Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are serious conditions with an unacceptably high overall mortality rate of ~25%. In addition, some patients develop a debilitating, persistent and sometimes fatal, fibrotic lung disease called fibroproliferative ALI. Unfortunately, there are no effective therapeutic approaches to prevent or treat this disorder. This project seeks to address this therapeutic need by investigating the role of dual specificity protein phosphatase-1 (DUSP1, aka MKP-1), a protein threonine/tyrosine phosphatase that dephosphorylates and inactivates the mitogen-activated protein kinases, p38 and JNK. In preliminary studies using mouse models of acute lung injury and fibrosis, we have shown that the development of lung fibrosis is ablated in mice lacking DUSP1. Our preliminary studies also show that genetic DUSP1 deficiency in mice impairs the ability of macrophages to undergo "alternative" programming leading to impaired production of pro-fibrotic growth factors including TGF-?. These and other considerations have led us to hypothesize that DUSP1 is a therapeutic target that, when blocked, will reduce or prevent alternative macrophage programming, pro-fibrotic growth factor production and the development of ALI/ARDS-associated parenchymal lung fibrosis. These hypotheses will be addressed with three specific aims. Using genetic and conditional manipulation of DUSP1 expression in mouse models, the goal of Specific Aim 1 is to address the hypothesis that DUSP1 expression by macrophages is required for the development of fibroproliferative ALI.
In Specific Aim 2, we will test the hypothesis that DUSP1-dependent fibrotic lung disease is mediated by alternatively programmed macrophages producing pro-fibrotic growth factors. Lastly, in Specific Aim 3, we will begin translating this work into humans by conducting pre-clinical studies in which we will assess two currently available small molecule DUSP1 expression inhibitors, currently approved for use in humans, for their ability to phenocopy DUSP1 deficiency and inhibit the development of parenchymal lung fibrosis in mice. Our proposed studies represent the first time that protein phosphatases have been investigated as therapeutic targets for the treatment of fibroproliferative ALI. Thus, a long-term goal of this proposal is to translate our anticipated findings into a clinical trial of DUSP1 inhibitors in ALI nd ARDS patients who are at risk for developing fibrotic lung disease. In addition, DUSP1 may also be a valid therapeutic target in other fibrotic lung disease, e.g. progressive pulmonary fibrosis.

Public Health Relevance

Acute lung injury is a serious condition that can lead to long-term scarring of the lungs and impaired lung function in some patients. Little is known about how lung scar formation develops or how to treat patients who develop lung scarring. This project seeks to address each of these issues with the longer term goal of developing novel therapeutic approaches to treat this devastating and often fatal disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL114754-01A1
Application #
8503966
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Eu, Jerry Pc
Project Start
2013-06-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$377,230
Indirect Cost
$139,230
Name
National Jewish Health
Department
Type
DUNS #
076443019
City
Denver
State
CO
Country
United States
Zip Code
80206
Gump, Jacob M; Staskiewicz, Leah; Morgan, Michael J et al. (2014) Autophagy variation within a cell population determines cell fate through selective degradation of Fap-1. Nat Cell Biol 16:47-54
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
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