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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 ARDSmortality. 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 sampleswere collected from 17 patients withARDSand 10 healthy donors.Human lung epithelial cells were challenged with hydrogen chloride followed by mechanical stretch for 72 hours.Wild-type andMK gene-deficient (MK2/2) 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 MK2/2 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.
Keywords: lung injury; mechanical ventilation; angiotensinconverting enzyme
Acute respiratory distress syndrome (ARDS) remains a major clinical challenge in critically ill patients (1, 2). Mechanical ventilation is often necessary, but can induce or aggravate lung injury, an entity referred to as ventilator-induced lung injury (3). Lung-protective strategies that reduce lung stretch have led to decreased ARDS mortality, likely by minimizing biotrauma, a major contributor to ventilator-induced lung injury (4, 5). However, ARDS mortality rate remains unacceptably high and there is no proven pharmacologic therapy (6).
ARDS represents a stereotypic response to lung injury with transition from exudative inflammatory responses, with epithelial-capillary barrier damage, to a fibroproliferative phase. Most patients with ARDS survive the acute phase, but many succumb to death, often in association with pulmonary fibrosis (7). Progressive pulmonary fibrosis also contributes to the poor quality of...