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Mechanisms of Impaired Inflammation Resolution in Cystic Fibrosis Lung Disease

Award Number: R01HL174700
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Mechanisms of Impaired Inflammation Resolution in Cystic Fibrosis Lung Disease - Patients with cystic fibrosis (CF) suffer from chronic infections and lung inflammation leading to bronchiectasis and, ultimately, respiratory failure. Although recent advances, including the approval of highly effective CFTR modulator therapy (HEMT), have improved the overall quality of life of people with CF (PwCF), chronic infection and inflammation are the primary cause of morbidity. Although the magnitude of the inflammatory response is known to be increased in the CF lung, the mechanisms underlying persistent inflammation are unknown. We have shown that lung macrophages are critical to the local inflammatory response in CF. Lung macrophages include functionally distinct subpopulations including CD169+ and CD169- lung macrophages. Our preliminary data demonstrate that CF CD169- lung macrophages have decreased expression of Nrf2, a transcription factor known to regulate cellular metabolism, compared to non-CF bronchiectasis and control subjects, and this did not improve with HEMT. We also found that CF CD169- lung macrophages are persistently glycolytic and inflammatory, even in the setting of HEMT, while non-CF bronchiectasis and healthy CD169- lung macrophages can transition to an inflammation resolving phenotype. As immune cell crosstalk can be mediated by extracellular vesicles (EVs), we investigated the impact of CD169+ lung macrophage EVs on the inflammatory response of CD169- lung macrophages and found that CF CD169+ lung macrophage EVs induce persistent inflammation in CD169- lung macrophages. Lastly, we have preliminary data showing altered expression of miRNAs predicted to inhibit Nrf2 and reduced levels of inflammation resolving lipids in EVs from CF CD169+ lung macrophages. Thus, we hypothesize that specific miRNAs and lipids within CF CD169+ LM EVs reduce Nrf2 levels in CD169- LMs, causing persistent glycolysis and failure to transition to an inflammation resolving phenotype. In Aim 1, we will test the hypothesis that there are functionally important immunometabolic differences in CF lung macrophages that are specific to CF and persist after HEMT. In this Aim, we will fully characterize subpopulations of lung macrophages in the CF lung and will quantify differences in cellular metabolism and inflammation resolution between CD169+ and CD169- lung macrophages in PwCF, non-CF bronchiectasis subjects, and healthy subjects. In Aim 2, we will test the hypothesis that specific miRNAs within EVs released by CF CD169+ lung macrophages impact the inflammatory response of CD169- lung macrophages. In Aim 3, we will test the hypothesis that the lipid content of EVs released by CF CD169+ lung macrophages prevents the shift to an inflammation resolution phenotype in r CD169- lung macrophages. The proposed studies are unique because they involve human subjects before and after HEMT and thus, our data will be directly relevant to PwCF. In addition, our studies will provide new and essential information on the mechanisms of persistent lung inflammation in CF and will allow us to identify targets for novel therapies to reduce harmful CF lung inflammation and improve the lives and longevity of people living with CF.


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 = $574,776 )
2025	2025	DARTMOUTH-HITCHCOCK CLINIC	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Lung Diseases Research	001	2	7/9/2025	NON-COMPETING CONTINUATION	$57,477
2025	2025	DARTMOUTH-HITCHCOCK CLINIC	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Lung Diseases Research	000	2	4/9/2025	NON-COMPETING CONTINUATION	$517,299
														Subtotal = $574,776

Issue Date FY: 2024 ( Subtotal = $635,396 )
2024	2024	DARTMOUTH-HITCHCOCK CLINIC	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Lung Diseases Research	000	1	7/22/2024	NEW	$635,396
														Subtotal = $635,396

Grand Total All Awards = $1,210,172

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Mechanisms of Impaired Inflammation Resolution in Cystic Fibrosis Lung Disease

Award Number: R01HL174700

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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