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

Award Number: R01HL143452
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = -$198,746 )
2025	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	4	11/25/2024	NON-COMPETING CONTINUATION	-$198,746
														Subtotal = -$198,746

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	4	6/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $810,859 )
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	001	4	7/29/2021	NON-COMPETING CONTINUATION	$747,278
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	002	4	9/16/2021	SUPPLEMENT FOR EXPANSION	$63,581
2021	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	3	2/8/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $810,859

Issue Date FY: 2020 ( Subtotal = $820,822 )
2020	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	002	3	9/9/2020	SUPPLEMENT FOR EXPANSION	$63,581
2020	2020	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	001	3	7/15/2020	NON-COMPETING CONTINUATION	$757,241
2020	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	2	3/24/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $820,822

Issue Date FY: 2019 ( Subtotal = $778,606 )
2019	2019	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	001	2	8/1/2019	NON-COMPETING CONTINUATION	$778,606
2019	2018	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	1	11/15/2018	NEW	$0
														Subtotal = $778,606

Issue Date FY: 2018 ( Subtotal = $803,292 )
2018	2018	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Lung Diseases Research	000	1	9/12/2018	NEW	$803,292
														Subtotal = $803,292

Grand Total All Awards = $3,014,833

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

Award Number: R01HL143452

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/15/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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