Acute lung injury (ALI) and its more severe form, the acute respiratory distress syndrome (ARDS), are characterized by bilateral pulmonary infiltrates of non-cardiac origin and severe arterial hypoxemia. These diseases account for nearly 200,000 hospitalizations and 75,000 deaths in the United States each year. Despite recent advances, mortality remains high and the majority of survivors suffer from persistent pulmonary dysfunction and lung fibrosis. Animal models have yielded important insights into the mechanisms that initiate lung injury, however few studies have focused on the processes that drive its resolution. In this regard, we believe that macrophages play a pivotal role. There is abundant accumulation of macrophages in the lungs during early ALI. In patients with non-resolving ALI, macrophages persist and serve as a rich source of pro- fibrotic molecules including transforming growth factor-? (TGF-?). In mouse models of self-limited ALI, macrophages undergo apoptosis that is driven by Fas. Conversely in ALI models characterized by persistent inflammation and fibrosis, macrophage apoptosis is difficult to detect. These observations form the basis for our central hypothesis that macrophage apoptosis is required for the resolution of ALI and that macrophage resistance to apoptosis results in fibrosis.
Aim 1 will test this hypothesis in mouse models of self-limited and non-resolving ALI by: a) systemically administering caspase inhibitors to inhibit macrophage apoptosis, b) using mice with conditional ablation of the Fas death receptor on macrophages, c) selectively inducing macrophage apoptosis in transgenic mice.
Aim 2 will test the hypothesis that the anti-apoptotic molecule, c- FLIP, is upregulated in macrophages that are resistant to apoptosis using mouse models of non-resolving ALI. Experiments in Aim 2 will also test the ability of the thiazolidinedione, pioglitazone, to sensitize macrophages to Fas-induced apoptosis by downregulating c-FLIP and will explore the effects of pioglitazone treatment on inflammation and fibrosis.
Aim 3 will test the hypothesis that alveolar macrophages from subjects with non- resolving ALI are resistant to apoptosis. An ongoing NIH-sponsored trial will serve as the source of macrophages and BAL fluid for this aim. Macrophages will be analyzed for the presence of apoptosis and levels of procollagen peptide III will be quantified in BAL fluid. The correlation between macrophage apoptosis and procollagen peptide III levels will be assessed using univariate and multivariate analysis. The focus on the macrophage in resolving lung injury is a new and untapped area that has not been previously addressed. Results of our study will provide essential insight into the processes that regulate the resolution of inflammation in the lungs and will pave the way for novel therapeutic strategies to target non-resolving acute lung injury.

Public Health Relevance

Acute 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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Ni, Kevin; Gill, Amar; Tseng, Victor et al. (2018) Rapid clearance of heavy chain-modified hyaluronan during resolving acute lung injury. Respir Res 19:107
Friedman, Jacob E (2018) Developmental Programming of Obesity and Diabetes in Mouse, Monkey, and Man in 2018: Where Are We Headed? Diabetes 67:2137-2151
McCubbrey, Alexandra L; Barthel, Lea; Mohning, Michael P et al. (2018) Deletion of c-FLIP from CD11bhi Macrophages Prevents Development of Bleomycin-induced Lung Fibrosis. Am J Respir Cell Mol Biol 58:66-78
McCubbrey, Alexandra L; Allison, Kristen C; Lee-Sherick, Alisa B et al. (2017) Promoter Specificity and Efficacy in Conditional and Inducible Transgenic Targeting of Lung Macrophages. Front Immunol 8:1618
Mould, Kara J; Barthel, Lea; Mohning, Michael P et al. (2017) Cell Origin Dictates Programming of Resident versus Recruited Macrophages during Acute Lung Injury. Am J Respir Cell Mol Biol 57:294-306
Gibbings, Sophie L; Thomas, Stacey M; Atif, Shaikh M et al. (2017) Three Unique Interstitial Macrophages in the Murine Lung at Steady State. Am J Respir Cell Mol Biol 57:66-76
Janssen, William J; Bratton, Donna L; Jakubzick, Claudia V et al. (2016) Myeloid Cell Turnover and Clearance. Microbiol Spectr 4:
Janssen, William J; Stefanski, Adrianne L; Bochner, Bruce S et al. (2016) Control of lung defence by mucins and macrophages: ancient defence mechanisms with modern functions. Eur Respir J 48:1201-1214
Desch, A Nicole; Gibbings, Sophie L; Goyal, Rajni et al. (2016) Flow Cytometric Analysis of Mononuclear Phagocytes in Nondiseased Human Lung and Lung-Draining Lymph Nodes. Am J Respir Crit Care Med 193:614-26
McCubbrey, Alexandra L; Nelson, Joshua D; Stolberg, Valerie R et al. (2016) MicroRNA-34a Negatively Regulates Efferocytosis by Tissue Macrophages in Part via SIRT1. J Immunol 196:1366-75

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