Sepsis pathophysiology involves activation of both pro- and anti-inflammatory responses, along with alterations in thrombotic and metabolic pathways. We previously revealed that genes for several inflammatory and thrombotic mediators are highly expressed in visceral adipose tissues during sepsis; however, what causes the fat tissue to be so reactive and whether adipose-derived factors are mediators of sepsis is currently not known. Our preliminary data using both a preclinical mouse model of sepsis, as well as, patient-derived samples suggest that visceral fat is the major source of plasminogen activator inhibitor type 1 (PAI-1), a pro-thrombotic factor which is implicated in the pathogenesis of sepsis and multi-organ failure. In addition, we recently found that gamma delta (??)-T cells, a subset of innate-like T cells, are surprisingly abundant in visceral fat tissue. These findings have led to our hypothesis that these cells are responsible for PAI-1 overproduction by adipose tissues during sepsis and contribute to the development of organ injury. The major goals of this project are (1) to demonstrate that ??-T cells are key regulators of PAI-1 production in visceral fat tissue, and (2) to establish that visceral fat-derived PAI-1 promotes organ injury during sepsis. To achieve these goals, a series of ex vivo adipose explant culture experiments utilizing tissues from several transgenic mouse strains will be performed, and visceral fat tissues will be surgically removed or transplanted from wild-type to PAI-1 knockout mice. Completion of this project will establish the concept that overproduction of PAI-1 from visceral fat contributes to the pathophysiology of sepsis-associated organ injury and reveal key mechanisms for PAI-1 overproduction. This information will aid in the development of future therapeutic strategies to reduce sepsis severity.

Public Health Relevance

Sepsis is a serious clinical condition with a high mortality rate. This project will link inflammatory responses in adipose tissue with the development of organ injury in sepsis by studying gamma-delta T-cell signaling and PAI-1 secretion from adipose tissues. The obtained information will be useful in designing therapeutic targets for severe sepsis.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM129532-01
Application #
9579370
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Dunsmore, Sarah
Project Start
2018-09-01
Project End
2023-05-31
Budget Start
2018-09-01
Budget End
2019-05-31
Support Year
1
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Surgery
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526