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Investigating the Role of HDL-Associated Serum Amyloid A in Sepsis-Induced Acute Lung Injury and Mortality

Award Number: R01HL173026
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Investigating the Role of HDL-Associated Serum Amyloid A in Sepsis-Induced Acute Lung Injury and Mortality - Abstract/Project Summary Sepsis is a life-threatening condition caused by a dysregulated immune response to infection. The prognosis for sepsis remains poor, with mortality rates exceeding 30%, due to a lack of effective treatment options. Thus far, despite over 100 randomized controlled trials, no treatments have shown a survival benefit, and no specific therapies are available for sepsis. One reason for the failed trials may be the lack of understanding of the pathways involved in the resolution of the immune response in sepsis. We have identified Serum Amyloid A (SAA), a family of acute phase proteins, as required for sepsis survival. Our preliminary and published data show that using two well-established sepsis mouse models, SAA-deficient (TKO) mice had exacerbated lung injury and increased mortality compared to wild-type (WT) mice in sepsis. Adenovirus-mediated overexpression of SAA not only increased survival in TKO mice but also in WT mice. Lungs of TKO mice had significantly increased neutrophils, myeloperoxidase (MPO) activity, and markers of leukocyte infiltration compared to WT mice. SAA and SAA-bound to high-density lipoprotein (SAA-HDL) decreased neutrophil transmigration through laminin- coated membranes in vitro. SAA in circulation is associated with HDL. Several clinical and animal studies indicate that decreasing HDL levels is a risk factor for sepsis, and raising HDL may be an effective therapy. SAA is the predominant apoprotein on HDL during acute inflammation. Based on these findings, we propose 2 specific aims with the central hypothesis that systemic SAA-HDL resolves sepsis-induced lung injury and mortality by regulating neutrophil infiltration into the injured lung: (Aim 1) We will test the hypothesis that SAA mediates the resolution of sepsis by impeding neutrophil accumulation in injured lungs and we will identify molecular players involved in SAA-neutrophil interaction. (Aim 2) We will demonstrate that SAA imparts HDL’s sepsis protective effects and decreasing systemic SAA-HDL negatively impacts sepsis outcomes. This study is significant and innovative since it will refute the old paradigm that SAA promotes inflammation in an acute inflammatory setting and will establish for the first time that SAA mediates HDL’s protective effects in sepsis by resolving sepsis- induced inflammation. The study is clinically relevant because many generalized anti-inflammatory therapies may decrease circulating SAA levels and thus inadverdently negatively impact sepsis outcomes. The results of this proposal will validate the importance of maintaining plasma SAA/SAA-HDL levels as one of the critical parameters to be considered in developing any therapeutic strategy for this serious disease and developing SAA memetic peptides as a therapeutic approach.


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: 2026 ( Subtotal = $685,397 )
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Lung Diseases Research	001	2	3/13/2026	NON-COMPETING CONTINUATION	$20,981
2026	2026	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Lung Diseases Research	000	2	1/30/2026	NON-COMPETING CONTINUATION	$664,416
														Subtotal = $685,397

Issue Date FY: 2025 ( Subtotal = $699,385 )
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Lung Diseases Research	001	1	4/25/2025	NEW	$0
2025	2025	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Lung Diseases Research	000	1	12/30/2024	NEW	$699,385
														Subtotal = $699,385

Grand Total All Awards = $1,384,782

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Investigating the Role of HDL-Associated Serum Amyloid A in Sepsis-Induced Acute Lung Injury and Mortality

Award Number: R01HL173026

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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