title: Mechanical Stress and the Induction of Lung Fibrosis via the Midkine Signaling Pathway.
abstract: BACKGROUND
  Lung-protective ventilatory strategies have been widely used in patients with acute respiratory distress syndrome (ARDS), but the ARDS mortality rate remains unacceptably high and there is no proven pharmacologic therapy.
  
  
  OBJECTIVE
  Mechanical ventilation can induce oxidative stress and lung fibrosis, which may contribute to high dependency on ventilator support and increased ARDS mortality. 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.
  
  
  METHODS
  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-deficient (MK(-/-)) mice received two-hit injury of acid aspiration and mechanical ventilation, and were monitored for 14 days.
  
  
  RESULTS
  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-mesenchymal 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(-/-) mice.
  
  
  CONCLUSIONS
  Mechanical stretch can induce an epithelial-mesenchymal transition phenotype mediated by the MK-Notch2-angiotensin-converting enzyme signaling pathway, contributing to lung remodeling. The MK pathway is a potential therapeutic target in the context of ARDS-associated lung fibrosis.
authors.affiliation: 1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: 1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Pan
authors.affiliation: 2 Department of Anesthesia and Critical Care, University of Turin, AOU Città della Salute e della Scienza di Torino-Ospedale Molinette, Turin, Italy.|3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Vito
authors.initials: V
authors.lastname: Fanelli
authors.affiliation: 1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Sulong
authors.initials: S
authors.lastname: Wu
authors.affiliation: 3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Alice Aili
authors.initials: AA
authors.lastname: Luo
authors.affiliation: 3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Diana
authors.initials: D
authors.lastname: Islam
authors.affiliation: 3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: 1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Pu
authors.initials: P
authors.lastname: Mao
authors.affiliation: 3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Mirna
authors.initials: M
authors.lastname: Ghazarian
authors.affiliation: 1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.|3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Wenmei
authors.initials: W
authors.lastname: Zeng
authors.affiliation: 3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.|4 Department of Anesthesiology and Intensive Care Medicine, Technische Universität, Dresden, Germany.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Spieth
authors.affiliation: 3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Dingyan
authors.initials: D
authors.lastname: Wang
authors.affiliation: 3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Khang
authors.affiliation: 1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Hongyin
authors.initials: H
authors.lastname: Mo
authors.affiliation: 1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Liu
authors.affiliation: 5 Faculty of Medicine, RWTH Aachen University, Aachen, Germany; and.
authors.forename: Stefan
authors.initials: S
authors.lastname: Uhlig
authors.affiliation: 6 Department of Physiology.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.affiliation: 3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.|6 Department of Physiology.|7 Department of Anesthesia, and.|8 Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: John
authors.initials: J
authors.lastname: Laffey
authors.affiliation: 1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.|3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.|8 Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Slutsky
authors.affiliation: 1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Li
authors.affiliation: 1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.|3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.|6 Department of Physiology.|7 Department of Anesthesia, and.|8 Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Haibo
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000097:blood*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D000078792:Midkine; D011658:Pulmonary Fibrosis / Q000097:blood / Q000503:physiopathology*; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*; D013314:Stress, Mechanical
chemical_list: D016207:Cytokines; D000078792:Midkine
keywords: angiotensin-converting enzyme; lung injury; mechanical ventilation