Submitted on May 29, 2007
Accepted on June 3, 2008
DEPLETION OF RESIDENT ALVEOLAR MACROPHAGES DOES NOT PREVENT FAS-MEDIATED LUNG INJURY IN MICE
Reinout Alexander Bem1, Alex W Farnand2, Venus Wong1, Amy Koski1, Michael E. Rosenfeld3, Nico van Rooijen4, Charles W. Frevert1, Thomas R. Martin1, and Gustavo Matute-Bello2*
1 Pulmonary and Critical Care Medicine, University of Washington, VA Medical Center, Seattle, Washington, United States
2 Division of Pulmonary and Critical Care Medicine, University of Washington, Center of Lung Biology, Seattle, Washington, United States
3 Department of Medicine, University of Washington, Departments of Environmental and Occupational Health Sciences and Pathology, Seattle, Washington, United States
4 Faculty of Medicine, Department of Cell Biology, Free University, Amsterdam, Netherlands
* To whom correspondence should be addressed. E-mail: matuteb{at}u.washington.edu.
Activation of the Fas/FasL system in the lungs results in a form of injury characterized by alveolar epithelial apoptosis and neutrophilic inflammation. Studies in vitro show that Fas activation induces apoptosis in alveolar epithelial cells and cytokine production in alveolar macrophages. The main goal of this study was to determine the contribution of alveolar macrophages to Fas-induced lung inflammation in mice, by depleting alveolar macrophages using clodronate-containing liposomes. Liposomes containing clodronate or PBS were instilled by intratracheal instillation. After 24 hr, the mice received intratracheal instillations of the Fas-activating monoclonal antibody Jo2 or an isotype control antibody, and were studied 18 hours later. The Jo2 mAb induced increases in bronchoalveolar lavage fluid (BALF) total neutrophils, lung caspase-3 activity, BALF total protein, and worsened histological lung injury in the macrophage-depleted mice. Studies in vitro showed that Fas activation induced the release of the cytokine KC in a mouse lung epithelial cell line, MLE-12. These results suggest that the lung inflammatory response to Fas activation is not primarily dependent on resident alveolar macrophages and may instead depend on cytokine release by alveolar epithelial cells.
