Sepsis is a significant cause of morbidity and mortality. Severe sepsis complicated with multiple organ injury and acute lung injury (ALI)-induced respiratory failure frequently serves as a direct reason of death. During sepsis, unrestrained stimulation of leukocytes and structural cells can induce Systemic Inflammatory Response Syndrome (SIRS) resulting in tissue injury and susceptibility to nosocomial infection. Unfortunately, as no effective medicine is available to treat the developing SIRS/organ injury in these individuals, there is a strong need to further dissect the complex events that lead to the initiation and progression of SIRS. The long-term goal of this project is to identify endogenous inhibitors of phagocyte function that could decrease different arms of the inflammatory response while restoring antimicrobial effector functions. This renewal is built upon published and preliminary data generated while investigating the role of the phosphatase and tensin homolog PTEN in microRNA-mediated MyD88 degradation and the generation of SIRS during sepsis. We found that PTEN deficiency enhances mortality in septic mice; that miR21 (a microRNA that targets PTEN) is a homeostatic regulator of macrophage inflammatory response and that preventing excessive glycolysis decreases SIRS development, ALI formation and improves animal survival. Our preliminary data suggest that in addition to controlling transcriptional programs, PTEN also directly inhibits the inflammasome (intracellular inflammatory platforms)-dependent release of potent inflammatory mediators. PTEN also stimulates fatty acid oxidation (FAO), which inhibits inflammation. Furthermore, we also found that miR21 inhibits the expression of genes involved in FAO, which correlates with decreased animal survival, increased lung inflammation and mortality. From these findings, we formulated our central hypothesis that during sepsis, myeloid-specific signaling along the miR21/PTEN/FAO axis becomes dysregulated and drives lung injury and lethality during sepsis. This hypothesis will be examined by testing the 1) role of PTEN in inflammasome activation in phagocytes in sepsis and 2) Determine the role of the miR21/PTEN axis in lung injury and mortality during sepsis. We will employ a series of state-of-the-art techniques, along with epistatic and gain of function approaches to unveil new signaling programs that ultimately might influence ALI and mortality during systemic infections. The combination of the PI?s experience in sepsis, lung immunology and inflammation, the assembled team of collaborators, and the environment at Vanderbilt University Medical Center ensure that this work will be accomplished. The identification of specific components and their modes of action in maintenance of sepsis may identify targets for therapeutic intervention resulting in improved immune responsiveness in settings of host vulnerability, and may suggest strategies to dampen the immune response in settings of exaggerated inflammation.

Public Health Relevance

Sepsis remains the leading cause of mortality in intensive care units and is the most common cause of organ injury after trauma and surgical intervention. Organ injury starts with an overwhelming inflammatory response that cause a shift in metabolic pathways that lead to vascular damage, exaggerated leukocyte infiltration and release of inflammatory mediators. This project seeks to investigate the role of a molecular brake in the metabolic changes induced during sepsis that protects from an acute lung injury and mortality.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL124159-07
Application #
10005956
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Sarkar, Rita
Project Start
2014-07-15
Project End
2023-06-30
Budget Start
2020-07-01
Budget End
2021-06-30
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
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Dejani, Naiara N; Brandt, Stephanie L; Piñeros, Annie et al. (2016) Topical Prostaglandin E Analog Restores Defective Dendritic Cell-Mediated Th17 Host Defense Against Methicillin-Resistant Staphylococcus Aureus in the Skin of Diabetic Mice. Diabetes 65:3718-3729

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