Rong Zhang1, Ying Pan1, Vito Fanelli2,3, Sulong Wu1, Alice Aili Luo3, Diana Islam3, Bing Han3, Pu Mao1, Mirna Ghazarian3, Wenmei Zeng1,3, Peter M Spieth3,4, Dingyan Wang3, Julie Khang3, Hongyin Mo1, Xiaoqing Liu1, Stefan Uhlig5, Mingyao Liu6, John Laffey3,6,7,8, Arthur S Slutsky1,3,8, Yimin Li1, Haibo Zhang1,3,6,7,8. 1. 1 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. 2. 2 Department of Anesthesia and Critical Care, University of Turin, AOU Città della Salute e della Scienza di Torino-Ospedale Molinette, Turin, Italy. 3. 3 The Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada. 4. 4 Department of Anesthesiology and Intensive Care Medicine, Technische Universität, Dresden, Germany. 5. 5 Faculty of Medicine, RWTH Aachen University, Aachen, Germany; and. 6. 6 Department of Physiology. 7. 7 Department of Anesthesia, and. 8. 8 Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada.
Abstract
RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.
RATIONALE: 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. OBJECTIVES: 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. MEASUREMENTS AND MAIN 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.