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Adipose-Derived Inflammatory and Coagulant Mediators in Patients With Sepsis
Brittany A Zwischenberger1,2, Beverly K Balasuriya1,2, Dwight D Harris1,2
1Aging and Critical Care Research Laboratory, University of Kentucky, Lexington, Kentucky.
Abstract:
Results from preclinical sepsis studies using rodents are often criticized as not being reproducible in humans. Using a murine model, we previously reported that visceral adipose tissues (VAT) are highly active during the acute inflammatory response, serving as a major source of inflammatory and coagulant mediators. The purpose of this study was to determine whether these findings are recapitulated in patients with sepsis and to evaluate their clinical significance. VAT and plasma were obtained from patients undergoing intra-abdominal operations with noninflammatory conditions (control), local inflammation, or sepsis. In mesenteric and epiploic VAT, gene expression of pro-inflammatory (TNFα, IL-6, IL-1α, IL-1β) and pro-coagulant (PAI-1, PAI-2, TSP-1, TF) mediators was increased in sepsis compared with control and local inflammation groups. In the omentum, increased expression was limited to IL-1β, PAI-1, and PAI-2, showing a depot-specific regulation. Histological analyses showed little correlation between cellular infiltration and gene expression, indicating a resident source of these mediators. Notably, a strong correlation between PAI-1 expression in VAT and circulating protein levels was observed, both being positively associated with markers of acute kidney injury (AKI). In another cohort of septic patients stratified by incidence of AKI, circulating PAI-1 levels were higher in those with versus without AKI, thus extending these findings beyond intra-abdominal cases. This study is the first to translate upregulation of VAT mediators in sepsis from mouse to human. Collectively, the data suggest that development of AKI in septic patients is associated with high plasma levels of PAI-1, likely derived from resident cells within VAT.
Insights
Visceral adipose tissue (VAT) actively releases inflammatory mediators during sepsis in humans, mirroring rodent studies. High levels of plasminogen activator inhibitor-1 (PAI-1) in VAT correlate with acute kidney injury (AKI) in septic patients.
Area of Science:
- Sepsis Pathophysiology
- Adipose Tissue Biology
- Renal Medicine
Background:
- Preclinical sepsis models in rodents often fail to translate to human outcomes.
- Visceral adipose tissue (VAT) was previously identified as a key source of inflammatory and coagulant mediators in murine sepsis models.
- The role and clinical significance of VAT-derived mediators in human sepsis remain largely unexplored.
Purpose of the Study:
- To investigate whether findings from rodent sepsis studies regarding VAT mediator production are recapitulated in human sepsis patients.
- To evaluate the clinical significance of VAT-derived inflammatory and coagulant mediators in sepsis.
- To determine the association between VAT mediator expression and the development of acute kidney injury (AKI) in sepsis.
Main Methods:
- Obtained visceral adipose tissue (VAT) and plasma samples from patients undergoing intra-abdominal operations, categorized into non-inflammatory (control), local inflammation, and sepsis groups.
- Analyzed gene expression of pro-inflammatory (TNFα, IL-6, IL-1α, IL-1β) and pro-coagulant (PAI-1, PAI-2, TSP-1, TF) mediators in mesenteric and epiploic VAT depots.
- Correlated VAT mediator expression with histological findings, circulating plasma levels, and clinical markers of acute kidney injury (AKI).
Main Results:
- Gene expression of key pro-inflammatory and pro-coagulant mediators was significantly increased in mesenteric and epiploic VAT from septic patients compared to controls.
- Omental VAT showed depot-specific regulation, with increased expression limited to IL-1β, PAI-1, and PAI-2.
- A strong positive correlation was observed between VAT PAI-1 expression, circulating PAI-1 levels, and markers of AKI in septic patients.
- Septic patients with AKI exhibited higher circulating PAI-1 levels compared to those without AKI.
Conclusions:
- This study successfully translates the upregulation of VAT mediators during sepsis from mouse models to human patients.
- Increased expression of PAI-1 within VAT is associated with elevated circulating levels and contributes to the development of AKI in sepsis.
- Resident cells within VAT are likely a primary source of these upregulated mediators during human sepsis.
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