# Improvement of Organ Function after Severe Hypovolemia

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2022 · $541,529

## Abstract

PROJECT DESCRIPTION: Hemorrhagic shock (HS) is a significant cause of death in the US and is
frequently followed by infection and sepsis. As a result, many patients suffering from HS or HS+sepsis
develop acute lung injury (ALI), a life-threatening complication. We have previously discovered that eCIRP,
a new DAMP, released after HS or sepsis worsens disease severity and lethality. Our preliminary studies
have confirmed elevated levels of eCIRP in the circulation of patients and animals after HS, as well as in the
supernatant of macrophages exposed to hypoxia/reoxygenation (H/R). We have also shown that H/R or
endotoxin promotes gasdermin D (GSDMD) cleavage into pore-forming subunits. The release of eCIRP
after endotoxin was decreased by a GSDMD pore formation inhibitor and in cells from GSDMD knockout
mice, implicating an important role of GSDMD in eCIRP’s active release. We have demonstrated that
eCIRP activates stimulator of interferon genes (STING) in vitro and in vivo, leading to the upregulation and
release of type I interferons (IFNs). Furthermore, we have shown that STING activation is critical to the
development of systemic inflammation, tissue injury, ALI, and mortality after HS. We have also
demonstrated that eCIRP promotes mitochondrial (mt) DNA fragmentation, thus providing a plausible
mechanism for how eCIRP activates STING. In addition, we have shown for the first time that type I IFNs
play a pivotal role in the development of ALI after HS. Based on these novel findings, we hypothesize that
eCIRP, released through GSDMD pores, activates STING via fragmented mtDNA and increases the release
of type I IFNs, ultimately leading to ALI and death after HS or HS+sepsis. Moreover, we have predicted in
silico and confirmed in vitro that our newly discovered RNA mimic A12 binds to eCIRP with high affinity, in-
hibiting eCIRP’s ability to induce TNFα release from macrophages. A12 had a long half-life in the circulation
and reduced inflammation and tissue injury after HS. Therefore, we further hypothesize that eCIRP
inhibition with A12 attenuates ALI and mortality in mice subjected to HS or HS+sepsis. In this project, we
plan to establish the role of GSDMD pore formation on the active release of eCIRP, determine the detailed
mechanism by which eCIRP activates STING, and examine the beneficial effects of the novel eCIRP
inhibitor A12 on ALI and survival after HS or HS+sepsis. These studies shall provide novel mechanistic
insights into the pathogenesis of ALI and organ injury after HS or HS complicated by sepsis, as well as a
new potential therapeutic strategy to treat patients under those conditions.

## Key facts

- **NIH application ID:** 10375241
- **Project number:** 2R01HL076179-13
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** PING WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $541,529
- **Award type:** 2
- **Project period:** 2004-02-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375241

## Citation

> US National Institutes of Health, RePORTER application 10375241, Improvement of Organ Function after Severe Hypovolemia (2R01HL076179-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10375241. Licensed CC0.

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