Sepsis!is a major cause of morbidity and mortality in both adults and children with >1.6 million cases per year in the United States. Neutrophils are key early responders to infection. Neutrophils eliminate microbes by phagocytosis and by oxidant-mediated killing. Neutrophil myeloperoxidase (MPO) produces the potent oxidant, hypochlorous acid (HOCl), which reacts with both microbial and host molecular targets including lipids. PI Dr. David Ford has shown HOCl targets the vinyl ether bond of plasmalogen lipids, resulting in the production of 2- chlorofatty aldehyde (2-ClFALD) and other chlorolipids, including 2-chlorofatty acid (2-ClFA), in response to leukocyte activation. This led our multi-PI team during the previous grant interval to determine chlorolipids elicit endothelial activation leading to leukocyte and platelet adherence, and to demonstrate chlorolipids associate with ARDS and 30-day mortality in human sepsis. To further investigate the role of chlorolipids in sepsis pathophysiology, our multi-PI group has accrued new preliminary data showing that: 1) inhibitors of TLR4, CD36 and glutathione S-transferase (GST) decrease 2-ClFA-elicited endothelial dysfunction; 2) the TLR4 inhibitor, TAK-242, reduces 2-ClFA-elicited and cecal ligation and puncture (CLP) sepsis-elicited mesenteric microcirculatory dysfunction using in vivo intravital microscopy; 3) 2-ClFA modifies specific endothelial cell proteins, which may represent a new paradigm to target for intervention of 2-ClFA-caused endothelial activation; 4) chlorolipids cause gut epithelial barrier leakiness, including in vivo gut bacterial translocation; 5) plasma levels of ?-oxidation products of 2-ClFA, 2-chlorodicarboxylic acids (2-ClDCAs), measured on admission to the intensive care unit (ICU) with sepsis are elevated in patients that develop acute kidney injury (AKI); and 6) 2-ClDCA causes endothelial cell dysfunction. The role of chlorolipids in sepsis is expanding, and these preliminary data indicate there are knowledge gaps that need to be addressed in the proposed studies, which will test our overall hypothesis that chlorolipids produced by activated neutrophils during sepsis are mediators of severe endothelial dysfunction resulting in multiple organ failure. There are three specific aims.
Specific Aim 1 will test the hypothesis that chlorolipid-mediated dysfunction in human endo- thelial and epithelial cells can be pharmacologically targeted.
Specific Aim 2 will test the hypothesis that in vivo chlorolipid- and sepsis-elicited microcirculatory dysfunction and gut barrier dysfunction can be pharmacologically inhibited.
Specific Aim 3 will test the hypothesis that plasma 2-ClDCA levels associate with specific organ dysfunctions and death in human sepsis. Overall, a multi-disciplinary approach with our multi-PI team and Co-Is will examine chlorolipids produced by activated neutrophils during sepsis as critical mediators of microcirculatory dysfunction leading to organ failure, and test inhibitors of, and pathways activated by, chlorolipid-elicited endothelial dysfunction as intervention points. This collaborative investigation has the potential to provide new therapeutic and diagnostic targets for patients with sepsis.

Public Health Relevance

The role of members of the chlorolipid family as mediators of endothelial dysfunction during sepsis is expanding. Our studies will examine the mechanisms by which chlorolipids mediate multi-organ injury during sepsis, and the causal contribution of chlorolipids to sepsis-associated organ failure and mortality in human sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM115553-05
Application #
9818013
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2015-09-01
Project End
2022-06-30
Budget Start
2019-09-01
Budget End
2020-06-30
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
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