# Endothelial JAK3 expression and inflammatory lung injury in sepsis

> **NIH NIH R21** · UNIVERSITY OF KENTUCKY · 2020 · $191,250

## Abstract

Project Summary
Sepsis remains a major cause of death in critically ill patients. New therapeutic strategies are
needed to treat this devastating disease. Excessive inflammatory responses, which lead to
inflammatory tissue injury, contribute to the pathogenesis of multiple organ failure in sepsis.
Recent studies have demonstrated that JAK3 is a promising target against various inflammatory
diseases. However, the regulation and function of JAK3 in sepsis have not been studied. In our
preliminary studies, we demonstrated that JAK3 expression is highly up-regulated during sepsis.
Selective JAK3 inhibition by JAK3 inhibitors, including a FDA-approved inhibitor Tofacitinib,
blocked endothelial inflammatory signaling and inflammatory lung injury during sepsis.
Furthermore, we demonstrated that JAK3 expression is controlled by HDAC6, a histone
deacetylase that modulates nuclear and non-nuclear protein function through deacetylation.
HDAC6 knockdown or inhibition prevented TNF-α induced endothelial JAK3 expression, STAT1
activation, and leukocyte adhesion molecule ICAM-1 expression. In a mouse model of
polymicrobial sepsis, HDAC6 inhibition blocked sepsis-induced JAK3 expression. In the proposed
studies, we will conduct a serial of experiments to assess the therapeutic potential of JAK3
inhibition against sepsis-induced inflammatory lung injury, and to investigate the regulation of
JAK3 by HDAC6 during sepsis.

## Key facts

- **NIH application ID:** 9858236
- **Project number:** 5R21AI142576-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Jian Fu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $191,250
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9858236

## Citation

> US National Institutes of Health, RePORTER application 9858236, Endothelial JAK3 expression and inflammatory lung injury in sepsis (5R21AI142576-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9858236. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*