# Indole Metabolites as Xenobiotic Danger signals in Acute Lung Injury

> **NIH NIH R56** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $607,952

## Abstract

ABSTRACT
This application is for an NHLBI R01 entitled “Indole Metabolites as Xenobiotic Danger Signals in Acute Lung
Injury.” I am a physician in Pulmonary and Critical Care Medicine at the University of Pittsburgh, and I am building
a research program focused on the studying the intersection of danger signals and host responses in epithelial
cells in the pathogenesis of Acute Respiratory Distress Syndrome (ARDS). ARDS is an urgent public health problem
characterized by severe inflammatory lung injury with impaired gas exchange, a high mortality risk (up to 40%), and
long-term morbidity in survivors. Beyond supportive clinical care bundles that define the standard-of-care for ARDS,
there are few effective therapeutic strategies. Recent work has convincingly demonstrated that mortality in ARDS
and a larger group of patients at risk for ARDS is linked to excessive inflammation. However, the underlying
biological pathways driving these processes are only partially understood. Danger signals are proximal activators
of the innate immune system, and recognition of danger signals by the host initiate regulated cell death programs
and inflammatory pathways in lung epithelial cells. Danger signal activation of regulated cell death and
inflammation evolved to promote pathogen clearance, but these processes are deleterious and even fatal to the
host when activated in excess. In this proposal we describe novel danger signals to lung epithelial cells derived
from metabolites that function as Metabolism-Associated Molecular Patterns (MAMPs). Using high throughput
screens of metabolite libraries, we identified microbe-derived indole metabolites as novel danger signals that
activate regulated cell death pathways in lung epithelial cells. We show indole metabolites exacerbate LPS-
induced lung injury in vivo in mice, and in humans with ARDS we measured indole metabolites and found several
to be highly elevated compared to mechanically-ventilated patients without lung injury. In this proposal we will
investigate the following Aims: Aim 1: Determine the mechanism of indole metabolite-mediated cell death. We will
investigate indole metabolite toxicity to lung epithelial cells through CYP2F1/2-dependent biotransformation and
activation of inflammatory cell death programs. Aim 2: Determine the role of cAMP signaling in protecting from
indole metabolite cellular toxicity. We will validate key candidate genes identified through an RNAi screen and
repurposed drugs that augment cAMP signaling for protective effects against indole metabolite toxicity. Aim 3:
Determine ex-vivo toxicity of indole metabolites to human lungs and associations of indole metabolite levels with
hyperinflammatory respiratory failure and clinical outcomes. We will test indole metabolites in a human ex-vivo
lung perfusion platform and enroll patients in our Acute Lung Injury Registry to determine if indole metabolite levels
are associated with the hyperinflammatory respiratory failure subphenotype. ...

## Key facts

- **NIH application ID:** 11175788
- **Project number:** 1R56HL174649-01
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** John W Evankovich
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $607,952
- **Award type:** 1
- **Project period:** 2024-09-16 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11175788

## Citation

> US National Institutes of Health, RePORTER application 11175788, Indole Metabolites as Xenobiotic Danger signals in Acute Lung Injury (1R56HL174649-01). Retrieved via AI Analytics 2026-06-03 from https://api.ai-analytics.org/grant/nih/11175788. Licensed CC0.

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