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This review addresses the current state of Lung Protective Ventilation and PEEP settings in critical ill patients, especially with Acute Respiratory Distress Syndrome (ARDS). Mechanisms of mediator and cytokine activation are described and results from clinical studies on mechanical ventilation are compared with results obtained in experimental studies. Furthermore, several ventilation strategies, particularly the Open Lung Maneuver, are discussed highlighting their role in the prevention of VALI. Finally, the Open Lung Maneuver is described through an example of an illustrative case.