# Mechanism of Trauma/Hemorrhagic Shock-Predisposed Sepsis

> **NIH NIH R21** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $238,500

## Abstract

Abstract
 It is well known in clinics that survivors of severe trauma and hemorrhagic shock (T/HS) face a significant
risk of developing sepsis from infections, which causes high mortality. However, as the mechanisms of T/HS-
predisposed infection remain unclear, few specific targets linking T/HS to elevated risk of sepsis have been
identified. This proposal aims to address this important clinical problem by elucidating a previously unknown
mechanism of T/HS regulation of immunometabolism that predisposes patients to infection. Here, we focus
on the formation of a positive feedback loop for 12(S)-HETE-ALOX15, which is an unusual mechanism for
the metabolite,12(S)-HETE, to upregulate the expression of its rate-limiting enzyme ALOX15.
 Emerging studies have demonstrated the important role of fatty acids (FAs) in the regulation of
inflammation. A previous study identified plasma 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] as a
biomarker predicting trauma patient mortality, where 12(S)-HETE levels in non-surviving patients with severe
trauma are 5-time higher than those in trauma survivors at the time of hospital admission. 12(S)-HETE is a
metabolite from arachidonic acid (AA) generated by lipoxygenases. ALOX15, a lipoxygenase, is the rate-
limiting enzyme in generating 12(S)-HETE. In our preliminary studies, we observed that 1) 12(S)-HETE
increased host susceptibility to infection following T/HS; 2) 12(S)-HETE induces enhanced ALOX15
expression in macrophages (MPs), which forms a positive feedback loop that leads to enhanced generation
of 12(S)-HETE, augmented MP death, and decreased bacteria clearance; and 3) blocking the feedback loop
by genetic deletion of 12(S)-HETE receptor GPR31 or suppression of ALOX15 increased the bacteria
clearance ability in the lungs and improved the survival rate following post-T/HS infection. Based on these
findings, we hypothesize that the 12(S)-HETE-induced ALOX15 expression forms a positive feedback
loop and serves as a novel mechanism underlying T/HS-predisposed sepsis. Blocking the feedback
loop by ALOX15 inhibitor may present a therapeutic and preventive strategy for T/HS-predisposed
sepsis. We propose two specific aims to test this hypothesis: Aim 1 is to determine the mechanism of 12(S)-
HETE upregulation of ALOX15 expression in T/HS; and Aim 2 is to determine the role of 12(S)-HETE-
ALOX15 feedback loop in the mechanism of T/HS-predisposed sepsis.
 To our knowledge, this study is the first attempt to evaluate the role of the T/HS-induced 12(S)-HETE-
ALOX15 feedback loop in infection and sepsis susceptibility. We reason that the metabolite-enzyme
feedback loop may represent an unexplored mechanism of T/HS-primed infection. Understanding this
mechanism may provide a novel therapeutic target for the prevention and treatment of post-T/HS sepsis.

## Key facts

- **NIH application ID:** 10949698
- **Project number:** 1R21AI185275-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jie Fan
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $238,500
- **Award type:** 1
- **Project period:** 2024-06-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10949698

## Citation

> US National Institutes of Health, RePORTER application 10949698, Mechanism of Trauma/Hemorrhagic Shock-Predisposed Sepsis (1R21AI185275-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10949698. Licensed CC0.

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