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Identifying mechanisms of lung toxicity from skin exposure to vesicants

Award Number: R01ES036491
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: 04/23/2026
PERIOD OF PERFORMANCE END DATE: 04/22/2029

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Identifying mechanisms of lung toxicity from skin exposure to vesicants - PROJECT SUMMARY Mustard vesicating agents sulfur mustard (SM) and nitrogen mustard (NM) are alkylating vesicants that cause severe skin, eye, systemic and lung toxicity. Phosgene oxime (CX), an urticant or nettle agent, is the least studied but most potent vesicant with instantaneous toxic effects and penetration that poses a threat of mortality and long-term morbidity. The secondary lung toxicity and its mechanism from dermal route of exposure to these vesicants due to their systemic effects have not been explored and there are no approved and effective therapies to treat such injuries that can lead to mortality and long-term effects. Recent novel findings from our laboratory demonstrate that acute dermal exposure of mice to mustard vesicant NM or nettle vesicant CX leads to the development of not only acute skin but also lung injury with qualitatively similar pulmonary lesions characterized by acute, diffuse intramural edema and hemorrhage. These pulmonary toxic lesions were accompanied by an increase in mast cell degranulation and inflammatory cytokines like Interleukin (IL) 33 indicating that mast cell activation and immune cell recruitment could be a mutual mechanism of vesicant lung injury from their skin exposure. Overall, our studies have implied a role of mast cells in vesicant NM inhalation-related lung injury (published) and CX dermal exposure related skin injury; however, mast cell activation and related signaling in lung injury from their dermal exposure is not explored. Also, there are no reported studies on CX lung toxicity and, hence, these studies are novel and critical area of research. This proposal aims to further establish the role of mast cells and delineate related mechanism(s) of acute and long-term lung toxicity from both mustard and nettle vesicating agents following their dermal exposure in mice. We hypothesize that dermal NM or CX exposure causes systemic toxicity induced lung injury, and mast cells significantly contribute to the mechanism of toxicity. To test this hypothesis, the proposed specific aims are: SPECIFIC AIM 1: Establish the role of mast cells in lung toxicity from acute dermal exposure to vesicating agents. We will use mast cell deficient (B6.Cg-KitW-sh/HNihrJaeBsmJ; MCD) and wild-type C57BL/6 (WT) mice to examine the role for mast cells in vesicant related lung injury following their dermal exposure. Following acute CX or NM cutaneous exposures, we will conduct time-response studies from 2h up to 3 months to characterize the acute and long-term lung toxicity in both the WT and MCD mice. SPECIFIC AIM 2: Determine and compare the mast cell associated mechanisms of lung injury from acute dermal exposure to vesicating agents. We will utilize the BALF, blood plasma samples and lung tissues from Aim 1 studies, for both NM and CX exposures, to determine the a) bioactive lipid profiles and b) differential transcriptome profiling and changes in immune cells (Visium Spatial Gene Expression) with adverse pulmonary morphology in WT and MCD mice. These studies will establish if mast cell activation and related signaling parallel in skin, systemic and lung injury from mustard and nettle vesicating agents’ dermal exposure with a goal to identify novel broad-spectrum treatment strategies.


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 = $1,403,056 )
2026	2026	MICHIGAN STATE UNIVERSITY	426 AUDITORIUM RD	EAST LANSING	MI	48824	INGHAM	USA	Environmental Health	000	1	4/21/2026	NEW	$1,403,056
														Subtotal = $1,403,056

Grand Total All Awards = $1,403,056

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Identifying mechanisms of lung toxicity from skin exposure to vesicants

Award Number: R01ES036491

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: 04/23/2026

PERIOD OF PERFORMANCE END DATE: 04/22/2029

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