# Function and mechanisms of extracellular microRNAs in sepsis-induced lung injury

> **NIH NIH R35** · UNIVERSITY OF MARYLAND BALTIMORE · 2021 · $384,150

## Abstract

Project summary
Sepsis is a clinical syndrome with life-threatening organ dysfunction that is caused by a dysregualted
host response to infection. Lung is one of the first organs to fail during sepsis and contribute to high
mortality. Lung endothelial dysfunction is a hallmark of sepsis-induced acute lung injury (ALI),
where inflammation plays an important role. We have recently found a rise in the plasma cell-free
RNA including miRNAs in sepsis. These extracellular (ex) RNAs are released from host cells as well
as invading bacteria and closely correlated with sepsis severity. Plasma miRNA array identifies six
miRNAs that are elevated in response to sepsis; four of them (miR-34a, -122, -145, -146a) induce
marked cytokine production and complement activation in macrophages via the innate immune
TLR7 signaling. Importantly, systemic inhibition of ex-miR-146a attenuates cytokine IL-6
production in the plasma and the lung tissue of septic animals. These preliminary data suggest an
important role of ex-miRNAs in acute lung inflammation and possible lung injury in sepsis.
This MIRA research program will test the hypothesis that ex-miRNA plays an important role in acute
lung injury during polymicrobial sepsis. Specifically, the Program will address the following 3 key
questions: 1) what is the role of ex-miRNAs in sepsis-induced ALI? 2) what are the underlying
molecular mechanisms responsible for the ex-miRNA-mediated ALI in sepsis? 3) can we develop an
anti-miRNA strategy to treat sepsis-induced ALI? To answer these key questions, the Program is
structured with 3 projects. In Project-1, we will define the role of the target 4 ex-miRNAs in sepsis-
induced ALI using anti-miR strategy and carefully evaluate the biological function of these ex-
miRNAs and their carriers (exosomes and Ago-2) in inflammatory response. In Project-2, we will
determine the underlying mechanisms by which miRNAs increase lung endothelial cell permeability
with focus on cell junction protein VE-cadherin and Claudin-5. The impact of the ex-miRNAs on the
cell-cell interaction between leukocytes and lung endothelial cells will also be examined. In Project-3,
through a series of pre-clinical and proof-of-concept studies, we will assess the feasibility and
efficacy of developing a new therapeutic strategy by targeting ex-miRNAs and their specific receptor
TLR7 in the treatment of sepsis-induced ALI. The toxicity and safety of the anti-miRNAs and TLR7
antagonist will be carefully tested.

## Key facts

- **NIH application ID:** 10247518
- **Project number:** 5R35GM124775-05
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Lin Zou
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $384,150
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247518

## Citation

> US National Institutes of Health, RePORTER application 10247518, Function and mechanisms of extracellular microRNAs in sepsis-induced lung injury (5R35GM124775-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10247518. Licensed CC0.

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