"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1530\/JME-17-0254"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvy055"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.00326"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1101\/604306"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012592"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199411103311907"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.15.6642"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/s1043-2760(03)00049-3"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4000"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/0955-2235(95)00032-1"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2012.02.008"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.14006"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glq032"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00997"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s12265-015-9666-9"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.79.6.7527411"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(199803)174:3<301:AID-JCP4>3.0.CO;2-S"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2017.12.016"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/bi062229i"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1530\/JME-17-0311"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.05.015"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201901719RR"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M306248200"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.071021"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1186\/1465-9921-14-102"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.611665"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2017.11.005"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.135700"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.6.701"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2007.1914"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cytogfr.2006.02.002"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2006.05.003"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0014-5793(01)02760-0"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M209155200"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.99.3_supplement.55s"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.606330"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrneph.2016.48"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M802429200"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.1629"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00081.2019"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2012.00795.x"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.2003.18.6.1066"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M001384200"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.122.6_suppl.286s"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.2009-040GL"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2016.08.047"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14532"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1378\/chest.06-2568"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.2202\/1544-6115.1027"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12734"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1474-9726.2010.00608.x"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1513\/pats.200601-001TK"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1111\/acel.12219"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.158.5.9804025"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00077309"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.606462"}],"container-title":["Journal of Cellular Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcp.30687","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/jcp.30687","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/jcp.30687","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,22]],"date-time":"2024-05-22T10:35:24Z","timestamp":1716374124000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/jcp.30687"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,30]]},"references-count":57,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2022,4]]}},"alternative-id":["10.1002\/jcp.30687"],"URL":"https:\/\/doi.org\/10.1002\/jcp.30687","archive":["Portico"],"relation":{},"ISSN":["0021-9541","1097-4652"],"issn-type":[{"value":"0021-9541","type":"print"},{"value":"1097-4652","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,30]]},"assertion":[{"value":"2021-10-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-01-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}