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We examined the hypothesis that injurious strategies of mechanical ventilation alter the expression and distribution within the lung of tumor necrosis factor-α and interleukin-6 that are both duration and ventilation strategy dependent.Male Sprague Dawley rats.Lungs from rats were preserved immediately after death or were randomized to ex vivo ventilation with either a) noninjurious ventilation; b) high end-inspiratory lung volume with positive end-expiratory pressure (PEEP); c) high end-inspiratory lung volume without PEEP; or d) intermediate lung distension without PEEP, for periods ranging from 30 mins to 3 hrs.Changes in cytokines were assessed by in situ hybridization, immunocytochemistry, simultaneous in situ hybridization and immunocytochemistry, Northern analysis, and enzyme-linked immunosorbent assay. Whereas minimal expression of tumor necrosis factor-α and interleukin-6 mRNA was found in lungs subjected to noninjurious ventilation, the three injurious strategies resulted in a diffuse increase in expression of tumor necrosis factor-α and interleukin-6. The principal cells involved were the bronchial, bronchiolar, and alveolar epithelium. The changes in tumor necrosis factor-α mRNA and protein expression were dependent on both duration of ventilation and the ventilation strategy used.The vast pulmonary epithelium is a major contributor to ventilation-induced changes in cytokine production and may play an important role in the pathogenesis of lung injury and systemic sequelae in ventilated subjects.