# IL-33 signaling as a target to reduce ventilator-induced lung inflammation

> **NIH NIH R56** · UNIV OF MASSACHUSETTS MED SCH WORCESTER · 2022 · $810,172

## Abstract

PROJECT SUMMARY/ABSTRACT
Since being heralded into clinical practice by the Danish polio epidemic of 1952, positive pressure mechanical
ventilation has saved countless lives and enabled the safe practice of surgery under general anesthesia. In
recent years, however, it has become clear that mechanical ventilation itself can injure the lung by initiating
and propagating an inflammatory process termed ventilator-induced lung injury (VILI). Whereas VILI was
initially mainly considered an aggravating factor for critically ill patients with acute respiratory distress
syndrome, new evidence suggests that it can occur also in subjects with uninjured lungs undergoing ventilation
for other reasons, for example while receiving general anesthesia. The long-term goal of this research is to
dissect the mechanisms of VILI and identify strategies to ameliorate it. The proposed studies align with this
goal because they investigate a novel role for the IL-33/ST2 signaling pathway by addressing the overarching
hypothesis that IL-33 is an upstream pathogenetic effector of VILI through its effect on NF-κB mediated
inflammation. This hypothesis will be tested through three closely knit specific aims. Aim 1 will establish the
role of IL-33 in VILI by demonstrating that its expression increases with tidal volume, that it parallels the
response of established VILI cytokines and NF-κB, and that IL-33 deletion blunts such response. Aim 2 builds
on aim 1 by probing the efficacy of IL-33 scavenging with IL-33 decoy receptors as an approach for interrupting
IL-33/ST2/NF-κB signaling and decreasing inflammation in VILI. This aim will leverage a novel biologic with
high affinity for IL-33 (“IL-33 trap”) that preliminary data suggest could have therapeutic potential. The IL-33
trap will be compared with the more traditional approach of anti-ST2 receptor blocking antibodies. Aim 3 flows
from aims 1 and 2 as it will determine for how long the activation of NF-κB triggered by release of mechano-
sensitive cytokines like IL-33 persists after ventilation ceases, thus rendering the lung vulnerable to other
insults, as are those that can occur in the postoperative period. A distinctive feature that permeates all three
aims of this project is the application of a unique molecular imaging method based on positron emission
tomography (PET) of NF-κB transcriptional activity to measure the effect of IL-33/ST2 signaling on downstream
cytokine expression in vivo, noninvasively, repeatedly and with high spatial resolution. It is expected that the
combination of clinically relevant murine ventilation model, novel VILI effector (IL-33, aim 1), therapeutic
biologic (IL-33 trap, aim 2), and translational perspective (aim 3), will make the proposed experiments uniquely
poised to yield fundamental new knowledge on the pathogenesis of VILI and on potential preventative and
therapeutic strategies.

## Key facts

- **NIH application ID:** 10704302
- **Project number:** 1R56HL161209-01
- **Recipient organization:** UNIV OF MASSACHUSETTS MED SCH WORCESTER
- **Principal Investigator:** Guido Musch
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $810,172
- **Award type:** 1
- **Project period:** 2022-09-21 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10704302

## Citation

> US National Institutes of Health, RePORTER application 10704302, IL-33 signaling as a target to reduce ventilator-induced lung inflammation (1R56HL161209-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10704302. Licensed CC0.

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