{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:39:11Z","timestamp":1790948351033,"version":"4.1.0"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2015,12,10]],"date-time":"2015-12-10T00:00:00Z","timestamp":1449705600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2015,12,10]],"date-time":"2015-12-10T00:00:00Z","timestamp":1449705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Despite decades of research, the pathogenesis of acute respiratory distress syndrome (ARDS) remains poorly understood, thus impeding the development of effective treatment. Diffuse alveolar damage (DAD) and lung epithelial cell death are prominent features of ARDS. Lung epithelial cells are the first line of defense after inhaled stimuli, such as in the case of hyperoxia. We hypothesized that lung epithelial cells release \u2018messenger\u2019 or signaling molecules to adjacent or distant macrophages, thereby initiating or propagating inflammatory responses after noxious insult. We found that, after hyperoxia, a large amount of extracellular vesicles (EVs) were generated and released into bronchoalveolar lavage fluid (BALF). These hyperoxia-induced EVs were mainly derived from live lung epithelial cells as the result of hyperoxia-associated endoplasmic reticulum (ER) stress. These EVs were remarkably different from epithelial \u2018apoptotic bodies\u2019, as reflected by the significantly smaller size and differentially expressed protein markers. These EVs fall mainly in the size range of the exosomes and smaller microvesicles (MVs) (50\u2013120\u2009nm). The commonly featured protein markers of apoptotic bodies were not found in these EVs. Treating alveolar macrophages with hyperoxia-induced, epithelial cell-derived EVs led to an increased secretion of pro-inflammatory cytokines and macrophage inflammatory protein 2 (MIP-2). Robustly increased macrophage and neutrophil influx was found in the lung tissue of the mice intranasally treated with hyperoxia-induced EVs. It was determined that EV-encapsulated caspase-3 was largely responsible for the alveolar macrophage activation\n                    <jats:italic>via<\/jats:italic>\n                    the ROCK1 pathway. Caspase-3-deficient EVs induced less cytokine\/MIP-2 release, reduced cell counts in BALF, less neutrophil infiltration and less inflammation in lung parenchyma, both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . Furthermore, the serum circulating EVs were increased and mainly derived from lung epithelial cells after hyperoxia exposure. These circulating EVs also activated systemic macrophages other than the alveolar ones. Collectively, the results show that hyperoxia-induced, lung epithelial cell-derived and caspase-3 enriched EVs activate macrophages and mediate the inflammatory lung responses involved in lung injury.\n                  <\/jats:p>","DOI":"10.1038\/cddis.2015.282","type":"journal-article","created":{"date-parts":[[2015,12,10]],"date-time":"2015-12-10T08:44:13Z","timestamp":1449737053000},"page":"e2016-e2016","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":152,"title":["Lung epithelial cell-derived extracellular vesicles activate macrophage-mediated inflammatory responses via ROCK1 pathway"],"prefix":"10.1038","volume":"6","author":[{"given":"H-G","family":"Moon","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J H","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H S","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,12,10]]},"reference":[{"key":"BFcddis2015282_CR1","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1056\/NEJMoa050333","volume":"353","author":"GD Rubenfeld","year":"2005","unstructured":"Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M et al. Incidence and outcomes of acute lung injury. N Engl J Med 2005; 353: 1685\u20131693.","journal-title":"N Engl J Med"},{"key":"BFcddis2015282_CR2","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1196\/annals.1299.074","volume":"1010","author":"A Pagano","year":"2003","unstructured":"Pagano A, Barazzone-Argiroffo C . Alveolar cell death in hyperoxia-induced lung injury. Ann NY Acad Sci 2003; 1010: 105\u2013116.","journal-title":"Ann NY Acad Sci"},{"key":"BFcddis2015282_CR3","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1152\/jappl.1988.64.3.1079","volume":"64","author":"WJ Lamm","year":"1988","unstructured":"Lamm WJ, Luchtel D, Albert RK . Sites of leakage in three models of acute lung injury. J Appl Physiol 1988; 64: 1079\u20131083.","journal-title":"J Appl Physiol"},{"key":"BFcddis2015282_CR4","doi-asserted-by":"publisher","first-page":"1535","DOI":"10.1152\/japplphysiol.00519.2004","volume":"97","author":"X Li","year":"2004","unstructured":"Li X, Shu R, Filippatos G, Bhal BM . Apoptosis in lung injury and remodeling. J Appl Physiol 2004; 97: 1535\u20131542.","journal-title":"J Appl Physiol"},{"key":"BFcddis2015282_CR5","doi-asserted-by":"publisher","first-page":"6653","DOI":"10.2741\/3179","volume":"13","author":"V Bhandari","year":"2008","unstructured":"Bhandari V . Molecular mechanisms of hyperoxia-induced acute lung injury. Front Biosci 2008; 13: 6653\u20136661.","journal-title":"Front Biosci"},{"key":"BFcddis2015282_CR6","doi-asserted-by":"publisher","first-page":"L379","DOI":"10.1152\/ajplung.00010.2008","volume":"295","author":"G Matute-Bello","year":"2008","unstructured":"Matute-Bello G, Frevert CW, Martin TR . Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 2008; 295: L379\u2013L399.","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"BFcddis2015282_CR7","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1002\/ar.21102","volume":"293","author":"D Jiang","year":"2010","unstructured":"Jiang D, Liang J, Noble PW . Regulation of non-infectious lung injury, inflammation, and repair by the extracellular matrix glycosaminoglycan hyaluronan. Anat Rec (Hoboken) 2010; 293: 982\u2013985.","journal-title":"Anat Rec (Hoboken)"},{"key":"BFcddis2015282_CR8","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1165\/rcmb.2009-0210ST","volume":"44","author":"G Matute-Bello","year":"2011","unstructured":"Matute-Bello G, Frevert CW, Martin TR . An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol 2011; 44: 725\u2013738.","journal-title":"Am J Respir Cell Mol Biol"},{"key":"BFcddis2015282_CR9","doi-asserted-by":"publisher","first-page":"C182","DOI":"10.1152\/ajpcell.00086.2013","volume":"305","author":"J Fukumoto","year":"2013","unstructured":"Fukumoto J, Fukumoto I, Parthasarathy PT, Cox R, Huynh B, Ramanathan GK et al. NLRP3 deletion protects from hyperoxia-induced acute lung injury. Am J Physiol Cell Physiol 2013; 305: C182\u2013C189.","journal-title":"Am J Physiol Cell Physiol"},{"key":"BFcddis2015282_CR10","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/nrd3978","volume":"12","author":"S EL Andaloussi","year":"2013","unstructured":"EL Andaloussi S, M\u00e4ger I, Breakefield XO, Woods MJ . Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov 2013; 12: 347\u2013357.","journal-title":"Nat Rev Drug Discov"},{"key":"BFcddis2015282_CR11","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1038\/ni.2647","volume":"14","author":"J Li","year":"2013","unstructured":"Li J, Liu K, Liu Y, Xu Y, Zhang F, Yang H et al. Exosomes mediate the cell-to-cell transmission of IFN-\u03b1-induced antiviral activity. Nat Immunol 2013; 14: 791\u2013803.","journal-title":"Nat Immunol"},{"key":"BFcddis2015282_CR12","first-page":"537","volume":"71","author":"J Qin","year":"2014","unstructured":"Qin J, Xu Q . Functions and application of exosomes. Acta Pol Pharm 2014; 71: 537\u2013543.","journal-title":"Acta Pol Pharm"},{"key":"BFcddis2015282_CR13","doi-asserted-by":"publisher","first-page":"531","DOI":"10.5483\/BMBRep.2014.47.10.164","volume":"17","author":"YJ Yoon","year":"2014","unstructured":"Yoon YJ, Kim OY, Gho YS . Extracellular vesicles as emerging intercellular communicasomes. BMM Rep 2014; 17: 531\u2013539.","journal-title":"BMM Rep"},{"key":"BFcddis2015282_CR14","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nri2567","volume":"9","author":"C Th\u00e9ry","year":"2009","unstructured":"Th\u00e9ry C, Ostrowski M, Segura E . Membrane vesicles as conveyors of immune responses. Nat Immunol 2009; 9: 581\u2013593.","journal-title":"Nat Immunol"},{"key":"BFcddis2015282_CR15","doi-asserted-by":"publisher","first-page":"12844","DOI":"10.1128\/JVI.05853-11","volume":"85","author":"Jr Meckes DG","year":"2011","unstructured":"Meckes Jr DG, Rab-Traub N . Microvesicles and viral infection. J Virol 2011; 85: 12844\u201312854.","journal-title":"J Virol"},{"key":"BFcddis2015282_CR16","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1016\/j.micinf.2012.07.008","volume":"14","author":"AC Torrecilhas","year":"2012","unstructured":"Torrecilhas AC, Schumacher RI, Alves MJ, Colli W . Vesicles as carriers of virulence factors in parasitic protozoan diseases. Microbes Infect 2012; 14: 1465\u20131474.","journal-title":"Microbes Infect"},{"key":"BFcddis2015282_CR17","doi-asserted-by":"publisher","first-page":"29","DOI":"10.2174\/1871528111312010005","volume":"12","author":"HM Hosseini","year":"2013","unstructured":"Hosseini HM, Fooladi AA, Nourani MR, Ghanezadeh F . The role of exosomes in infectious diseases. Inflamm Allergy Drug Targets 2013; 12: 29\u201337.","journal-title":"Inflamm Allergy Drug Targets"},{"key":"BFcddis2015282_CR18","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1016\/j.imlet.2006.09.005","volume":"107","author":"S Keller","year":"2006","unstructured":"Keller S, Sanderson MP, Stoeck A, Alteveogt P . Exosomes: from biogenesis and secretion to biological function. Immunol Lett 2006; 107: 102\u2013108.","journal-title":"Immunol Lett"},{"key":"BFcddis2015282_CR19","doi-asserted-by":"publisher","first-page":"3234","DOI":"10.1182\/blood-2007-03-079152","volume":"110","author":"S Bhatnagar","year":"2007","unstructured":"Bhatnagar S, Shinagawa K, Castellino FJ, Schorey JS . Exosomes released from macrophages infected with intracellular pathogens stimulate a proinflammatory response in vitro and in vivo. Blood 2007; 110: 3234\u20133244.","journal-title":"Blood"},{"key":"BFcddis2015282_CR20","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.1016\/j.freeradbiomed.2011.02.031","volume":"50","author":"M Zhang","year":"2011","unstructured":"Zhang M, Lee SJ, An C, Xu JF, oshi B, Nabi IR et al. Caveolin-1 mediates Fas-BID signaling in hyperoxia-induced apoptosis. Free Radic Biol Med 2011; 50: 1252\u20131262.","journal-title":"Free Radic Biol Med"},{"key":"BFcddis2015282_CR21","doi-asserted-by":"publisher","first-page":"1742","DOI":"10.1016\/j.freeradbiomed.2009.09.022","volume":"47","author":"JS Gewandter","year":"2009","unstructured":"Gewandter JS, Staversky RJ, O'Reilly MA . Hyperoxia augments ER-stress-induced cell death independent of BiP loss. Free Radic Biol Med 2009; 47: 1742\u20131752.","journal-title":"Free Radic Biol Med"},{"key":"BFcddis2015282_CR22","first-page":"a008659","volume":"5","author":"DR Mcllwain","year":"2013","unstructured":"Mcllwain DR, Berger T, Mak TW . Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 2013; 5: a008659.","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"BFcddis2015282_CR23","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1186\/1472-6750-8-92","volume":"8","author":"HJ Kang","year":"2008","unstructured":"Kang HJ, Lee YM, Jeong YJ, Park K, Jang M, Park SG et al. Large-scale preparation of active caspase-3 in E. coli by designing its thrombin-activatable precursors. BMC Biotechnol 2008; 8: 92.","journal-title":"BMC Biotechnol"},{"key":"BFcddis2015282_CR24","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1002\/ijc.10832","volume":"103","author":"E Ueta","year":"2003","unstructured":"Ueta E, Kamatani T, Yamamoto T, Osaki T . Tyrosine-nitration of caspase 3 and cytochrome c does not suppress apoptosis induction in squamous cell carcinoma cells. Int J Cancer 2003; 103: 717\u2013722.","journal-title":"Int J Cancer"},{"key":"BFcddis2015282_CR25","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nri3600","volume":"14","author":"T Hussell","year":"2014","unstructured":"Hussell T, Bell TJ . Alveolar macrhopages: plasticity in a tissue-specific context. Nat Rev Immunol 2014; 14: 81\u201393.","journal-title":"Nat Rev Immunol"},{"key":"BFcddis2015282_CR26","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/nri2215","volume":"8","author":"H Kono","year":"2008","unstructured":"Kono H, Rock KL . How dying cells alert the immune system to danger. Nat Rev Immunol 2008; 8: 279\u2013289.","journal-title":"Nat Rev Immunol"},{"key":"BFcddis2015282_CR27","doi-asserted-by":"crossref","first-page":"5391","DOI":"10.4049\/jimmunol.159.11.5391","volume":"159","author":"M Bellone","year":"1997","unstructured":"Bellone M, Iezzi G, Rovere P, Galati G, Ronchetti A, Protti MP et al. Processing of engulfed apoptotic bodies yields T cell epitopes. J Immunol 1997; 159: 5391\u20135399.","journal-title":"J Immunol"},{"key":"BFcddis2015282_CR28","doi-asserted-by":"publisher","first-page":"20684","DOI":"10.1073\/pnas.1116848108","volume":"108","author":"Y Berda-Haddad","year":"2011","unstructured":"Berda-Haddad Y, Robert S, Salers P, Zekraoui L, Farnariere C, Dinarello CA et al. Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1\u03b1. Proc Natl Acad Sci USA 2011; 108: 20684\u201320689.","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFcddis2015282_CR29","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1681\/ASN.2010040430","volume":"22","author":"DL Rosin","year":"2011","unstructured":"Rosin DL, Okusa MD . Dangers within: DAMP responses to damage and cell death in kidney disease. J Am Soc Nephrol 2011; 22: 416\u2013425.","journal-title":"J Am Soc Nephrol"},{"key":"BFcddis2015282_CR30","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1038\/nri2725","volume":"10","author":"J Tschopp","year":"2010","unstructured":"Tschopp J, Schroder K . NLRP3 inflammasome activation: The convergence of multiple signalling pathways on ROS production? Nat Rev Immunol 2010; 10: 210\u2013215.","journal-title":"Nat Rev Immunol"},{"key":"BFcddis2015282_CR31","doi-asserted-by":"publisher","first-page":"1844","DOI":"10.1016\/j.bbamcr.2013.03.013","volume":"1833","author":"AN B\u00f6ing","year":"2013","unstructured":"B\u00f6ing AN, Stap J, Hau CM, Afink GB, Ris-Stalpers C, Reits EA et al. Active caspase-3 is removed from cells by release of caspase-3-enriched vesicles. Biochim Biophys Acta 2013; 1833: 1844\u20131852.","journal-title":"Biochim Biophys Acta"},{"key":"BFcddis2015282_CR32","doi-asserted-by":"publisher","first-page":"4445","DOI":"10.1172\/JCI76246","volume":"124","author":"F Loison","year":"2014","unstructured":"Loison F, Zhu H, Karatepe K, Kasorn A, Liu P, Ye K et al. Proteinase 3-dependent caspase-3 cleavage modulates neutrophil death and inflammation. J Clin Invest 2014; 124: 4445\u20134458.","journal-title":"J Clin Invest"},{"key":"BFcddis2015282_CR33","first-page":"165","volume":"34","author":"MV Fiandalo","year":"2012","unstructured":"Fiandalo MV, Kyprianou N . Caspase control: protagonists of cancer cell apoptosis. Exp Oncol 2012; 34: 165\u2013175.","journal-title":"Exp Oncol"},{"key":"BFcddis2015282_CR34","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/1756-6606-5-15","volume":"14","author":"Z Li","year":"2012","unstructured":"Li Z, Sheng M . Caspases in synaptic plasticity. Mol Brain 2012; 14: 15.","journal-title":"Mol Brain"},{"key":"BFcddis2015282_CR35","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1016\/j.stem.2008.03.012","volume":"2","author":"V Janzen","year":"2008","unstructured":"Janzen V, Fleming HE, Riedt T, Karlsson G, Riese MJ, Lo Celso C et al. Hematopoietic stem cell responsiveness to exogenous signals is limited by caspase-3. Cell Stem Cell 2008; 2: 584\u2013594.","journal-title":"Cell Stem Cell"},{"key":"BFcddis2015282_CR36","doi-asserted-by":"publisher","first-page":"e725","DOI":"10.1038\/cddis.2013.250","volume":"11","author":"K Boland","year":"2013","unstructured":"Boland K, Flanagan L, Prehn JH . Paracrine control of tissue regeneration and cell proliferation by Caspase-3. Cell Death Dis 2013; 11: e725.","journal-title":"Cell Death Dis"},{"key":"BFcddis2015282_CR37","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1038\/cdd.2010.140","volume":"18","author":"AS Gabet","year":"2011","unstructured":"Gabet AS, Coulon S, Fricot A, Vandekerckhove J, Chang Y, Ribeil JA et al. Caspase-activated ROCK-1 allows erythroblast terminal maturation independently of cytokine-induced Rho signaling. Cell Death Differ 2011; 18: 678\u2013689.","journal-title":"Cell Death Differ"},{"key":"BFcddis2015282_CR38","doi-asserted-by":"publisher","first-page":"339","DOI":"10.1038\/35070009","volume":"3","author":"ML Coleman","year":"2001","unstructured":"Coleman ML, Sahai EA, Yeo M, Bosch M, Dewar A, Olson MF . Membrane blebbing during apoptosis results from caspase-mediated activation of ROCK I. Nat Cell Biol 2001; 3: 339\u2013345.","journal-title":"Nat Cell Biol"},{"key":"BFcddis2015282_CR39","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/s10059-013-0154-2","volume":"36","author":"I Hwang","year":"2013","unstructured":"Hwang I . Cell-cell communication via extracellular membrane vesicles and its role in the immune response. Mol Cells 2013; 36: 105\u2013111.","journal-title":"Mol Cells"},{"key":"BFcddis2015282_CR40","doi-asserted-by":"publisher","first-page":"C621","DOI":"10.1152\/ajpcell.00228.2013","volume":"306","author":"G Turturici","year":"2014","unstructured":"Turturici G, Tinnirello R, Sconzo G, Geraci F . Extracellular membrane vesicles as a mechanism of cell-to-cell communication: advantages and disadvantages. Am J Physiol Cell Physiol 2014; 306: C621\u2013C633.","journal-title":"Am J Physiol Cell Physiol"},{"key":"BFcddis2015282_CR41","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1002\/path.1291","volume":"199","author":"KN Lai","year":"2003","unstructured":"Lai KN, Leung JC, Metz CN, Lai FM, Bucala R, Lan HY . Role for macrophage migration inhibitory factor in acute respiratory distress syndrome. J Pathol 2003; 199: 496\u2013508.","journal-title":"J Pathol"},{"key":"BFcddis2015282_CR42","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1136\/thoraxjnl-2011-200590","volume":"67","author":"S Bertok","year":"2012","unstructured":"Bertok S, Wilson MR, Morley PJ, de Wildt R, Bayliffe A, Takata M . Selective inhibition of intra-alveolar p55 TNF receptor attenuates ventilator-induced lung injury. Thorax 2012; 67: 244\u2013251.","journal-title":"Thorax"},{"key":"BFcddis2015282_CR43","doi-asserted-by":"publisher","first-page":"1147","DOI":"10.1164\/rccm.201102-0327UP","volume":"183","author":"I Vad\u00e1sz","year":"2011","unstructured":"Vad\u00e1sz I, Sznajder JI . Update in acute lung injury and critical care 2010. Am J Respir Crit Care Med 2011; 183: 1147\u20131152.","journal-title":"Am J Respir Crit Care Med"}],"updated-by":[{"DOI":"10.1038\/s41419-020-2310-x","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2020,2,12]],"date-time":"2020-02-12T00:00:00Z","timestamp":1581465600000}}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/cddis2015282.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2015282","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/cddis2015282.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T05:14:17Z","timestamp":1672895657000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/cddis2015282"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,12,10]]},"references-count":43,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2015,12]]}},"alternative-id":["BFcddis2015282"],"URL":"https:\/\/doi.org\/10.1038\/cddis.2015.282","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,12,10]]},"assertion":[{"value":"24 April 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 August 2015","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 September 2015","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 December 2015","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}