Among other effects, mechanical ven tilation superimposes a mecha

Among other effects, mechanical ven tilation superimposes a mechanical stress within the lung tissue, and may induce an additional injury. In patients with the acute respiratory distress syndrome, protective venti latory strategies have demonstrated selleck compound a reduction in mor tality, highlighting the relevance of this pathogenetic mechanism. However, there are no universally applicable ventilatory settings that minimize the risk of VALI in all patients. There are no pharmacological strategies that have been successfully used to treat or prevent VALI. Recently, a sur vival benefit in patients receiving mechanical ventilation and macrolide therapy has been reported. Similarly, several studies have shown better survival Inhibitors,Modulators,Libraries rates in patients with pneumonia treated with macrolides, compared to those receiving other antibiotics.

These results have been confirmed even in cases of macrolide resistant bacteria and in ventilator associated Inhibitors,Modulators,Libraries pneumonia. The mechanisms responsible for these benefits of macrolides are unknown. Macrolides exert some anti inflammatory effects including modulation of leukocyte recruitment, a shift in cytokine release towards anti inflammatory molecules or inhibition of the extracellular matrix remodeling by targeting matrix metalloproteases. Inflammation is one of the key steps required for ventilator induced lung injury and different anti inflammatory drugs have shown a decrease in VILI. Based on the anti inflammatory properties of macrolides, we hypothe sized that clarithromycin could exert some beneficial effects in a model of VILI by attenuating the inflammatory response.

Inhibitors,Modulators,Libraries To test this hypothesis, we submitted mice treated with vehicle, clarithromycin or levofloxacin to different ventilatory strategies and studied the severity of lung injury and the extent of the inflammatory response. Finally, as macrolide treatment Inhibitors,Modulators,Libraries decreased leukocyte infiltration, the steps needed for cell recruitment were assessed. Materials and methods Animals 8 12 week old C57/BL6 mice were used in all the experi ments. Mice were kept under specific pathogens free conditions, with full access to food and water, in 12 hour light/dark cycles. The experimental protocol was approved by the University Animal Research Ethics Committee. Experimental model Mice were randomly assigned to receive one of three treat ments previous to ventilation Vehicle, clarithromycin or levofloxacin.

Two doses with a 12 hour interval between Inhibitors,Modulators,Libraries them were administered intraperitoneally. It has been reported that doses in the 25 100 mg/kg range result in clinically achievable drug levels in humans. One hour after reference 4 the second dose, mice were anesthetized with intraperitoneal ketamine and xylazin, a tracheostomy was performed, and they were connected to a mechanical ventilator. The animals were randomized to receive low pressures, using an Evita 2 Dura ventilator.

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