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We hypothesized that the novel cytokine, midkine (MK), which can be up-regulated in oxidative stress, plays a key role in the pathogenesis of ARDS-associated lung fibrosis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Blood samples were collected from 17 patients with ARDS and 10 healthy donors. Human lung epithelial cells were challenged with hydrogen chloride followed by mechanical stretch for 72 hours. Wild-type and MK gene\u2013deficient (MK\u2212\/\u2212) mice received two-hit injury of acid aspiration and mechanical ventilation, and were monitored for 14 days.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Plasma concentrations of MK were higher in patients with ARDS than in healthy volunteers. Exposure to mechanical stretch of lung epithelial cells led to an epithelial\u2013mesenchymal transition profile associated with increased expression of angiotensin-converting enzyme, which was attenuated by silencing MK, its receptor Notch2, or NADP reduced oxidase 1. An increase in collagen deposition and hydroxyproline level and a decrease in lung tissue compliance seen in wild-type mice were largely attenuated in MK\u2212\/\u2212 mice.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Mechanical stretch can induce an epithelial\u2013mesenchymal transition phenotype mediated by the MK\u2013Notch2\u2013angiotensin-converting enzyme signaling pathway, contributing to lung remodeling. The MK pathway is a potential therapeutic target in the context of ARDS-associated lung fibrosis.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201412-2326oc","type":"journal-article","created":{"date-parts":[[2015,5,6]],"date-time":"2015-05-06T11:04:59Z","timestamp":1430910299000},"page":"315-323","source":"Crossref","is-referenced-by-count":108,"title":["Mechanical Stress and the Induction of Lung Fibrosis via the Midkine Signaling Pathway"],"prefix":"10.1093","volume":"192","author":[{"given":"Rong","family":"Zhang","sequence":"first","affiliation":[{"name":"The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Pan","sequence":"additional","affiliation":[{"name":"The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First 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