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

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-1beta, IL-6, TNF-alpha, 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-alpha, 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-alpha, IL-1beta, 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.

Therapeutic implications of immunoparalysis in critically ill patients.

In opposite to the classic view of the systemic inflammatory response, there is increasing evidence that, during critical illness, there is a systemic antiinflammatory state intended to avoid the spread of the local proinflammatory response. The resulting immunosuppression increases the risk of nosocomial infections, and has been related to an increase in morbidity and mortality in critically ill patients. Monocytes play a key role in orchestrating the inflammatory response, and a functional impairment of this population is the responsible for these phenomena. The decreased surface expression of class II molecules of the Main Histocompatibility Complex is both a marker of this state and a pathogenetic mechanism, as it decreases the antigen presentation capabilities of the mononuclear phagocytes. There are some therapeutic strategies to overcome this situation. Cytokines like IFNgamma or GM-CSF have been tested in animal models and patients, but there are no conclusive data. Other drugs like Flt3, AS101 or antibodies against IL-10 have been tested only in experimental models. The development of a new framework on the inflammatory response, the need for a consensus in immune monitoring and the development of experimental and clinical trials are required to improve the outcome of severe patients with systemic injuries.