• A A Luo, V Fanelli, P M Spieth, S Uhlig, J Laffey, A S Slutsky, and H Zhang.
• 1St. Michaels Hospital, University of Toronto 2Department of Anesthesia and Critical Care, University of Turin, Italy 3Department of Anesthesiology and Intensive Care Medicine, Technische Universität Dresden, Germany 4Faculty of Medicine, RWTH Aachen University, Germany.
• Shock. 2015 Oct 1;44 Suppl 2:9.

IntroductionThe mortality rate of acute respiratory distress syndrome (ARDS) remains unacceptably high despite that lung protective ventilatory strategies have been widely used. Pharmacological therapy is required to further reduce ARDS mortality. Mechanical ventilation is associated with oxidative stress and lung fibrosis, which may contribute to increased mortality and poor quality of life in ARDS. We hypothesized that the cytokine, midkine (MK), that can be upregulated during oxidative stress, facilitates the development of ARDS- associated lung fibrosis.MethodsPlasma samples were collected from 17 ARDS patients and 10 healthy volunteers. Wild type and MK gene deficient (MK-/-) mice received HCl aspiration and mechanical ventilation, and were monitored for 14 days for assessment of lung injury. Human lung epithelial cells were challenged with HCl followed by mechanical stretch for 72 h for studying MK signaling.ResultsPlasma concentrations of MK were higher in ARDS patients than in healthy donors. 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. Mechanical stretch of human lung epithelial cells resulted epithelial-mesenchymal transition (EMT) profiles associated with increased expression of NADPH oxidase1 (Nox1) angiotensin-converting enzyme (ACE), which was attenuated by silencing Nox1, MK, or the MK receptor Notch2.ConclusionMK may serves as a biomarker for ARDS, as well as acting as an effector activating MK- Notch2-ACE signaling pathway, contributing to lung remodeling. The MK appears to be a potential therapeutic target in the context of ARDS associated lung fibrosis.

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