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Trafficking and function of macrophage subpopulations within the lung microenvironment during pneumonia

Award Number: R01HL145396
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Trafficking and function of macrophage subpopulations within the lung microenvironment during pneumonia - Pneumonia is a common disease and a frequent cause of morbidity and mortality. S. pneumoniae is the most common cause of community-acquired pneumonia and a major health concern. Understanding lung host defense in response to this organism and successful resolution of inflammatory and immune responses is important and likely to have impact on novel ways to intervene therapeutically. Lung macrophages are a critical arm of host defense in healthy lungs and in response to infection or any injury. The classification of subpopulations is very topical and controversial. We have focused on macrophage categories designated by surface markers that identify three subpopulations; alveolar macrophages (AMs), interstitial macrophages (IMs) and inflammatory macrophages (InfMs). In unchallenged lungs, our preliminary studies show that AMs are the only lavageable macrophage present in the airways/alveoli. Digests of PBS-treated (control) lungs reveal that of total lung macrophages, about 28% are AMs, 50% are IMs, and 22% are InfMs. Gene profiling of isolated subpopulations reveals very distinct patterns of mRNA expression by each subpopulation, suggesting in health, each subpopulation has unique functions. During pneumonia, the percentage and number of each subpopulation changes dramatically. Initially, the total number of lung macrophages increases 3-4-fold, which reflects a decrease in the number of AMs, an increase in InfMs and no change in IMs. By 14 days, the numbers are nearly back to those in healthy lungs, but AMs are now from both bone marrow and lung-resident origins. Thus, these subpopulations are very dynamic and very likely to have specific functions that may change within each subpopulation over the course of a pneumonia. Furthermore, these cell-specific changes in number and function are very likely to be modulated by the alveolar microenvironment, which changes during infection and the immune response. Our studies use lung-protected radiation and bone marrow reconstitution that generates chimeric mice but does not alter the lung macrophage subpopulations. The Aims test the overall hypothesis that subpopulations of lung macrophages each play specific and important roles in host defense during bacterial pneumonia, with the expectation of identifying new and important mechanisms underlying these processes. Aim 1 determines trafficking kinetics, including changes in the subpopulations of lung macrophages during pneumonia and the mechanisms through which these changes occur. Aim 2 determines the function of each macrophage subpopulation. Aim 3 determines the effect of the alveolar microenvironment on the kinetics and function of macrophage subpopulations. These studies test the hypothesis that trafficking and function of particular subpopulations will be modulated by parenchymal ICAM-1, by the CX3CL1/R1 (fractalkine) axis, and by Nrf2-mediated cytoprotection against oxidant damage.


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 = -$2,680 )
2025	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	4	4/29/2025	NON-COMPETING CONTINUATION	-$2,680
														Subtotal = -$2,680

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	4	1/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $585,761 )
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	4	12/6/2021	NON-COMPETING CONTINUATION	$527,184
2022	2022	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	001	4	6/14/2022	NON-COMPETING CONTINUATION	$58,577
														Subtotal = $585,761

Issue Date FY: 2021 ( Subtotal = $585,761 )
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	3	12/21/2020	NON-COMPETING CONTINUATION	$527,184
2021	2021	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	001	3	5/19/2021	NON-COMPETING CONTINUATION	$58,577
														Subtotal = $585,761

Issue Date FY: 2020 ( Subtotal = $585,761 )
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	2	12/19/2019	NON-COMPETING CONTINUATION	$556,472
2020	2020	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	001	2	3/13/2020	NON-COMPETING CONTINUATION	$29,289
														Subtotal = $585,761

Issue Date FY: 2019 ( Subtotal = $585,761 )
2019	2019	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	104 AIRPORT DR STE 2200	CHAPEL HILL	NC	27599	ORANGE	USA	Lung Diseases Research	000	1	12/19/2018	NEW	$585,761
														Subtotal = $585,761

Grand Total All Awards = $2,340,364

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Trafficking and function of macrophage subpopulations within the lung microenvironment during pneumonia

Award Number: R01HL145396

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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