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Am J Physiol Lung Cell Mol Physiol 297: L586-L595, 2009. First published July 31, 2009; doi:10.1152/ajplung.90569.2008
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TNF{alpha} inhibits apoptotic cell clearance in the lung, exacerbating acute inflammation

Valeria M. Borges,1,4 R. William Vandivier,2 Kathleen A. McPhillips,1 Jennifer A. Kench,1 Konosuke Morimoto,3,5 Steve D. Groshong,2 Tiffany R. Richens,3 Brian B. Graham,3 Alaina M. Muldrow,2 Lea Van Heule,2 Peter M. Henson,1 and William J. Janssen2,3

1Program in Cell Biology, Department of Pediatrics, and ; 2Department of Medicine, National Jewish Health, and ; 3Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado; ; 4Centro de Pesquisa Gonçalo Moniz Fiocruz, Salvador, Brazil; and ; 5Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan

Submitted 19 November 2008 ; accepted in final form 28 July 2009

Efficient removal of apoptotic cells is essential for resolution of inflammation. Failure to clear dying cells can exacerbate lung injury and lead to persistent inflammation and autoimmunity. Here we show that TNF{alpha} blocks apoptotic cell clearance by alveolar macrophages and leads to proinflammatory responses in the lung. Compared with mice treated with intratracheal TNF{alpha} or exogenous apoptotic cells, mice treated with the combination of TNF{alpha} plus apoptotic cells demonstrated reduced apoptotic cell clearance from the lungs and increased recruitment of inflammatory leukocytes to the air spaces. Treatment with intratracheal TNF{alpha} had no effect on the removal of exogenous apoptotic cells from the lungs of TNF{alpha} receptor-1 (p55) and -2 (p75) double mutant mice and no effect on leukocyte recruitment. Bronchoalveolar lavage from mice treated with TNF{alpha} plus apoptotic cells contained increased levels of proinflammatory cytokines IL-6, KC, and MCP-1, but exhibited no change in levels of anti-inflammatory cytokines IL-10 and TGF-β. Administration of TNF{alpha} plus apoptotic cells during LPS-induced lung injury augmented neutrophil accumulation and proinflammatory cytokine production. These findings suggest that the presence of TNF{alpha} in the lung can alter the response of phagocytes to apoptotic cells leading to inflammatory cell recruitment and proinflammatory mediator production.

apoptosis; phagocytosis


Address for reprint requests and other correspondence: W. J. Janssen, Dept. of Medicine, K729B, National Jewish Health, Denver, CO 80206 (e-mail: janssenw{at}njc.org).






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