{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:06:16Z","timestamp":1790856376078,"version":"4.1.0"},"reference-count":77,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,7,30]],"date-time":"2024-07-30T00:00:00Z","timestamp":1722297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>About 3% of patients with lupus develop severe diffuse alveolar hemorrhage (DAH) with pulmonary vasculitis. C57BL\/6 (B6) mice with pristane\u2010induced lupus also develop DAH, but BALB\/c mice are resistant. DAH is independent of Toll\u2010like receptor signaling and other inflammatory pathways. This study examined the role of the MEK1\/2 pathway (MEK1\/2\u2013ERK1\/2, JNK, p38).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>B6 and BALB\/c mice were treated with pristane with or without inhibitors of MEK1\/2 (trametinib\/GSK1120212 [GSK]), ERK1\/2 (SCH772984 [SCH]), JNK, or p38. Effects on lung hemorrhage and hemostasis were determined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      GSK and SCH abolished DAH, whereas JNK and p38 inhibitors were ineffective. Apoptotic cells were present in lung samples from pristane\u2010treated mice but not in mice receiving pristane and GSK, and endothelial dysfunction was normalized. Expression of the ERK1\/2\u2010regulated transcription factor early growth response 1 increased in pristane\u2010treated B6, but not BALB\/c, mice and was normalized by GSK. Pristane also increased expression of the anticoagulant genes\n                      <jats:italic>Tfpi<\/jats:italic>\n                      and\n                      <jats:italic>Thbd<\/jats:italic>\n                      in B6 mice. The ratio of\n                      <jats:italic>Tfpi<\/jats:italic>\n                      to tissue factor (\n                      <jats:italic>F3<\/jats:italic>\n                      ) to\n                      <jats:italic>Tfpi<\/jats:italic>\n                      increased in B6 (but not BALB\/c) mice and was normalized by GSK. Circulating thrombomodulin protein levels increased in B6 mice and returned to normal after GSK treatment. Consistent with augmented endothelial anticoagulant activity, pristane treatment increased tail bleeding in B6 mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Pristane treatment promotes lung endothelial injury and DAH in B6 mice by activating the MEK1\/2\u2013ERK1\/2 pathway and impairing hemostasis. The hereditary factors determining susceptibility to lung injury and bleeding in pristane\u2010induced lupus are relevant to the pathophysiology of life\u2010threatening DAH in systemic lupus erythematosus and may help to optimize therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/art.42936","type":"journal-article","created":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T00:38:34Z","timestamp":1719275914000},"page":"1538-1551","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<scp>MEK1<\/scp>\n                    \/2\u2010 and\n                    <scp>ERK1<\/scp>\n                    \/2\u2010Mediated Lung Endothelial Injury and Altered Hemostasis Promote Diffuse Alveolar Hemorrhage in Murine Lupus"],"prefix":"10.1002","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1203-1993","authenticated-orcid":false,"given":"Haoyang","family":"Zhuang","sequence":"first","affiliation":[{"name":"University of Florida College of Medicine  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6951-120X","authenticated-orcid":false,"given":"Shuhong","family":"Han","sequence":"additional","affiliation":[{"name":"University of Florida College of Medicine  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neil S.","family":"Harris","sequence":"additional","affiliation":[{"name":"University of Florida College of Medicine  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Westley H.","family":"Reeves","sequence":"additional","affiliation":[{"name":"University of Florida College of Medicine  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,7,30]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2011.108"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40077"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00051.2022"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.790043"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1177\/0961203320903798"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10067-022-06449-9"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/MJT.0000000000000427"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20080462"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.23023"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3495"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0070"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1629"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-2200"},{"issue":"1","key":"e_1_2_7_15_1","first-page":"23","article-title":"Antitumor activities of JTP\u201074057 (GSK1120212), a novel MEK1\/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo","volume":"39","author":"Yamaguchi T","year":"2011","journal-title":"Int J Oncol"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-8722-6-27"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.01.039"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-13-0513"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251194298"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0163-7258(00)00051-6"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38189"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2009.03.006"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2022.846216"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/physiolgenomics.00077.2002"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.00135"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc4000"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V98.5.1429"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-91442-8_7"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-17329-8"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1097\/MOH.0000000000000239"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/82168"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.76205"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI133780"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.575890"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-11-512764"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.14207"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1055\/a-1801-2055"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0042-1748193"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cegh.2023.101295"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxx031"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.117.309846"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-02-557538"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-018-0922-6"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2216455"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2516.2010.02321.x"},{"key":"e_1_2_7_46_1","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.56.7614"},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2012-201781"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.13307"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00408-012-9431-7"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00408-015-9720-z"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000000072"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.14814\/phy2.13071"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00408-016-9873-4"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1177\/0023677218811059"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-020-00687-7"},{"key":"e_1_2_7_56_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.188.12.2313"},{"key":"e_1_2_7_57_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.862522"},{"key":"e_1_2_7_58_1","doi-asserted-by":"publisher","DOI":"10.1093\/labmed\/lmx050"},{"key":"e_1_2_7_59_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00438-017-1365-6"},{"key":"e_1_2_7_60_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtha.2023.06.024"},{"key":"e_1_2_7_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2017.36"},{"key":"e_1_2_7_62_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1912409116"},{"key":"e_1_2_7_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2021.108764"},{"key":"e_1_2_7_64_1","doi-asserted-by":"publisher","DOI":"10.1097\/MBC.0b013e328337b475"},{"key":"e_1_2_7_65_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.073601"},{"key":"e_1_2_7_66_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10102509"},{"key":"e_1_2_7_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmcr.2021.101363"},{"key":"e_1_2_7_68_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semarthrit.2005.05.006"},{"key":"e_1_2_7_69_1","doi-asserted-by":"publisher","DOI":"10.1097\/RHU.0000000000001358"},{"key":"e_1_2_7_70_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.healun.2007.02.010"},{"key":"e_1_2_7_71_1","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201309-332LE"},{"key":"e_1_2_7_72_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.10816"},{"key":"e_1_2_7_73_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2018891192"},{"key":"e_1_2_7_74_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020003464"},{"key":"e_1_2_7_75_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2362.1997.2180766.x"},{"key":"e_1_2_7_76_1","doi-asserted-by":"publisher","DOI":"10.1111\/1756-185X.13458"},{"key":"e_1_2_7_77_1","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12248"},{"key":"e_1_2_7_78_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2008.03182.x"}],"container-title":["Arthritis &amp; Rheumatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/art.42936","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T20:20:34Z","timestamp":1759954834000},"score":1,"resource":{"primary":{"URL":"https:\/\/acrjournals.onlinelibrary.wiley.com\/doi\/10.1002\/art.42936"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,30]]},"references-count":77,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2024,10]]}},"alternative-id":["10.1002\/art.42936"],"URL":"https:\/\/doi.org\/10.1002\/art.42936","archive":["Portico"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.05.07.593006","asserted-by":"object"}]},"ISSN":["2326-5191","2326-5205"],"issn-type":[{"value":"2326-5191","type":"print"},{"value":"2326-5205","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,30]]},"assertion":[{"value":"2023-10-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-30","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}