Effects of melatonin in an experimental model of ventilator-induced lung injury

1 Intensive Care Unit, Hospital Universitario Central de Asturias; and 2 Departamento de Cirugía y Especialidades Médico-Quirurgicas, 3 Departamento de Biología Funcional, and 4 Departamento de Medicina, Universidad de Oviedo, Oviedo, Spain Submitted 26 February 2008 ; accepted in final form 16 September 2008 Melatonin is a free radical scavenger and a broad-spectrum antioxidant and has well-documented immunomodulatory effects. We studied the effects of this hormone on lung damage, oxidative stress, and inflammation in a model of ventilator-induced lung injury (VILI), using 8- to 12-wk-old Swiss mice ( n = 48). Animals were randomized into three experimental groups: control (not ventilated); low-pressure ventilation [peak inspiratory pressure 15 cmH 2 O, positive end-expiratory pressure (PEEP) 2 cmH 2 O], and high-pressure ventilation (peak inspiratory pressure 25 cmH 2 O, PEEP 0 cmH 2 O). Each group was divided into two subgroups: eight animals were treated with melatonin (10 mg/kg ip, 30 min before the onset of ventilation) and the remaining eight with vehicle. After 2 h of ventilation, lung injury was evaluated by gas exchange, wet-to-dry weight ratio, and histological analysis. Levels of malondialdehyde, glutathione peroxidase, interleukins IL-1β, IL-6, TNF- , and IL-10, and matrix metalloproteinases 2 and 9 in lung tissue were measured as indicators of oxidation status, pro-/anti-inflammatory cytokines, and matrix turnover, respectively. Ventilation with high pressures induced severe lung damage and release of TNF- , IL-6, and matrix metalloproteinase-9. Treatment with melatonin improved oxygenation and decreased histological lung injury but significantly increased oxidative stress quantified by malondialdehyde levels. There were no differences in TNF- , IL-1β, IL-6, or matrix metalloproteinases caused by melatonin treatment, but IL-10 levels were significantly higher in treated animals. These results suggest that melatonin decreases VILI by increasing the anti-inflammatory response despite an unexpected increase in oxidative stress. mechanical ventilation; oxidative stress Address for reprint requests and other correspondence: G. M. Albaiceta, Intensive Care Unit, Hospital Universitario Central de Asturias, Celestino Villamil s/n, 33006, Oviedo, Spain (e-mail: guillermo.muniz{at}sespa.princast.es )