# Mechanistic insights of inflammation and organ failure after trauma or critical illness

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $313,500

## Abstract

Abstract/Summary
 Aspiration of non-infectious gastro-esophageal contents and/or exposure to high concentrations of
supplemental oxygen are common events in trauma, anesthetized and/or other critically ill patients. Some of
these patients will develop a more serious and protracted pulmonary or systemic inflammatory response leading
to acute lung injury (ALI) or worse, acute respiratory distress syndrome (ARDS). Despite recent advances in
critical care medicine, overall mortality from ARDS remains unacceptably high, reflecting the lack of specific
therapies. Currently, the pathogenesis of this devastating syndrome remains incompletely understood,
particularly after the “non-infectious” or “sterile” stimuli as mentioned above.
 The characteristic features of ALI/ARDS include an intense inflammatory response, severe injury to the
epithelial / endothelial barrier and alveolar edema. Recent evidence suggests that type I alveolar epithelial (ATI)
cell have previously unrecognized functions in innate immunity and are underappreciated players in lung cell-
cell cross-talk. Based on our published and preliminary data, we propose that ATI cell-derived microvesicles
(ATI-MVs) mediate the intercellular communication between ATI cells and alveolar macrophages (AMs) by the
shuttling of selective miRNAs, thus broadcasting distress signals to the recipient cells and initiating the
inflammatory cascades.
 In our previous work, we have reported that epithelial extracellular vesicles (EVs) are inducible and detectable
in both mouse broncho-alveolar lavage fluid (BALF). After exposure to aspirated acid or hyperoxia (sterile
model of ALI), most of the induced E Vs originate from living ATI epithelial cells and fall into the range of
microvesicles (MVs). We further showed that MV-shuttling miRNAs promoted classic macrophage activation
and migration in vitro and lung inflammation in vivo. Lipid raft protein caveolin-1 (cav-1) facilitates the selection
of miRNA complex in the MVs. Based on our published and the supporting data, we hypothesize that the type I
alveolar epithelial MVs mediate non-infectious stimuli-associated inflammation via promoting macrophage
activation and recruitment through MV-miRNAs. We also hypothesize that the stimuli-induced cav-1 /
hnRNPA2B1 interaction and modification regulate the incorporation of selective miRNAs into MVs. We will test
our hypotheses in the following specific aims. In aim I: we will characterize the secretion of MV-miRNAs and their
target cells in the presence of non-infectious stimuli. In aim II, we will determine the mechanisms of the miRNA
selection in MVs. In aim III, we will determine the functions of MV-miRNAs after non-infectious stimuli.

## Key facts

- **NIH application ID:** 9894815
- **Project number:** 5R01GM127596-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Yang Jin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $313,500
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9894815

## Citation

> US National Institutes of Health, RePORTER application 9894815, Mechanistic insights of inflammation and organ failure after trauma or critical illness (5R01GM127596-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9894815. Licensed CC0.

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