# Inflammasome activation in trauma-hemorrhagic shock

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $151,350

## Abstract

PROJECT SUMMARY/ABSTRACT
 Controlling inflammation and cellular damage is the key to preventing and treating multiple organ failure
(MOF) following trauma. However, many of the mechanisms that regulate inflammation and cell death in
specific organs remain unknown. This means that despite advances in supportive measures for patients with
MOF, there have been few advances in MOF treatments, or in our ability to adequately prevent the onset of
MOF. Our overarching goal is to ultimately develop new therapeutics for trauma patients based on regulating
the inflammatory response and its effects on cellular death and survival pathways following trauma and
hemorrhagic shock with resuscitation (HS/R). In this proposal we will continue to investigate novel molecular
pathways following HS/R that lead to activation of caspase-11 in end-organs, particularly liver. We will also
determine how activation of inflammatory caspases regulates cell death and inflammation, which in turn
determines organ cell survival after HS/R. Knowing how these cell-signaling pathways function and interact
may guide us toward future therapeutic targets for prevention and treatment of MOF after trauma.
 Inflammatory caspases include caspases-1, 11 (mice), 4/5 (human), and are associated with
inflammatory cell death (pyroptosis) and release of inflammatory cytokines (IL-1β, IL-18). Caspase-11 was
recently identified as the intracellular receptor for lipopolysaccharide (LPS) and forms what has been termed
the non-canonical inflammasome. LPS-mediated caspase-11 activation in macrophages results in cleavage of
gasdermin D (GsdmD) and subsequent release of IL-1β, induction of pyroptosis, and initiation of NLRP3
inflammasome and caspase-1 activation. Caspase-11 can also be activated by endogenous oxidized
phospholipid (oxPAPC) in LPS-primed dendritic cells, although this interaction does not result in pyroptosis.
Our exciting new data show that caspase-11 is activated during HS/R, a non-infectious/sterile injury model,
suggesting a novel mechanism of activation of caspase-11 by endogenous damage associated
molecular patterns (DAMPs) without a requirement for LPS. We show that once again mitochondria are
integral in activation of inflammatory responses after HS/R, and cardiolipin externalization on damaged and
stressed mitochondria can activate caspase-11. Surprisingly activation of caspase-11 in HC after HS/R does
not lead to pyroptosis, but is vital for active release of HC HMGB1 in exosomes, and caspase-11 activation
is detrimental in HS/R. Our preliminary findings lead us to our main hypothesis that DAMP-induced
caspase-11 activation has cell specific functions during HS/R, and is an important regulator of cell
death and organ damage.
We expect to confirm novel, mitochondrial DAMP-mediated pathways of activation of caspase-11, and novel
functions of caspase-11 in liver that may make it an attractive therapeutic target during trauma/HS.

## Key facts

- **NIH application ID:** 10071283
- **Project number:** 3R01GM102146-08S1
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Melanie J. Scott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $151,350
- **Award type:** 3
- **Project period:** 2013-01-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071283

## Citation

> US National Institutes of Health, RePORTER application 10071283, Inflammasome activation in trauma-hemorrhagic shock (3R01GM102146-08S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071283. Licensed CC0.

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