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Halolipid-Neutrophil Extracellular Trap Axis in Halogen Lung Injury

Award Number: R01ES034383
ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/18/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Halolipid-Neutrophil Extracellular Trap Axis in Halogen Lung Injury - Exposures to chlorine (Cl2) and bromine gases (Br2) are public health threats. Cl2 and Br2 exposures occur as a result of industrial accidents as well as in chemical warfare. Cardiopulmonary failure is a major concern following exposures, which contributes to mortality and morbidity; but the mechanisms underlying end organ injury after exposure to Cl2 or Br2 remain to be determined. We discovered that Cl2 and Br2 gas exposure target host plasmalogen lipids, resulting in high levels of 2-halofatty aldehyde and 2-halofatty acids in the lung and circulation. Recently, we have shown 2-chlorofatty acids, at levels found in the plasma of mice and rats exposed to Cl2, elicit neutrophil extracellular trap (NET) formation. Since NETs are critical and early initiators of coagulopathies that cause end organ injury, the proposed studies will test the hypothesis that Cl2 and Br2 derived 2-halofatty acids elicit NET formation to induce lung injury. Furthermore, our preliminary data show 2- bromofatty acid also causes NET formation, underscoring the potential for NET formation as a unifying mechanism mediating both Cl2 and Br2 gas toxicity that will identify common therapeutic targets and countermeasure development opportunities. Moreover, while Cl2 and Br2 are similar, their unique physicochemical properties endow differences in mechanisms by which each cause injury. Salient to this proposal, we have shown that 2-bromofatty aldehyde reactivity with nucleophiles is 25-fold greater than that of 2-chlorofatty aldehyde. In addition to testing the role of NET formation, proposed studies will also identify protein targets of 2-bromofatty and 2-chlorofatty aldehydes and their respective 2-halofatty acids in mediating NET formation, and we anticipate results from these studies will demonstrate overlapping and unique targets in the pathways by which Cl2 and Br2 mediate circulatory and pulmonary dysfunction. There are two specific aims for the proposed studies. Specific Aim 1 will identify chlorolipids and bromolipids as critical mediators of NET formation and subsequent lung injury following Cl2 and Br2 exposure. Specific Aim 2 will identify mechanisms by which chlorolipids and bromolipids elicit NET formation in human neutrophils. We will employ both mouse and rat models of Cl2 and Br2 gas exposure. This, together with testing two distinct toxicants at LD50 levels, meet criteria for this RFA. Collectively, the proposed studies will delineate a common mechanism for Cl2 and Br2 toxicity mediated by halolipid-stimulated NET formation and organ failure. This mechanism could lead to a common treatment for both of these Chemical Countermeasures Research Program concerns in the future.


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 = -$12,730 )
2026	2024	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Environmental Health	000	3	12/17/2025	NON-COMPETING CONTINUATION	-$12,730
														Subtotal = -$12,730

Issue Date FY: 2024 ( Subtotal = $450,008 )
2024	2024	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Environmental Health	000	3	7/12/2024	NON-COMPETING CONTINUATION	$450,008
														Subtotal = $450,008

Issue Date FY: 2023 ( Subtotal = $450,008 )
2023	2023	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Environmental Health	000	2	7/20/2023	NON-COMPETING CONTINUATION	$450,008
														Subtotal = $450,008

Issue Date FY: 2022 ( Subtotal = $462,883 )
2022	2022	SAINT LOUIS UNIVERSITY	221 N GRAND BLVD	SAINT LOUIS	MO	63103	SAINT LOUIS CITY	USA	Environmental Health	000	1	8/17/2022	NEW	$462,883
														Subtotal = $462,883

Grand Total All Awards = $1,350,169

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Halolipid-Neutrophil Extracellular Trap Axis in Halogen Lung Injury

Award Number: R01ES034383

ORGANIZATION: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/18/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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