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Alveolar macrophages contribute to alveolar barrier dysfunction in ventilator-induced lung injury

University of California, San Francisco, Departments of ¹Medicine and ²Anesthesia; ³Cardiovascular Research Institute; ⁴Northern California Institute for Research and Education; ⁵San Francisco Veterans Affairs Medical Center, San Francisco, California; and ⁶The Paul Scherrer Institute, Villigen, Switzerland

Submitted 13 February 2006 ; accepted in final form 18 July 2006

In patients requiring mechanical ventilation for acute lung injury or acute respiratory distress syndrome (ARDS), tidal volume reduction decreases mortality, but the mechanisms of the protective effect have not been fully explored. To test the hypothesis that alveolar macrophage activation is an early and critical event in the initiation of ventilator-induced lung injury (VILI), rats were ventilated with high tidal volume (HV_T) for 10 min to 4 h. Alveolar macrophage counts in bronchoalveolar lavage (BAL) fluid decreased 45% by 20 min of HV_T (P < 0.05) consistent with activation-associated adhesion. Depletion of alveolar macrophages in vivo with liposomal clodronate significantly decreased permeability and pulmonary edema following 4 h of HV_T (P < 0.05). BAL fluid from rats exposed to 20 min of HV_T increased nitric oxide synthase activity nearly threefold in naïve primary alveolar macrophages (P < 0.05) indicating that soluble factors present in the air spaces contribute to macrophage activation in VILI. Media from cocultures of alveolar epithelial cell monolayers and alveolar macrophages exposed to 30 min of stretch in vitro also significantly increased nitrite production in naïve macrophages (P < 0.05), but media from stretched alveolar epithelial cells or primary alveolar macrophages alone did not, suggesting alveolar epithelial cell-macrophage interaction was required for the subsequent macrophage activation observed. These data demonstrate that injurious mechanical ventilation rapidly activates alveolar macrophages and that alveolar macrophages play an important role in the initial pathogenesis of VILI.

alveolar epithelial barrier function; ventilator-associated lung injury; acute lung injury; acute respiratory distress syndrome

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