High-pressure ventilation induces barotrauma and pulmonary inflammation, thus leading to ventilator-induced lung injury (VILI). By limiting the pulmonal inflammation cascade the anti-inflammatory cytokine interleukin (IL)-10 may have protective effects. Via inhalation, IL-10 reaches the pulmonary system directly and in high concentrations.Thirty six male, anesthetized and mechanically ventilated Sprague–Dawley rats were randomly assigned to the following groups (n=9, each): SHAM: pressure controlled ventilation with p max =20cmH 2 O, PEEP=4; VILI: ventilator settings were changed for 20min to p max =45cmH 2 O, PEEP=0; IL-10 high : inhalation of 10μg/kg IL-10 prior to induction of VILI; and IL-10 low : inhalation of 1μg/kg IL-10 prior to induction of VILI. All groups were ventilated and observed for 4h.High-pressure ventilation increased the concentrations of macrophage inflammatory protein (MIP)-2 and IL-1β in bronchoalveolar lavage fluid (BALF) and plasma. This effect was reduced by the inhalation of IL-10 (10μg/kg). Additionally, IL-10 increased the animal survival time (78% vs. 22% 4-h mortality rate) and reduced NO-release from ex vivo cultured alveolar macrophages. Moreover, VILI-induced pulmonary heat shock protein-70 expression was reduced by IL-10 aerosol in a dose-dependent manner. Similarly, the activation of matrix metalloproteinase (MMP)-9 in BALF was reduced dose-dependently by IL-10. IL-10-treated animals showed a lower macroscopic lung injury score and less impairment of lung integrity and gas exchange.Prophylactic inhalation of IL-10 improved survival and reduced lung injury in experimental VILI. Results indicate that this effect may be mediated by the inhibition of stress-induced inflammation and pulmonary biotrauma.