Macrophages are known to undergo apoptosis during the resolution of inflammation in the lungs, however the mechanisms that regulate macrophage cell death are not known. The appropriate time frame during which macrophages must be removed to resolve inflammation and complete tissue repair also remains unknown. Addressing these gaps in knowledge is of significant importance since persistence of macrophages in inflammatory lesions is associated with tissue injury, abnormal tissue repair and even fibrosis. Our data show that activation of the death receptor, Fas, drives the apoptosis of recruited macrophages in self-limited models of acute lung injury and that macrophage apoptosis is reduced in non-resolving models of acute lung injury (ALI). Based on our preliminary data, we hypothesize that the anti-apoptotic molecule, cellular FLICE inhibitory protein (c-FLIP) is a critical regulator of macrophage apoptosis, and that c-FLIP prevents appropriately timed macrophage apoptosis in non-resolving forms of acute lung injury. This hypothesis will be tested in mouse models of ALI and in macrophages obtained from human subjects with the acute respiratory distress syndrome. Mouse models of ALI will also be used to determine the optimal time during which macrophages must be cleared from the lungs to terminate inflammation and the pathologic consequences of delayed macrophage apoptosis. Achieving the aims of this proposal will provide important insights into the biologic mechanisms that regulate the termination of inflammation and affect tissue repair, paving the way for novel therapies to treat non-resolving ALI and other forms of inflammatory lung disease.

Public Health Relevance

Lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), affect over 190,000 individuals in the United States each year, accounting for over 75,000 deaths, 3.6 million hospital days and $350 million in direct health care costs. During ALI there is massive expansion of macrophages in the lungs. We believe that programmed cell death (apoptosis) of these cells is required for recovery from ALI and that scarring develops in the lungs when macrophages are resistant to cell death. This proposal will help identify the mechanisms that underlie acute lung injury and pave the way for novel therapies for this disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Injury, Repair, and Remodeling Study Section (LIRR)
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Harabin, Andrea L
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National Jewish Health
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Kearns, Mark T; Barthel, Lea; Bednarek, Joseph M et al. (2014) Fas ligand-expressing lymphocytes enhance alveolar macrophage apoptosis in the resolution of acute pulmonary inflammation. Am J Physiol Lung Cell Mol Physiol 307:L62-70
Aschner, Yael; Khalifah, Anthony P; Briones, Natalie et al. (2014) Protein tyrosine phosphatase ? mediates profibrotic signaling in lung fibroblasts through TGF-? responsiveness. Am J Pathol 184:1489-502
Yunt, Zulma X; Mohning, Michael P; Barthel, Lea et al. (2014) Kinetics of the angiogenic response in lung endothelium following acute inflammatory injury with bleomycin. Exp Lung Res 40:415-25
Redente, Elizabeth F; Keith, Rebecca C; Janssen, William et al. (2014) Tumor necrosis factor-* accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages. Am J Respir Cell Mol Biol 50:825-37
Desch, A Nicole; Gibbings, Sophie L; Clambey, Eric T et al. (2014) Dendritic cell subsets require cis-activation for cytotoxic CD8 T-cell induction. Nat Commun 5:4674
Roy, Michelle G; Livraghi-Butrico, Alessandra; Fletcher, Ashley A et al. (2014) Muc5b is required for airway defence. Nature 505:412-6
Burnham, Ellen L; Janssen, William J; Riches, David W H et al. (2014) The fibroproliferative response in acute respiratory distress syndrome: mechanisms and clinical significance. Eur Respir J 43:276-85
Bhargava, Rhea; Janssen, William; Altmann, Christopher et al. (2013) Intratracheal IL-6 protects against lung inflammation in direct, but not indirect, causes of acute lung injury in mice. PLoS One 8:e61405
Burnham, Ellen L; Hyzy, Robert C; Paine 3rd, Robert et al. (2013) Chest CT features are associated with poorer quality of life in acute lung injury survivors. Crit Care Med 41:445-56