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Novel role of neutrophils in mediating endothelial regeneration and vascular repair in sepsis and ARDS

Award Number: R01HL179839
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Novel role of neutrophils in mediating endothelial regeneration and vascular repair in sepsis and ARDS - Acute respiratory distress syndrome (ARDS) is a form of acute-onset hypoxemic respiratory failure with bilateral pulmonary infiltrates, which is caused by acute inflammatory edema of the lungs not attributable to left heart failure. Despite improvements in supportive care for patients, there is currently no effective treatment for ARDS, and mortality rates for patients with ARDS are as high as 40%. A fundamental pathological change found in ARDS that results from sepsis is injury to the endothelial barrier, and, as a result, increased vascular permeability to protein. Thus, restoration of endothelial barrier function following vascular injury is essential for resolving inflammatory lung injury and reversing lung edema. Beyond host defense function, neutrophils are classically known as pro-inflammatory actors that induce endothelial barrier dysfunction and exacerbate injury in ARDS. Thus, previous attempts in ARDS treatment have aimed to reduce neutrophil recruitment and activation but unfortunately without success. Our preliminary findings support an unexplored important function of neutrophils in activating endothelial regeneration and vascular repair. Genetic depletion of neutrophils post-lipopolysaccharide (LPS, i.p.) challenge resulted in impaired endothelial regeneration and vascular repair leading to high mortality. Single-cell RNA sequencing analysis revealed a novel neutrophil subpopulation in the lung that emerges after LPS challenge. DEG analysis has identified these neutrophils as important regulators of vasculature development and angiogenesis and thereby supporting its unexplored role in mediating endothelial regeneration and vascular repair after sepsis-induced inflammatory lung injury. The clinical relevance of these findings is supported by the identification of such regenerative and reparative neutrophil subpopulation in COVID-19 patients. Thus, we hypothesize that the emerging neutrophil subpopulation is regenerative and reparative which mediates endothelial regeneration and vascular repair through neutrophil-EC crosstalk in the vascular niche leading to resolution of inflammatory lung injury following sepsis challenge. The proposed studies will address the following Specific Aims. Studies in Aim 1 will define the unexpected role of neutrophils in mediating endothelial regeneration and vascular repair and thus resolution of inflammatory lung injury following sepsis challenge and will delineate the underlying molecular mechanisms. Studies in Aim 2 will determine the fundamental role of the novel neutrophil subpopulation in mediating endothelial regeneration and vascular repair and the molecular mechanisms. Delineation of the novel role of neutrophils in endothelial regeneration and vascular repair represents a paradigm shift from the current understanding of neutrophil functions in ARDS, with significant implications for future therapeutics that promote recovery from sepsis and ARDS.


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 = $781,860 )
2026	2026	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	1	8/26/2026	NEW	$781,860
														Subtotal = $781,860

Grand Total All Awards = $781,860

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Novel role of neutrophils in mediating endothelial regeneration and vascular repair in sepsis and ARDS

Award Number: R01HL179839

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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