Acute lung injury (ALI) most commonly occurs after severe bacterial infections such as pneumonia or sepsis. A clear impediment to successful ALI therapy resides in a complex disease course often characterized by an initial burst in host inflammation from pro- inflammatory mediators resulting in extensive tissue injury;a second phase of immunosuppression ensues that poses risks for secondary bacterial infections. IL-1, generated by the inflammasome and invasive bacterial infections both contribute to disease pathobiology and illness severity. The mechanistic platform of this project resides on our discovery of a unique molecular model of inflammation whereby a relatively new protein, Fbxo3, potently triggers IL-1 release from human inflammatory cells after bacterial infection by destabilizing a crucial inflammasome inhibitor, Fbxl2. By targeting the ApaG molecular signature present in both host Fbxo3 and many bacteria, we developed a first-in-class genus of small molecule inhibitors that display dual anti-inflammatory and anti-bacterial activity in murine ALI models. Hence, in this application we will first elucidate how bacterial pathogens transcriptionally activate Fbxo3, allowing the protein to eliminate an inflammasome inhibitor, Fbxl2 (Aim 1). We will specifically elucidate how Fbxl2 targets the NALP7 inflammasome. Next we will optimize the pharmacologic design and test a novel small molecule that exhibits distinct, and yet complementary anti-inflammatory and anti-bacterial properties in ALI models (Aim 2). These studies will provide a new mechanistic pathway of innate immunity that will serve as a basis to fulfill an unmet therapeutic need in subjects with altered immune responses during critical illness.

Public Health Relevance

Acute lung injury (ALI) is a major cause of morbidity and mortality in the US and evidence suggests that patients die from overwhelming inflammation or immunosuppression, the latter making people prone to bacterial infections. Lung inflammation is caused from the release of proteins, called cytokines. We have discovered a new model of inflammation in subjects with ALI. This discovery led us to develop a new family of drugs that reduce cytokine-driven inflammation but are also anti- bacterial. This discovery fulfills an unmet need in ALI therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL081784-07
Application #
8769613
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
Project Start
2005-10-01
Project End
2018-03-31
Budget Start
2014-08-01
Budget End
2015-03-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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