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.
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.
