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Induction of cellular antioxidant defense by amifostine improves ventilator-induced lung injury*

Fu, Panfeng PhD; Murley, Jeffrey S. PhD; Grdina, David J. PhD; Birukova, Anna A. MD; Birukov, Konstantin G. MD, PhD

doi: 10.1097/CCM.0b013e3182284a5f
Laboratory Investigations

Objectives: To test the hypothesis that preconditioning animals with amifostine improves ventilator-induced lung injury via induction of antioxidant defense enzymes. Mechanical ventilation at high tidal volume induces reactive oxygen species production and oxidative stress in the lung, which plays a major role in the pathogenesis of ventilator-induced lung injury. Amifostine attenuates oxidative stress and improves lipopolysaccharide-induced lung injury by acting as a direct scavenger of reactive oxygen and nitrogen species. This study tested effects of chronic amifostine administration on parameters of oxidative stress, lung barrier function, and inflammation associated with ventilator-induced lung injury.

Design: Randomized and controlled laboratory investigation in mice and cell culture.

Setting: University laboratory.

Subjects: C57BL/6J mice.

Interventions: Mice received once-daily dosing with amifostine (10–100 mg/kg, intraperitoneal injection) 3 days consecutively before high tidal volume ventilation (30 mL/kg, 4 hrs) at day 4. Pulmonary endothelial cell cultures were exposed to pathologic cyclic stretching (18% equibiaxial stretch) and thrombin in a previously verified two-hit model of in vitro ventilator-induced lung injury.

Measurements and Main Results: Three-day amifostine preconditioning before high tidal volume attenuated high tidal volume-induced protein and cell accumulation in the alveolar space judged by bronchoalveolar lavage fluid analysis, decreased Evans Blue dye extravasation into the lung parenchyma, decreased biochemical parameters of high tidal volume-induced tissue oxidative stress, and inhibited high tidal volume-induced activation of redox-sensitive stress kinases and nuclear factor-kappa B inflammatory cascade. These protective effects of amifostine were associated with increased superoxide dismutase 2 expression and increased superoxide dismutase and catalase enzymatic activities in the animal and endothelial cell culture models of ventilator-induced lung injury.

Conclusions: Amifostine preconditioning activates lung tissue antioxidant cell defense mechanisms and may be a promising strategy for alleviation of ventilator-induced lung injury in critically ill patients subjected to extended mechanical ventilation.

From the Section of Pulmonary and Critical Care (PF, AAB, KGB), Lung Injury Center, Department of Medicine, and Department of Radiation and Cellular Oncology (JSM, DJG), University of Chicago, IL.

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Supported, in part, by NIH grants NIH/NHLBI PO1-058064, HL076259, and HL087823, and ALA Career Investigator Award for KGB; NIH/NHLBI HL89257 for AAB; NIH/NCI RO1 CA99005 and DDE grant DE-FG02-05ER64086 for DJG and JSM. Consultations on biostatistical data analysis of this study were supported by grant UL1RR024999 from the National Center For Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

The authors have not disclosed any potential conflicts of interest.

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© 2011 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins