{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T20:36:33Z","timestamp":1791491793982,"version":"4.3.4"},"reference-count":62,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2026,1,2]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>Patients with sepsis-induced acute lung injury (ALI)\/acute respiratory distress syndrome (ARDS) commonly suffer from severe pulmonary thrombosis, but clinical trials of anticoagulant therapies in patients with sepsis and ARDS have failed. Patients with ARDS plus thrombocytopenia also exhibit increased mortality, and widespread pulmonary thrombosis is often seen in patients with COVID-19 ARDS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      Different amounts of microbeads were administered intravenously to adult mice to induce various levels of pulmonary thrombosis. ALI was induced by either intraperitoneal lipopolysaccharide or cecal ligation and puncture. Endothelial cell (EC)\u2013targeted nanoparticles were used to deliver plasmid DNA expressing the CRISPR\/Cas9 (clustered regularly interspaced short palindromic repeats\/clustered regularly interspaced short palindromic repeat\u2013associated 9) system for EC-specific gene knockout of Alox15 (arachidonate 15-lipoxygenase) or plasmid DNA expressing Alox15 for EC-specific overexpression. Lipidomic profiling and in vivo rescue studies with the identified Alox15-regulated lipids were performed. In addition, thrombocytopenia was induced by genetic depletion of platelets using\n                      <jats:italic toggle=\"yes\">DTR<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">Pf4Cre<\/jats:italic>\n                      <\/jats:sup>\n                      mice, and the effects of restoration of pulmonary thrombosis were assessed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We show that although severe pulmonary thrombosis or thrombocytopenia augments sepsis-induced ALI, the induction of mild pulmonary thrombosis conversely reduces EC apoptosis, ALI, and mortality via sustained expression of endothelial Alox15. Endothelial\n                      <jats:italic toggle=\"yes\">Alox15<\/jats:italic>\n                      knockout in adult mice abolished the protective impact of mild lung thrombosis. Conversely, overexpression of endothelial\n                      <jats:italic toggle=\"yes\">Alox15<\/jats:italic>\n                      inhibited the increases in ALI caused by severe pulmonary thrombosis. Treatment of the endothelial\n                      <jats:italic toggle=\"yes\">Alox15<\/jats:italic>\n                      knockout mice with 1-palmitoyl-2-oleoyl-3-arachidonoyl-rac-glycerol (C\n                      <jats:sub>57<\/jats:sub>\n                      H\n                      <jats:sub>100<\/jats:sub>\n                      O\n                      <jats:sub>6<\/jats:sub>\n                      ), a top candidate of the 32 Alox15-regulated lipids identified by lipidomic profiling, markedly reversed the defective phenotype, suggesting that Alox15 protects from lung injury via protective lipids. The clinical relevance of the findings was supported by the observation of reduced ALOX15-expressing ECs in lung autopsy samples of patients with ARDS. In addition, restoration of pulmonary thrombosis in thrombocytopenic mice normalized endotoxemia-induced ALI.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>We have demonstrated that moderate levels of lung thrombosis protect against sepsis-induced inflammatory lung injury via endothelial Alox15. Overexpression of endothelial Alox15 inhibits severe pulmonary thrombosis-induced increases in ALI. Thus, upregulation of ALOX15 expression or treatment with ALOX15-dependent protective lipid(s) represents a promising therapeutic strategy for treatment of ARDS, especially in subpopulations of patients with thrombocytopenia or widespread pulmonary thrombosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.326357","type":"journal-article","created":{"date-parts":[[2025,11,14]],"date-time":"2025-11-14T10:00:18Z","timestamp":1763114418000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":7,"title":["The Unexpected Protective Role of Thrombosis in Lung Injury via Endothelial Alox15"],"prefix":"10.1161","volume":"138","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9251-357X","authenticated-orcid":true,"given":"Colin E.","family":"Evans","sequence":"first","affiliation":[{"name":"Program for Lung and Vascular Biology (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Division of Critical Care, Department of Pediatrics (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Northwestern University Feinberg School of Medicine, Chicago, IL."},{"name":"Now with Department of Cell Biology and Anatomy, Cardiovascular Translational Research Center, University of South Carolina School of Medicine, Columbia, SC (C.E.E.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3797-1014","authenticated-orcid":true,"given":"Sushreesangita P.","family":"Behera","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Pediatric Genetic Medicine and Nanotechnology Development Center (GeneMeNDer), Stanley Manne Children\u2019s Research Institute (S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-1175-7109","authenticated-orcid":true,"given":"Xianming","family":"Zhang","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Pediatric Genetic Medicine and Nanotechnology Development Center (GeneMeNDer), Stanley Manne Children\u2019s Research Institute (S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Division of Critical Care, Department of Pediatrics (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Northwestern University Feinberg School of Medicine, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9929-7144","authenticated-orcid":true,"given":"Narsa","family":"Machireddy","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Pediatric Genetic Medicine and Nanotechnology Development Center (GeneMeNDer), Stanley Manne Children\u2019s Research Institute (S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Division of Critical Care, Department of Pediatrics (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Northwestern University Feinberg School of Medicine, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7609-8476","authenticated-orcid":true,"given":"Kefyalew D.","family":"Addisu","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Pediatric Genetic Medicine and Nanotechnology Development Center (GeneMeNDer), Stanley Manne Children\u2019s Research Institute (S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Division of Critical Care, Department of Pediatrics (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Northwestern University Feinberg School of Medicine, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0508-5043","authenticated-orcid":true,"given":"Mollie","family":"Phillips","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, Cardiovascular Translational Research Center, University of South Carolina School of Medicine, Columbia (M.P., R.D., M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana","family":"Dhar","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, Cardiovascular Translational Research Center, University of South Carolina School of Medicine, Columbia (M.P., R.D., M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2681-6134","authenticated-orcid":true,"given":"Mrinmay","family":"Chakrabarti","sequence":"additional","affiliation":[{"name":"Department of Cell Biology and Anatomy, Cardiovascular Translational Research Center, University of South Carolina School of Medicine, Columbia (M.P., R.D., M.C.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1378-6594","authenticated-orcid":true,"given":"Bowen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Surgery (B.W.), Northwestern University Feinberg School of Medicine, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odile","family":"David","sequence":"additional","affiliation":[{"name":"Department of Pathology, the University of Illinois at Chicago (O.D.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0041-0339","authenticated-orcid":true,"given":"You-Yang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Program for Lung and Vascular Biology (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Section for Injury Repair and Regeneration Research, Stanley Manne Children\u2019s Research Institute (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Pediatric Genetic Medicine and Nanotechnology Development Center (GeneMeNDer), Stanley Manne Children\u2019s Research Institute (S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Ann &amp; Robert H. Lurie Children\u2019s Hospital of Chicago, IL."},{"name":"Division of Critical Care, Department of Pediatrics (C.E.E., S.P.B., X.Z., N.M., K.D.A., Y.-Y.Z.), Northwestern University Feinberg School of Medicine, Chicago, IL."},{"name":"Division of Pulmonary and Critical Care Medicine, Departments of Pharmacology and Medicine (Y.-Y.Z.), Northwestern University Feinberg School of Medicine, Chicago, IL."},{"name":"Feinberg Cardiovascular and Renal Research Institute (Y.-Y.Z.), Northwestern University Feinberg School of Medicine, Chicago, IL."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0069-0"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcibr1007320"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa050333"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200204-302OC"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-199707000-00010"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200005043421806"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI60331"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2015432"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202009-3629ED"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abj7790"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(20)30434-5"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1186\/2052-0492-1-9"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrtlng.2009.07.005"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0094124"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-200107001-00030"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.37"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199908193410807"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00441.2016"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0034-1398376"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.thromres.2011.10.013"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.04.00065504"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00338.2002"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2002-06-1887"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2020.10.001"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.vph.2008.06.009"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2015-207461"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12931-015-0266-7"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.186.11.1831"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI27154"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1159\/000024011"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115388"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2005.01.012"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01634-2020"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1202290"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1097\/CCM.0b013e31828e9b03"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-200111000-00003"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(20)30470-7"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.110.215038"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1242\/bio.024653"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.020918"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.110196"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1111\/jth.12795"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2016.12.004"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2018.00189"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1177\/0310057X0403200502"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2007-0443OC"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2008.06.021"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-27221-7"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.171.12.6856"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0802592"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1186\/cc11518"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1900808"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.116.306853"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1159\/000453002"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-05-787259"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2019.04.014"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abm5755"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.001371"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2015-09-671982"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkq1039"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201709-1835oc"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.116.021494"}],"container-title":["Circulation Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCRESAHA.125.326357","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T19:00:27Z","timestamp":1767380427000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCRESAHA.125.326357"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,2]]},"references-count":62,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1,2]]}},"alternative-id":["10.1161\/CIRCRESAHA.125.326357"],"URL":"https:\/\/doi.org\/10.1161\/circresaha.125.326357","relation":{},"ISSN":["0009-7330","1524-4571"],"issn-type":[{"value":"0009-7330","type":"print"},{"value":"1524-4571","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,2]]},"assertion":[{"value":"2025-02-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-07","order":1,"name":"revised","label":"Revised","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-14","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}