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Am J Physiol Lung Cell Mol Physiol (July 28, 2006). doi:10.1152/ajplung.00055.2006
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Submitted on February 13, 2006
Accepted on July 18, 2006

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

James Andrew Frank1*, Charlie M Wray2, Daniel F McAuley3, Reto Schwendener4, and Michael A Matthay5

1 Medicine, University of California, San Francisco, San Francisco, California, United States; Cardiovascular Research Institute, San Francisco, California, United States; Northern California Institute for Research and Education and the San Francisco VA Medical Center, San Francisco, California, United States
2 Northern California Institute for Research and Education and the San Francisco VA Medical Center, San Francisco, California, United States
3 Cardiovascular Research Institute, San Francisco, California, United States
4 Paul Scherrer Institute, Villigen, Switzerland
5 Medicine, University of California, San Francisco, San Francisco, California, United States; Anesthesia, University of California, San Francisco, San Francisco, California, United States; Cardiovascular Research Institute, San Francisco, California, United States

* To whom correspondence should be addressed. E-mail: frankja{at}itsa.ucsf.edu.

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, rats were ventilated with high tidal volume (HVT) for 10 min to 4 h. Alveolar macrophage counts in bronchoalveolar lavage (BAL) fluid decreased 45% by 20 minutes of HVT (P<0.05) consistent with activation-associated adhesion. Depletion of alveolar macrophages in vivo with liposomal clodronate significantly decreased permeability and pulmonary edema following 4h of HVT (P<0.05). BAL fluid from rats exposed to 20 min of HVT increased nitric oxide synthase activity nearly 3-fold in naive primary alveolar macrophages (P<0.05) indicating that soluble factors present in the airspaces contribute to macrophage activation in ventilator-induced lung injury (VILI). Media from co-cultures of alveolar epithelial cell monolayers and alveolar macrophages exposed to 30 min of stretch in vitro also significantly increased nitrite production in naive 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.




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