# Macrophage Pyroptosis Mechanism of Post-Trauma Acute Lung Injury

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $391,250

## Abstract

Macrophage Pyroptosis Mechanism of Post-Trauma Acute Lung Injury
ABSTRACT
 Trauma is a major cause of systemic inflammatory response syndrome (SIRS) and multiple organ
dysfunction syndrome (MODS), in which acute lung injury (ALI) is an important component. The underlying
mechanism of how trauma leads to SIRS, MODS, and ALI has yet to be fully determined, but understanding
these mechanisms is of prime importance as early interventional treatment of trauma patients may prevent
organ failure and damage that usually occurs days later. Our long-term goal is to determine the mechanism
by which trauma promotes ALI, thereby, potentially identifying novel targets for prophylactic intervention.
 We have reported a novel mechanism by which damage-associated molecular pattern (DAMP)
molecules induce macrophage (Mφ) pyroptosis, a caspase-1-dependent programmed cell death. The
ultimate osmotic lysis of pyroptotic cells releases intracellular contents and causes inflammation. Our
following preliminary studies further show that: 1) HMGB1 induces human peripheral monocyte pyroptosis;
2) circulating monocyte pyroptosis does occur in trauma patients, and intracellular inflammasome
components are released and can be detected in sera of trauma patients about four days after trauma; 3)
Mφ phagocytosis of extracellular Nlrp3 inflammasome components activates inflammatory responses in the
Mφ; 4) in a mouse model of HS/trauma, alveolar macrophage (AMφ) pyroptosis is induced in a HMGB1-
RAGE-dependent manner; and 5) AMφ pyroptosis is associated with augmented lung inflammation.
 Based on the above findings, we hypothesize that: 1) HMGB1-RAGE signaling serves as a novel
mechanism that induces Mφ pyroptosis following trauma; and 2) Mφ pyroptosis promotes the development of
ALI after trauma by influencing inflammatory processes; and 3) inflammasome components that are released
from pyroptotic Mφ serve as novel secondary danger signals to induce amplified inflammation. In order to test
these hypotheses, we propose the following two specific aims: Specific Aim 1: To determine the molecular
mechanism through which trauma induces Mφ pyroptosis. Specific Aim 2: To determine the role of Mφ
pyroptosis in the development of ALI following trauma.

## Key facts

- **NIH application ID:** 9963346
- **Project number:** 5R01HL139547-03
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Jie Fan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,250
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963346

## Citation

> US National Institutes of Health, RePORTER application 9963346, Macrophage Pyroptosis Mechanism of Post-Trauma Acute Lung Injury (5R01HL139547-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963346. Licensed CC0.

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