Activation of human macrophages by mechanical ventilation in vitro

Positive-pressure mechanical ventilation supports gas exchange in patients with respiratory failure but is also responsible for significant lung injur y. In this study, we have developed an in vitro model in which isolated lun g cells can be submitted to a prolonged cyclic pressure-stretching strain r esembling that of conventional mechanical ventilation. In this model, cells cultured on a Silastic membrane were elongated up to 7% of their initial d iameter, corresponding to a 12% increase in cell surface. The lung macropha ge was identified as the main cellular source for critical inflammatory med iators such as tumor necrosis factor-alpha, the chemokines interleukin (IL) -8 and -6, and matrix metalloproteinase-9 in this model system of mechanica l ventilation. These mediators were measured in supernatants from ventilate d alveolar macrophages, monocyte-derived macrophages, and promonocytic THP- 1 cells. Nuclear factor-kappa B was found to be activated in ventilated mac rophages. Synergistic proinflammatory effects of mechanical stress and mole cules such as bacterial endotoxin were observed, suggesting that mechanical ventilation might be particularly deleterious in preinjured or infected lu ngs. Dexamethasone prevented IL-8 and tumor necrosis factor-alpha secretion in ventilated macrophages. Mechanical ventilation induced low levels of IL -8 secretion by alveolar type II-like cells. Other lung cell types such as endothelial cells, bronchial cells, and fibroblasts failed to produce IL-8 in response to a prolonged cyclic pressure-stretching load. This model is o f particular value for exploring physical stress-induced signaling pathways , as well as for testing the effects of novel ventilatory strategies or adj unctive substances aimed at modulating cell activation induced by mechanica l ventilation.