# Effects of Exercise on Inflammation-Induced Lung and Muscle Injury in Critical Illness (NEXIS-FLAME)

> **NIH NIH R01** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2020 · $63,581

## Abstract

Project Summary
Early mobility, the process of engaging patients in exercise and/or physical therapy during their clinical care,
is a promising treatment for severe critical illnesses, such as acute respiratory failure (ARF), where it
improves a variety of clinical and functional outcomes. How early mobility/exercise exacts these benefits,
however, is unknown and understudied. This lack of knowledge is notable because the implementation of
exercise/activity interventions in these populations is extremely challenging and resource intensive.
Knowledge of the mechanisms underlying the beneficial effects of early mobility/exercise would provide
specific cellular and molecular targets that would allow clinicians to refine interventions and stimulate
development of exercise-mimetic therapeutics in settings where resources and personnel limit the application
of classical mobility/exercise interventions. To address this knowledge gap, our goal in this application is to
determine the mechanisms whereby exercise modulates systemic and end organ inflammation and damage
in ARF. We will use reverse and forward translational approaches to realize this goal, building on our pre-
clinical model of early mobility and human data in patients with lung injury. Based on strong preliminary data
from these sources, we propose a hypothetical model in which a systemic inflammatory response during the
early phase of critical illness, mediated via the IL-17/G-CSF axis, causes lung injury and skeletal muscle
wasting secondary to immune cell infiltration and inflammation. Moreover, exercise applied during this phase
lessens end-organ injury/wasting by specifically attenuating the systemic and local innate immune
responses. We will examine these hypotheses in critically ill humans by leveraging an NHLBI-funded
randomized controlled trial (NEXIS RCT, R01HL132887, NCT03021902) of early exercise and amino acid
supplementation versus usual care in critically ill patients with ARF, as well as carefully selected animal
models to extend our insights. As, the NEXIS RCT began recruitment in September 2017, we hope that the
current application will be funded allowing us to capture most of the NEXIS participants for crucial
biospecimen collection. We anticipate that our results will yield seminal, mechanistic knowledge of the
beneficial effects of exercise to reduce systemic and end organ inflammation and, in turn, lung and skeletal
muscle damage. Our results also hold the potential to identify a novel mechanism of exercise's systemic
benefits through modulation of a novel myokine that alters the systemic and local inflammatory response.
Our findings, therefore, will advance both basic scientific knowledge and clinical practice towards the goal of
improving short-term clinical and long-term functional outcomes in patients with critical illness and other
inflammatory conditions.

## Key facts

- **NIH application ID:** 10134022
- **Project number:** 3R01HL143452-03S1
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Daniel Clark Files
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $63,581
- **Award type:** 3
- **Project period:** 2018-09-15 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134022

## Citation

> US National Institutes of Health, RePORTER application 10134022, Effects of Exercise on Inflammation-Induced Lung and Muscle Injury in Critical Illness (NEXIS-FLAME) (3R01HL143452-03S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10134022. Licensed CC0.

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