# A Mechanistic Clinical Trial of JAK Inhibition to Prevent Ventilator-induced Diaphragm Dysfunction

> **NIH NIH R01** · STANFORD UNIVERSITY · 2020 · $391,250

## Abstract

The goal of this project is to identify a drug that could be administered to patients who
require mechanical ventilation (MV) in our intensive care units – a drug which would reduce the
time patients are required to be on the ventilator.
 It is known that MV leads to weakness of the diaphragm (ventilator-induced diaphragm
dysfunction – “VIDD”). Since the diaphragm is the muscle that is primarily responsible for
moving air into the lungs during breathing, if it becomes weak, then it becomes more difficult to
separate patients from the ventilator. The resulting long-term dependence on the ventilator is
associated with increased rates of complications and death. A drug that can be given at the
initiation of MV and prevent weakness of the diaphragm will therefore reduce ventilator
dependence and complications/deaths in intensive care unit (ICU) patients.
 Based upon work we have done previously, we know that inter-related molecules called
“JAK” and “STAT3” are important in the etiology of VIDD in both animals and in humans. When
we blocked the action of these molecules with a JAK inhibitor drug in mechanically ventilated
animals, diaphragm weakness did not occur. We therefore believe that a JAK inhibitor holds
promise as a drug to prevent VIDD in mechanically ventilated patients.
 We propose to study mechanically ventilated human subjects to determine if the FDA-
approved JAK inhibitor, Tofacitinib, will prevent the activation of the biological processes that we
know lead to VIDD and prevent VIDD itself. To achieve this, we will take 2 small diaphragm
biopsies, 6 hours apart, in patients undergoing esophagectomy, and we will study the effects
that MV and Tofacitinib have on the changes that occur in this tissue. Patients will be
randomized to receiving Tofacitinib vs placebo prior to esophagectomy and diaphragm biopsies:
Aim 1 –Study the biopsies to determine if JAK inhibition prevents the activation of JAK/STAT
and known downstream effectors of VIDD in human diaphragm subjected to MV.
Aim 2 –Study the biopsies to determine if JAK inhibition prevents the diaphragm weakness
which defines VIDD in human diaphragm subjected to MV.
 This study will provide the required information to support a subsequent clinical trial in
ICU patients, which we hope would establish that JAK inhibition will indeed reduce the duration
of MV, complications, and deaths. It will also advance this field by allowing us to study
pathways beyond JAK/STAT that may be important in causing VIDD in human diaphragm.

## Key facts

- **NIH application ID:** 10001628
- **Project number:** 5R01HL148185-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Leah M Backhus
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $391,250
- **Award type:** 5
- **Project period:** 2019-08-20 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001628

## Citation

> US National Institutes of Health, RePORTER application 10001628, A Mechanistic Clinical Trial of JAK Inhibition to Prevent Ventilator-induced Diaphragm Dysfunction (5R01HL148185-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001628. Licensed CC0.

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