# Amplification Mechanisms of Lung Endothelial Inflammation During Acute Lung Injury

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2023 · $574,586

## Abstract

PROJECT SUMMARY / ABSTRACT
Lung failure from endotoxemia and sepsis induces widespread and often rapid lung vascular endothelial injury due
to unfettered influx of inflammatory cells such as neutrophils and macrophages. This maladaptive inflammatory
response outpaces the reparative capacity of lungs, resulting in profound inflammatory lung injury and hypoxemia.
This proposal focuses on fundamental amplification mechanisms underlying the maladaptive inflammatory
activation of the lung endothelium. Our central hypothesis is that the inflammatory response to threat signals such
as the initial breaching of the endothelial plasma membrane by bacterial lipopolysaccharide (LPS) and rapid release
of mitochondrial DNA by the injured mitochondria into the cytosol massively and acutely amplifies the inflammatory
response and thus serves as essential feed-forward mechanisms for progression of acute lung injury (ALI). In Aim
1, we will determine the mechanisms by which the recently identified perforin Gasdermin D mediates
endothelial plasma membrane pore formation and the mechanisms of activation of the K+ efflux ion channel
TWIK2 that we have recently identified. We will address the role of amplifying K+ efflux on the severity and
rapidity of endothelial NLRP3 inflammasome activation and fulminant lung injury. In Aim 2, we will define
another crucial amplification mechanism, the potentially important role of Gasdermin D-mediated
mitochondrial (mt) membrane pore formation and the release of mtDNA, which may also catastrophically
amplifiy lung injury via activation of Type I interferon signaling. These mechanistically driven studies will utilize
genetic mouse models (endothelial specific knockout models in our labs) as well as comprehensive imaging,
electrophysiological and physiological approaches and thus provide the framework for identifying novel endothelial
amplification inflammatory mechanisms that induce lung vascular injury and ALI. We will elucidate how these
pathways can be targeted to reduce tissue damage and improve survival.

## Key facts

- **NIH application ID:** 10543845
- **Project number:** 5R01HL152515-03
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Asrar B. Malik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $574,586
- **Award type:** 5
- **Project period:** 2021-01-15 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10543845

## Citation

> US National Institutes of Health, RePORTER application 10543845, Amplification Mechanisms of Lung Endothelial Inflammation During Acute Lung Injury (5R01HL152515-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10543845. Licensed CC0.

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